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The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups. Key Points: • The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations. • Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.

Background: The current standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is R CHOP; however, approximately 40% of patients are not cured. The CD79b-targeting antibody-drug conjugate, polatuzumab vedotin, is approved in relapsed/refractory DLBCL in combination with bendamustine and rituximab, and has also demonstrated promising first line activity and safety when combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). Thus, in the Phase III POLARIX study (NCT03274492) we compared pola-R-CHP with R-CHOP in patients with previously untreated DLBCL. Methods: In this double-blind, placebo-controlled, international study, patients with previously untreated DLBCL and an International Prognostic Index (IPI) of 2-5 were randomized 1:1 to receive six cycles of pola-R-CHP (with a vincristine placebo) or R-CHOP (with a polatuzumab vedotin placebo); all patients also received two additional cycles of rituximab. Patients received polatuzumab vedotin 1.8mg/kg or vincristine 1.4mg/m² administered on Day 1, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m², doxorubicin 50mg/m², and placebo on Day 1, and oral prednisone 100mg once daily on Days 1-5. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed event-free survival (EFS), independent review committee-assessed complete response (CR) rate at the end of treatment by positron emission tomography-computed tomography (PET-CT), disease-free survival (DFS), overall survival (OS), and safety. Results: Overall, 879 patients were randomized, 440 to pola-R-CHP and 439 to R-CHOP. Median age was 65 (range 19-80) years, and the majority of patients had IPI 3-5 (62.0%). At the data cut-off of June 28, 2021, and after a median follow-up of 28.2 months, PFS was superior with pola-R-CHP vs R CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57-0.95; P Conclusion: The pola-R-CHP combination demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death compared with R-CHOP, with a similar safety profile in the first-line treatment of patients with DLBCL. Disclosures Tilly: Karyopharm: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance and travel, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy; Teva: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Acerta: Consultancy; Amgen: Consultancy; Apobiologix: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Lundbeck: Consultancy; Merck: Consultancy; Morphosys: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Friedberg: Bayer: Membership on an entity's Board of Directors or advisory committees; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Bristol-Myers Squibb: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Velos: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Herbaux: Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria; Janssen: Honoraria. Burke: Verastem: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy, Speakers Bureau; Kymera: Consultancy; Bristol-Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Gilead: Consultancy; Genentech, Inc.: Consultancy. Matasar: Memorial Sloan Kettering Cancer Center: Current Employment; Merck Sharp & Dohme: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Rocket Medical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria. Rai: Chugai Pharmaceutical Co., Ltd: Speakers Bureau; ONO Pharmaceutical Co., Ltd: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Eisai Co., Ltd: Speakers Bureau. Izutsu: AbbVie: Honoraria; Allergan Japan: Honoraria; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Oberic: Celgene: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Janssen: Honoraria, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Jurczak: Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months. Greil: Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Pinto: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; MSD: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Abrisqueta Costa: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hirata: Genentech, Inc.: Current Employment; Genentech/Roche: Current holder of stock options in a privately-held company. Jiang: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yan: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lee: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Flowers: AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Salles: Bayer: Honoraria; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Debiopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Consultancy; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rapt: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Velosbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy. OffLabel Disclosure: Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b on malignant B-cells. Polatuzumab vedotin in combination with bendamustine and rituximab (pola-BR) improved complete response rate and overall survival compared with BR alone in patients with relapsed/refractory diffuse large B-cell lymphoma. Pola-BR is approved for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies.

Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype and pts with progressive disease (PD) after BTKi therapy have a poor prognosis (Martin et al. Blood 2016). Glofitamab is a T-cell-engaging, CD20xCD3 bispecific antibody with a novel 2:1 molecular configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Glofitamab with obinutuzumab pretreatment (Gpt) has shown promising efficacy with frequent, durable complete responses (CR) and manageable tolerability with fixed dosing (NCT03075696; Dickinson et al. EHA 2020) and step-up dosing (SUD; Hutchings et al. J Clin Oncol 2021) in NHL. Glofitamab and obinutuzumab compete for binding to CD20 receptors; as a result, Gpt reduces the receptor occupancy (RO) of glofitamab. Pts with MCL have a 2-fold higher clearance of obinutuzumab vs other NHL histologies (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014), leading to lower obinutuzumab concentrations and higher glofitamab RO at the start of glofitamab treatment (Djebli et al . Blood 2020). A higher dose of Gpt prior to glofitamab SUD may therefore further reduce the risk of cytokine release syndrome (CRS) in MCL. We report preliminary data from the NP30179 Phase I/II trial in pts with R/R MCL who received a 1000mg or 2000mg dose of Gpt prior to glofitamab monotherapy. Methods: All pts received Gpt 7 days prior to the first glofitamab dose. Intravenous glofitamab SUD was given on days 1 and 8 of Cycle (C)1, then at the target dose from C2 day (D)1 (from C3D1 for SUD starting at 0.5mg), every 3 weeks for up to 12 cycles (0.5/2.5/10/30, 2.5/10/16 or 2.5/10/30mg after 1000mg Gpt, or 2.5/10/30mg after 2000mg Gpt). Pts on fixed dosing received glofitamab (0.6, 16 or 25mg) after 1000mg Gpt from C1 for up to 12 cycles. Response rates are based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 29 pts had received glofitamab: fixed dosing after 1000mg Gpt (n=3); SUD after 1000mg Gpt (n=7; 1 pt received SUD starting at 0.5mg) or 2000mg Gpt (n=19). Median age was 69 years (range, 41-84; 69% male), 83% of pts had Ann Arbor Stage III-IV disease and 62.1% had MCL international prognostic index score ≥6 at study entry. Median prior lines of therapy was 3 (range, 1-6), 69% (n=20) had prior BTKi therapy and 14% (n=4) had prior lenalidomide therapy. Many pts were refractory to their first line of therapy (52%; n=15) and/or their last prior therapy (69%; n=20). Median time since last therapy was 1.7 months (range, 0.1-107.5). In efficacy-evaluable pts (n=21), the overall response rate was 81.0% (n=17) and complete metabolic response rate was 66.7% (n=14; Table 1). Similar response rates were observed in pts who had received prior BTKi therapy vs pts who had not (Table 2). Median duration of CR follow-up was 2.4 months (range, 0.0-25); 85.7% (12/14) pts with a CR remained in remission at the data cut-off (median duration of response and median duration of CR were not reached). In safety-evaluable pts (n=29), the most common adverse events (AEs) were CRS (58.6%) and infusion-related reactions (24.1%). All CRS events were Grade (Gr) 1-2 (by ASTCT criteria), except for 1 Gr 4 CRS in the 1000mg Gpt + SUD cohort (3.4%; pt died due to cardiopulmonary insufficiency as a result of rapid PD; at time of death CRS was persisting). CRS rates were lower in the 2000mg Gpt + SUD cohort (9/19; 47.4%) vs the 1000mg Gpt + SUD (5/7; 71.4%) and 1000mg Gpt + fixed dosing (3/3; 100%) cohorts. Overall, median time to first CRS event and duration of CRS event were 16.8 hrs and 38.8 hrs, respectively. All CRS events were manageable (tocilizumab used in 4 pts, low-flow oxygen in 2 pts) and most resolved at data cut-off. Neurologic AEs occurred in 6 pts (20.7%, all Gr 1 [n=5] or Gr 2 [n=1]). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs occurred in 1 pt (3.4%): Gr 1 confusional state and Gr 2 ataxia, both resolving in 1 day. Tumor flare events occurred in 3 pts (10.3%, all Gr 1 [n=2] or Gr 2 [n=1]). No pts discontinued treatment due to AEs. Three deaths were reported and considered unrelated to study treatment: PD (n=2); cardiac arrest (n=1). Conclusions: Glofitamab SUD as monotherapy after Gpt induced high response rates in pts with MCL, most of whom had failed prior BTKi therapy. CRS rates were manageable and mostly low grade. ICANS-like AEs were infrequent, low grade and resolved within 1 day. No treatment discontinuations due to AEs were observed. Further analyses will be presented. Figure 1 Figure 1. Disclosures Phillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Genentech, Inc.: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Crump: Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Epizyme: Research Funding. Trněný: MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bartlett: Washington University School of Medicine: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zaucha: Takeda: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Filézac de L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Clark: Roche Products Ltd: Current Employment. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Background: Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma (NHL) in Western countries, accounting for 20-30% of all NHLs (Hübel K. Hemasphere. 2020;4:e317). While most patients (pts) respond well to first-line therapy, they typically experience frequent relapses and progressively shorter duration of response with subsequent lines of therapy (Batlevi CL. Blood Cancer J. 2020;10:74; Rivas-Delgado A. Br J Haematol. 2019;184:753-9), and increasingly refractory disease with limited treatment options. Thus, there is an unmet need for effective treatment options for pts with relapsed or refractory (R/R) FL. Parsaclisib is a potent, highly selective, next-generation phosphatidylinositol 3-kinase (PI3K)δ inhibitor. Here we report results of the primary analysis of CITADEL-203 (NCT03126019, EudraCT 2017-001624-22), a phase 2, multicenter, open-label study of parsaclisib monotherapy in R/R FL. Methods: Eligible pts were ≥18 years of age, had histologically confirmed R/R FL (grade 1, 2, or 3a), had received ≥2 prior systemic therapies (not including PI3K inhibitors or Bruton's kinase inhibitors), had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and were ineligible for hematopoietic stem cell therapy. Pts were allocated to receive 20 mg parsaclisib once daily (QD) for 8 weeks, followed by parsaclisib either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia was required. The primary endpoint was objective response rate (ORR) as determined by an independent review committee (IRC); secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. All radiology-based endpoints were confirmed by an IRC. Results: At data cutoff for the primary analysis (Jan 15, 2021), 126 pts (WG, n=23; DG, n=103) had been treated. The median (range) age was 67.5 (40-88) years, 55.6% of pts were male, and majority (93.7%) of pts had an ECOG PS ≤1. The median (range) time since initial diagnosis was 5.95 (0.2-32.2) years. 54.0% of pts had received 2 lines and 27.8% had received 3 lines of prior systemic therapy (median [range], 2 [1-8]); 41.3% of pts had relapsed disease and 49.2% were refractory to their most recent prior therapy. 87 pts (69.0%) had discontinued treatment, primarily due to progressive disease (36.5%) or adverse events (21.4%). The median (range) treatment duration and follow-up from first dose to data cutoff were 8.5 (0.5-27.2) and 20.6 (5.7-34.1) months for all treated pts, and 8.4 (0.8-27.2) and 17.6 (5.7-33.1) months for the DG. The ORR (95% CI) was 75.4% (66.9-82.6) for all treated pts and 77.7% (68.4-85.3) for the DG (Table 1); CRR (95% CI) was 18.3% (11.9-26.1) for all pts and 19.4% (12.3-28.4) for the DG. Among all treated pts with complete or partial response, 73.7% of responses occurred at the first disease assessment. Median (95% CI) DOR was 14.7 (12.0-20.3) months for all pts and 14.7 (10.4-not estimable [NE]) months for the DG. Median (95% CI) PFS was 14.0 (11.3-19.6) months for all pts and 15.8 (11.0-NE) months for the DG. Median OS was not reached. Among 126 treated pts, treatment-emergent adverse events (TEAEs) occurred in 97.6% (n=123) of pts (grade ≥3 in 58.7% [n=74]). The most common TEAEs were diarrhea (38.1%), nausea (24.6%), and cough (22.2%); most common grade ≥3 TEAEs included diarrhea (11.9%) and neutropenia (10.3%). TEAEs leading to dose interruption or dose reduction occurred in 46.8% and 17.5% of pts, respectively. TEAEs led to treatment discontinuation in 23.8% of all pts; the most common were diarrhea (7.1%), colitis (4.0%), pneumonitis, and rash (2.4% each). Serious TEAEs were experienced by 45.2% (n=57) of pts overall; the most common reported among all pts were diarrhea (7.1%), colitis (6.3%), and pneumonitis (2.4%). Two pts (1.6%) overall experienced a fatal TEAE. Conclusions: Parsaclisib monotherapy demonstrated a rapid and durable response, had an acceptable safety profile, and was generally well tolerated in pts with R/R FL. These data suggest that parsaclisib could be a favorable treatment option for pts with R/R FL. Figure 1 Figure 1. Disclosures Lynch: Morphosys: Consultancy; Takeda: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Rhizen: Research Funding; Bayer: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding. Avigdor: Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. McKinney: ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; BTG: Consultancy; Beigene: Research Funding; Verastem: Consultancy. Paneesha: AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Cunningham: Celgene: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; Clovis Oncology: Research Funding; MedImmune: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding. Morley: AbbVie; Takeda: Other: Conference support; Janssen: Honoraria; Kite: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Canales: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Eusa Pharma: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; iQone: Honoraria. Bastos-Oreiro: Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau. Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding. Zheng: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. DeMarini: Incyte: Current Employment, Current equity holder in publicly-traded company. Jiang: Incyte: Current Employment, Current equity holder in publicly-traded company. Trněný: Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Investigational PI3K delta inhibitor (parsaclisib) for patients with FL

Background: Naratuximab emtansine (nara, Debio 1562, formerly IMGN529) is an antibody-drug conjugate (ADC) consisting of a humanized anti-CD37 antibody, K7153A, conjugated via a thioether-based linker to a cytotoxic maytansinoid, DM1. CD37, a lymphocyte surface marker, is highly expressed in B-NHL. A Phase 1 monotherapy study of nara revealed a good safety profile and promising efficacy (22% overall response rate [ORR] in DLBCL at all doses). In preclinical models of B-NHL, nara demonstrated synergistic antitumor activity when combined with rituximab (RTX). Aim: The aim of thisopen-label Phase 2 study was to evaluate the safety and efficacy of nara + RTX and to characterize pharmacokinetics (PK) and pharmacodynamics (PDy) in patients (pts) with relapsed and/or refractory (R/R) B-NHL. Methods: R/R B-NHL pts who were not candidates for stem cell transplant, with 1-6 prior lines of treatment, were recruited to two study parts. In Part 1, which included a safety run-in followed by an expansion, pts received 0.7 mg/kg nara in combination with 375 mg/m 2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned either to the Q3W regimen (cohort A), or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg nara administered on days 1, 8 and 15 of 21-day cycles combined with 375 mg/m 2 RTX on day 1 (cohort B). Six cycles of treatment were administered with possible extension. Primary endpoints were safety and ORR. PK and PDy evaluations included ADC and DM1 catabolites' systemic levels and receptor occupancy on peripheral blood mononuclear cells (PBMCs), to investigate CD37 target engagement. Pts from cohorts A and B were requested to fill in the FACTLym quality of life questionnaire (QoL). Pts with double/triple hit lymphoma, bulky disease, and up to 6 prior lines of treatment for DLBCL were allowed. There was no limit on life expectancy. Pts were considered efficacy evaluable (EE) if they had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. Tumor assessment by CT was acceptable. The follow-up period was up to 1 year after last pt first dose (NCT02564744). Results: 100 pts were enrolled in the study: 80 DLBCL, 14 follicular lymphoma (FL) and 6 mantle cell lymphoma (MCL) pts; 81 pts (81%) experienced grade ≥ 3 treatment emergent adverse events, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%), and thrombocytopenia 12 (12%). Of the 80 DLBCL pts, 10 (12.5%) were primary refractory, 24 (30%) were refractory to last line, 62 (78%) had Ann Arbor stage III/IV, and 35 (44%) had received at least 2 prior systemic cancer therapies. The ORR in the 76 EE DLBCL pts was 44.7%, with 24 (31.6%) complete responses (CR) and 10 (13.2%) partial responses (PR). In addition, 9 (11.8%) stable disease (SD) and 33 (43.4%) progressive disease (PD) were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B) of Part 2, enrolling mainly relapsed pts. ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). In Part 1, 16 DLBCL pts were EE, of which 6 were primary refractory and 10 were refractory to last line. ORR in this group was 25%. Median duration of response (mDoR) in the 76 evaluable DLBCL pts was not reached (lower 95% confidence interval [CI] 12 months). Median duration of follow-up in responders was 15 months (95% CI 9-18 months). In the 14 FL pts, the ORR was 57%: 5 CR, 3 PR, 3 SD, and 3 PD; the mDoR in this population was not reached (lower 95% CI: 19 months), with a median duration of follow-up of 21.8 months (95% CI 19.1 - not reached). Of the 6 MCL pts, 4 were efficacy evaluable: 2 CR and 2 PD. Due to the low number of pts, the DoR curves are not presented. PK levels were sufficient to fully engage the CD37 target on PBMCs. A relationship between PK exposure and efficacy was identified. Data showed acceptable systemic release of cytotoxic DM1 and catabolites. DLBCL responders in cohorts A and B demonstrated on average a clinically meaningful improvement of 3 points (standard deviation: 6.6) in the Lymphoma Subscale of the FACT-Lym QoL. Summary/Conclusion: The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R B-NHL. The treatment was well tolerated and contributed to the pts' well-being, as demonstrated by the QoL results. Figure 1 Figure 1. Disclosures Levy: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Grudeva-Popova: University Hospital St George: Current Employment; Roche: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Jurczak: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. André: Johnson & Johnson: Research Funding; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Pharmacyclics: Research Funding; Millenium: Research Funding; ATARA: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data safety monitoring board; Rafael: Research Funding; Debiopharm: Research Funding. Rechavi-Robinson: Debiopharm International SA: Current Employment. Toffanin: Debiopharm International SA: Current Employment. Micallef: F. Hoffmann La Roche: Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Attinger: Debiopharm International SA: Current Employment. Rouits: Debiopharm International SA: Current Employment, Patents & Royalties. Roubaudi-Fraschini: Debiopharm International SA: Current Employment. Orfanos: Debiopharm International SA: Current Employment; F. Hoffmann La Roche: Ended employment in the past 24 months. Dymkowska: CANTARGIA AB: Consultancy; AUREALIS OY: Consultancy; Debiopharm International SA: Consultancy; Morphosys AG: Consultancy. Nauwelaerts: Novartis Pharmaceuticals AG, Basel: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.

Background: Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma (NHL) and accounts for 6% of all NHL cases in Western countries (Thandra KC. Med Sci. 2021;9:5). First-line treatment options are not curative and most patients (pts) experience relapse (Wu H. Front Oncol. 2020:10:588314; Kumar A. Blood Cancer J. 2019;9:50). Targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors, are used as second- and later-lines; however, treatment intolerance and failure are common with poor survival outcomes (Epperla N. Hematol Oncol. 2017;35:528-35; Jain P. Br J Haematol. 2018;182:404-11). Thus, novel therapies are needed for pts with relapsed or refractory (R/R) MCL. Parsaclisib is a potent, highly selective, next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) δ. Here, we report results of the primary analysis of the cohort of BTK inhibitor-naive pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544, EudraCT 2017-003148-19). Methods: Eligible pts were ≥18 years old, had pathologically confirmed MCL with documented cyclin D1 overexpression or t(11;14) translocation, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Pts must have received 1-3 prior systemic therapies and not had any prior treatment with a BTK and/or PI3K inhibitor. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia was required. The primary endpoint was objective response rate (ORR) as determined by an independent review committee (IRC); secondary endpoints included complete response rate (CRR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety and tolerability. All radiology-based endpoints were confirmed by an IRC. Results: At data cutoff for the primary analysis (Jan 15, 2021), 108 pts naive to prior BTK inhibitor had been treated (WG, n=31; DG, n=77). Median (range) age was 72.0 (43-90) years, 79.6% of pts were male, 92.6% had ECOG PS ≤1, and median (range) time since initial diagnosis was 3.6 (0.1-20.9) years. Among all pts, 63.9% had received 1 line and 25.9% had received 2 lines of prior systemic therapy (median [range], 1 [1-3]); 31.5% of pts had prior hematopoietic stem cell transplant, and 50.0% had relapsed and 43.5% were refractory to their most recent prior therapy. 78 pts (72.2%) had discontinued treatment; primary reasons were progressive disease in 49 (45.4%) and adverse events in 25 (23.1%) pts. Median (range) treatment duration and follow-up from first dose to data cutoff were 8.3 (0.1-30.0) and 22.9 (11.6-35.9) months for all pts, and 7.9 (1.7-27.4) and 18.2 (11.6-35.9) months for DG, respectively. The ORR (95% CI) was 68.5% (58.9-77.1) for all pts and 70.1% (58.6-80.0) for the DG (Table 1); CRR (95% CI) was 17.6% (10.9-26.1) for all pts and 15.6% (8.3-25.6) for the DG. Among all treated pts with complete or partial response, 89.2% of responses occurred at the first disease assessment. Median (95% CI) DOR was 13.7 (9.0-19.9) months for all pts and 12.1 (9.0-not estimable) months for the DG. Median (95% CI) PFS was 11.99 (8.3-16.9) months for all pts and 13.6 (10.0-16.9) months for the DG. Median OS was not reached. Among 108 treated pts, treatment-emergent adverse events (TEAEs) occurred in 90.7% (n=98) pts (grade ≥3 in 62.0% [n=67]). The most common TEAEs were diarrhea (34.3%), pyrexia (17.6%), and constipation (13.0%); most common grade ≥3 TEAEs were diarrhea (13.9%) and neutropenia (8.3%). TEAEs leading to dose interruption or dose reduction occurred in 47.2% and 8.3% of all pts, respectively. TEAEs led to treatment discontinuation in 25.0% of all pts; the most common were diarrhea (11.1%), colitis (4.6%), and hypokalemia (2.8%). Serious TEAEs occurred in 42.6% (n=46) of all pts; the most common were diarrhea (9.3%) and colitis (4.6%). Six pts (5.6%) overall experienced fatal TEAEs. Conclusion: Parsaclisib monotherapy demonstrated a rapid and durable response, had an acceptable safety profile, and was generally well tolerated in BTK inhibitor-naive pts with R/R MCL. These data suggest that parsaclisib could be a potential treatment option for pts with R/R MCL. Figure 1 Figure 1. Disclosures Mehta: Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Walewski: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Ribrag: Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, ; Janssen: Other: Travel, Accommodations, ; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Speakers Bureau. Rodriguez: Bristol-Myers Squibb; Celgene; EUSA Pharma; Janssen; Roche; Takeda: Consultancy; Bristol-Myers Squibb; Celgene; Janssen; Roche; Takeda: Speakers Bureau. Taszner: Roche, Takeda: Consultancy, Other: Travel. Zilioli: Takeda: Other: travel expenses, accommodation; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Zheng: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. DeMarini: Incyte: Current Employment, Current equity holder in publicly-traded company. Jiang: Incyte: Current Employment, Current equity holder in publicly-traded company. Zinzani: Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Investigational PI3Kdelta inhibitor (parsaclisib) for patients with MCL

Background: Marginal zone lymphoma (MZL) is the third most common lymphoma in Western countries, accounting for 8-12% of non-Hodgkin lymphoma (Delinger NM. Cancer Manag Res. 2018;10:315-24). MZL is categorized into nodal, extranodal, and splenic subtypes. While the relative 5-year survival rate for patients (pts) with MZL is 84.4% (Olszewski AJ, Castillo JJ. Cancer. 2013;119:629-38), pts often experience relapse or refractory (R/R) disease. Parsaclisib is a potent, highly selective, next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K)δ. Here we report results of the primary analysis of the cohort of Bruton's tyrosine kinase (BTK) inhibitor (BTKi)-naive pts with R/R MZL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-204 (NCT03144674, EudraCT 2017-000970-12). Methods: Pts ≥18 years of age, with histologically confirmed MZL, prior receipt of ≥1 line of systemic therapy including anti-CD20 treatment, and either disease progression or inadequate response to most recent regimen were eligible. Pts had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, radiologically measurable lymphadenopathy, lymphoid malignancy (extranodal), or histologically confirmed bone marrow infiltration (splenic). The study enrolled 2 cohorts: pts who received prior treatment with ibrutinib (cohort 1, N=10) or pts naive to BTKi therapy (cohort 2, N=100). Only data from cohort 2 are presented in this abstract. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Pts received prophylaxis for Pneumocystis jirovecii pneumonia during the study. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC); secondary endpoints were duration of response (DOR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. All radiology-based endpoints were evaluated by an IRC. Results: At data cutoff for the primary analysis (Jan 15, 2021), 100 pts with MZL enrolled in cohort 2 (nodal 31.0%, extranodal 34.0%, and splenic 35.0%) had been treated (WG, N=28; DG, N=72). Median (range) age was 71.0 (35-95) years, 53.0% were male, and 95.0% had ECOG PS ≤1. 49.0% of pts had received 1 line, 31.0% received 2 lines, and 20.0% received ≥3 lines of prior systemic therapy (median [range], 2.0 [1-8]); 46.0% of pts had relapsed disease and 49.0% were refractory to their most recent prior therapy. 65.0% of pts had discontinued treatment, primarily due to adverse events (29.0%) or progressive disease (28.0%). The median (range) duration of treatment and follow-up from first dose to data cutoff were 13.4 (0.4-30.9) and 22.8 (11.9-37.0) months for all pts (N=100), and 11.6 (0.4-30.9) and 21.0 (11.9-37.0) months for the DG (N=72), respectively. The ORR (95% CI) was 58.0% (47.7-67.8) for all pts and 58.3% (46.1-69.8) for the DG (Table 1); CRR (95% CI) was 6.0% (2.2-12.6) for all pts and 4.2% (0.9-11.7) for the DG. Among all treated pts who achieved complete or partial response, 65.5% of responses occurred at the first disease assessment (median time to response, 8.1 weeks); median DOR (95% CI) was 12.2 (8.1-17.5) months for all pts and the DG. Median PFS (95% CI) was 16.5 (13.5-19.6) and 16.5 (11.5-20.6) months for all pts and the DG, respectively. Median OS was not reached. Among 100 pts treated in cohort 2, treatment-emergent adverse events (TEAEs) occurred in 96.0% of pts (grade ≥3 in 63.0%). The most common TEAEs were diarrhea (47.0%) and cough (23.0%), and the most common grade ≥3 TEAEs included diarrhea (12.0%), neutropenia and pneumonia (9.0% each), and colitis (7.0%). TEAEs leading to dose interruption or dose reduction occurred in 56.0% and 16.0% of pts, respectively. TEAEs led to treatment discontinuation in 29.0% of pts, the most common were diarrhea (9.0%) and colitis (5.0%). Serious TEAEs were experienced by 47.0% of pts overall, the most common was pneumonia (9.0%). 6.0% of pts experienced fatal TEAEs including febrile neutropenia and sepsis (1 pt each) that were considered treatment-related. Conclusion: Pts with R/R MZL demonstrated a rapid and durable clinical response to parsaclisib monotherapy. Treatment was generally well tolerated, and the safety profile was manageable. Results suggest parsaclisib may be a potential treatment option for R/R MZL. Figure 1 Figure 1. Disclosures Phillips: AstraZeneca: Consultancy; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Avigdor: Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. Gurion: JC Health CARE; Roche: Honoraria; Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy. Corradini: KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Mehta: Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding. Lossos: NIH grants: Research Funding; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; University of Miami: Current Employment; NCI: Research Funding; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy. Zinzani: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thieblemont: Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy. Zheng: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rappold: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhao: Incyte: Current Employment, Current equity holder in publicly-traded company. Johnson: Epizyme: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Bristol-Myers: Honoraria; Celgene: Honoraria; Genmab: Honoraria; Incyte: Honoraria; Kite Pharma: Honoraria; Kymera: Honoraria; Morphosys: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Oncimmune: Consultancy; Janssen: Consultancy. OffLabel Disclosure: Investigational PI3Kdelta inhibitor (parsaclisib) for patients with MZL

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Methods: SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 × 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age ( Results: From 31 Oct 2017-22 Jul 2019, 479 pts without del(17p) were randomized to zanu (n=241) and BR (n=238). Treatment groups were well balanced for demographic and disease characteristics (zanu vs BR): median age, 70.0 y vs 70.0 y; unmutated IGHV, 53.4% (125/234) vs 52.4% (121/231); and del(11q), 17.8% vs 19.3%. At median follow-up (26.2 mo), PFS by IRC was significantly prolonged with zanu vs BR (HR 0.42, 95% CI 0.28-0.63, 1-sided and 2-sided P The most common AEs are shown in the Table. AEs of interest occurring during the full reporting period (pooled terms, zanu vs BR) included atrial fibrillation (any grade [gr]: 3.3% vs 2.6%), bleeding (any gr/gr≥3: 45.0%/3.8% vs 11.0%/1.8%), hypertension (any gr: 14.2% vs 10.6%), infection (any gr/gr≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any gr/gr≥3: 15.8%/11.7% vs 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 pts (8.3%) receiving zanu vs 31 pts (13.7%) receiving BR; 85.5% of pts receiving zanu remain on treatment. AEs leading to death occurred in 11 pts (4.6%) receiving zanu vs 12 pts (5.3%) receiving BR. No sudden deaths were reported. Conclusions: In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared to BR as assessed by IRC. Superiority was also observed in PFS by INV as well as ORR by both IRC and INV. Zanu was generally well tolerated, with low rates of atrial fibrillation consistent with those observed in the phase 3 ASPEN (Tam, Blood 2020;136:2038-2050) and ALPINE studies (Hillmen, EHA 2021 #LB1900). These data support the potential utility of zanu in the frontline management of pts with TN CLL/SLL. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Loxo: Consultancy; Roche: Consultancy, Honoraria. Giannopoulos: Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Jurczak: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Österborg: BeiGene: Research Funding; Gilead: Research Funding. Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Honoraria. Walker: BeiGene: Consultancy; Acerta: Consultancy. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Chan: AbbVie: Membership on an entity's Board of Directors or advisory committees; Eusa: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel, Accommodations, Expenses; Celgene: Other: Travel, Accommodations, Expenses; Roche: Speakers Bureau. Ciepluch: Copernicus Wojewodzkie Centrum Onkologii: Current Employment. Greil: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Trněný: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Brander: Verastem: Consultancy; ArQule: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; LOXO: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Brown: Janssen: Consultancy; MEI Pharma: Consultancy; Rigel: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Catapult: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; Nextcea: Consultancy; Gilead: Research Funding; SecuraBio: Research Funding; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Ghia: Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tian: BeiGene: Current Employment; AbbVie: Ended employment in the past 24 months. Marimpietri: BeiGene USA: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Hillmen: Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN CLL/SLL without del(17p) in the US

Background: CD20 antibody plus alkylator and/or anthracycline based immunochemotherapy (IC) is a standard frontline therapy for patients with follicular lymphoma (FL) with 10-year event-free survival (EFS) and overall survival (OS) rates of approximately 50% and 80% respectively in long-term follow-up of clinical trials. Currently available clinical prognostic indices for FL have been designed using PFS and OS endpoints. Early events, commonly defined as progression of disease within 24 months (POD24) or early transformation to a more aggressive histology, are associated with inferior outcomes and increased risk of death due to refractory FL. Timely identification of the minority of patients with elevated mortality risk might enhance clinical management and research strategies. The FLIPI24 Consortium was created to develop a clinical prognostic index using early events as the primary endpoint. We report the outcomes for the pooled cohort and investigate the implications of therapy patterns on potential model development. Methods: Individual patient data were pooled and harmonized from 11 prospective observational cohorts from Europe, North America, and Australia. Patients who were diagnosed with grades 1-3A FL and initiated frontline IC were eligible. EFS was defined as time from start of IC to progression, relapse, retreatment (2nd line), histologic transformation, or death due to any cause. Early events were defined using status at 24 months from start of IC. OS was defined as time from start of IC to death due to any cause. Kaplan Meier curves and Cox proportional hazards models were used to evaluate outcomes by clinical features and therapy types. Results: 9006 patients were abstracted and harmonized, 6111 patients initiated frontline IC between 2002 and 2018 and were included in this analysis. Median age at diagnosis was 61 years (IQR 52-69) and 50% were male. Complete FLIPI data were available in 5637 patients (92%) and 46%, 32%, and 22% were low, intermediate, and high risk, respectively. IC type was 3079 R-CHOP or like (50%) , 1529 R-CVP or like (25%), 918 R-bendamustine (B-R) or like (15%), and 585 fludarabine or other alkylator based IC (10%); 3187 received CD20 antibody maintenance (52%). Patients receiving R-CHOP were younger, more frequently grade 3A, and more frequently had elevated LDH; differences in other characteristics by IC type were not clinically meaningful. At median follow-up of 42 months (IQR 17-72), 2647 patients (43%) had an event (any) and 1494 patients (25%) died. Median survival after an early (non-death) event was 49 months (95% CI: 41-58); 5-year OS was 46% (95% CI: 43-49) compared to 89% (95% CI: 88-90) in patients without POD24. Across all IC types, EFS estimates at 2 and 10 years from start of IC were 80% (95% CI:79-81) and 49% (95% CI:48-51) and OS estimates were 92% (95% CI: 91-92) and 70% (95% CI: 69-72), respectively. FLIPI was highly associated with both EFS (c-statistic=0.61) and OS (c-statistic=0.65) from the initiation of IC (both p Treatment patterns changed significantly over the study timeframe. Use of B-R and/or maintenance increased to 30% and 70% respectively in N=2937 patients treated in 2010-2018 (Era2) compared to Conclusion: EFS and OS from this large pooled analysis of observational cohorts is similar to long-term follow-up of randomized clinical trials in the IC era and support the use of these data for model development. Modeling efforts for early events should adjust for initial IC selection and use of maintenance therapy. Utilization of bendamustine and/or maintenance therapy increased over the study timeframe from 2002-2018, and Era2 was associated with improved EFS but not OS. This cohort provides comprehensive and robust observational data to define clinical predictors in IC treated patients. Figure 1 Figure 1. Disclosures Maurer: Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Flowers: Janssen: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Xencor: Research Funding; Acerta: Research Funding; Bayer: Consultancy, Research Funding; Sanofi: Research Funding; 4D: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; EMD: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Kite: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Epizyme, Inc.: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Morphosys: Research Funding; Iovance: Research Funding; Spectrum: Consultancy; Pfizer: Research Funding; Ziopharm: Research Funding; Guardant: Research Funding; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics: Research Funding. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Weibull: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Kridel: Gilead Sciences: Research Funding. Gandhi: Janssen: Research Funding; Novartis: Honoraria. Cheah: Celgene: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding. Hawkes: Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Specialised Therapeutics: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Freeman: Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Speakers Bureau; Incyte: Honoraria; Abbvie: Honoraria; Teva: Research Funding; Roche: Research Funding; Janssen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Link: Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Trněný: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; NanoString: Research Funding.

Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively. For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1). For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2). Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting. Conclusions To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS. Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: Beigene: Honoraria, Research Funding; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Øvlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory.

Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). A number of therapies are used for second- and later-line treatment including Bruton's tyrosine kinase inhibitors (BTKi). However, treatment failure and intolerance are common and alternative therapies are needed. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor that demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for a cohort of BTK inhibitor-naïve pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments. Prior treatment with BTKi and PI3Ki were prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 104 pts were treated (WG, n = 31; DG, n = 73). Enrollment was ongoing (target:100 pts). At cut-off, a total of 50 (48%) pts had discontinued treatment, including 31 (30%) pts for disease progression. The median exposure (range) was 4.0 months (0.1-19.1). The median age was 72 years and 80% of pts were men. The median time since initial diagnosis was 3.6 years. The majority of pts (92%) had ECOG PS ≤1, and 57% had high-risk MCL International Prognostic Index. The median number of previous systemic therapies was 1; 31% of pts had prior hematopoietic stem cell transplant, and 44% were refractory to their most recent systemic therapy. At the data cut-off, 92 pts were evaluable for efficacy including 31 in WG and 61 in DG (Table). The median follow-up duration (range) for this population was 11.8 months (1.9-24.0) overall and 9.1 (1.9-24.0) for DG. The ORR (95% confidence interval CI) and CRR were 66.3% (55.7-75.8) and 15.2%, respectively in all evaluable pts, and were 65.6% (52.3-77.3) and 11.5% for DG. The median time to response for pts with a complete or partial response was 7.9 weeks. The median DOR (95% CI) was 11.0 months (6.6-14.7) for all responders and 9.0 months (7.7-14.7) for DG. The median PFS (95% CI) was 11.1 (5.8-16.6) months overall, and 11.1 (5.6-16.6) months for DG. Among 104 safety-evaluable pts, most common treatment-emergent AEs (TEAEs) occurring in >10% of pts were diarrhea (25.0%), pyrexia (16.3%), constipation (11.5%), and neutropenia (10.6%). Most common grade ≥3 TEAEs reported in ≥5% of pts were neutropenia (8.7%) and diarrhea (7.7%). TEAEs leading to dose interruption or dose reduction occurred in 31.7% and 1.9% of pts, respectively. TEAEs leading to discontinuation occurred in 16.3% of pts including diarrhea (5.8%) and colitis (2.9%). Serious TEAEs reported in ≥2 pts included diarrhea (5.8%), colitis (2.9%), pyrexia (2.9%) and cytomegalovirus infection (1.9%). Four pts experienced fatal TEAEs. The fatal TEAEs in one pt (monocytic acute myeloid leukemia, leukocytosis, and acute kidney injury) were considered related to treatment. TEAEs of clinical interest included neutropenia (10.6%), rash (8.7%), colitis (4.8%), pneumonia (1.9%), PJP and pneumonitis (1% each). New or worsening grade ≥3 laboratory test values of clinical interest included decreased neutrophils (8.7%), platelets (7.7%), and hemoglobin (1.9%), and increases in alanine/aspartate aminotransferase (2.9%/1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safely profile and was generally well tolerated. These preliminary results suggest that parsaclisib represents a potentially new drug class and treatment option for BTKi-naïve, R/R MCL. Updated study results will be presented. Disclosures Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Approximately 15-20% of treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL) have CD20-low tumors, while CD19 is homogeneously expressed in >90% of cases of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. 2009). CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation and is therefore an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized, Fc-enhanced, anti-CD19 monoclonal antibody with improved antibody-dependent cellular cytotoxicity and phagocytosis. Monotherapy with tafasitamab has shown clinical activity in relapsed/refractory (R/R) non-Hodgkin's lymphoma (Jurczak W, et al. 2018). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, combined treatment of tafasitamab with lenalidomide resulted in a high proportion of patients having a complete response (Salles GA, et al. 2020). First-MIND (NCT04134936) is a Phase Ib, randomized study of tafasitamab + R-CHOP (Arm A) or tafasitamab + lenalidomide + R-CHOP (Arm B) in patients with newly diagnosed DLBCL. Here, we report data from the safety run-in phase. Study design and methods Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index [IPI] 2-5) and an ECOG performance status of 0-2. Known double- or triple-hit lymphoma and transformed lymphoma are excluded. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Day [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) + lenalidomide (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). Granulocyte-colony stimulating factor prophylaxis was mandatory in all patients. The study includes a safety run-in phase and a main phase. In the safety run-in phase, 24 patients were enrolled. The primary objective is to assess safety; secondary objectives include ORR, PET-CR rate at end of treatment, PFS, event-free survival, long-term safety, pharmacokinetics and immunogenicity of tafasitamab. Exploratory objectives include the assessment of circulating cell-free tumor DNA. Approximately 60 patients will be recruited in 9 countries across Europe and the US. Results Recruitment is ongoing. Thirty-six patients were randomized; 18 in each arm. The data presented for the safety run-in phase consist of 24 patients: 13 patients in Arm A and 11 patients in Arm B. All completed the first treatment cycle; 88% of patients entered into Cycle 2 and 50% of patients entered into Cycle 3 of treatment. At baseline, their median age was 67 years (range: 47-76; Arm A) and 65 years (range: 40-74; Arm B). Overall, 33% of patients were male and 67% female; IPI scores were: IPI 2, 33%; IPI 3, 42%; IPI 4, 25%. Most patients had advanced stages III/IV (92%) and approximately 50% had bulky disease. Cell of origin was determined to be germinal center B-cell (GCB) DLBCL in 13%, non-GCB DLBCL in 42% and not yet classified in 46% of cases. A total of 248 treatment-emergent adverse events (AEs) by system organ class were documented: 111 in Arm A and 137 in Arm B. Grade ≥3 neutropenia was observed in 54% (Arm A) and 46% (Arm B) of patients. Thrombocytopenia Grade ≥3 was observed in 8% (Arm A) and 18% (Arm B) of patients. Diarrhea, fatigue and vomiting were comparable between the two arms. Febrile neutropenia was uncommon in both arms, with one event each (Figure 1). To date, 23 serious AEs were observed: 11 in Arm A (Grade 2, 1; Grade 3, 6; Grade 4, 4) and 12 in Arm B (Grade 2, 3; Grade 3, 7; Grade 4, 2). One suspected unexpected serious adverse reaction was reported in Arm B - pneumocystis jirovecii pneumonia. No treatment-associated deaths occurred. Conclusions R-CHOP can be safely combined with tafasitamab or tafasitamab + lenalidomide in patients with treatment-naïve DLBCL. Toxicities appear to be similar to what is expected with R-CHOP alone or in combination with lenalidomide. Enrollment is ongoing and updated safety and early efficacy data will be presented at the meeting. Disclosures Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. André:Takeda: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Stevens:Amgen, MorphoSys: Consultancy. Trněný:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses. Pérez Persona:Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Klöpfer:MorphoSys AG: Current Employment. Brackertz:MorphoSys AG: Current Employment. Lohrmann:MorphoSys AG: Current Employment. Lahiry:MorphoSys AG: Current Employment. Shah:MorphoSys AG: Current Employment. Fingerle-Rowson:MorphoSys AG: Current Employment. Brugger:MorphoSys AG: Current Employment. Burke:Epizyme: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy.

Background: Marginal zone lymphoma (MZL) is a clinically heterogeneous, indolent, non-Hodgkin lymphoma (NHL) with 3 subtypes classified as extranodal, nodal, and splenic MZL. Parsaclisib, a potent, highly-selective, next-generation phosphatidylinositol 3 kinase (PI3K) δ inhibitor, has shown promising response rates in a phase 1/2 study in patients with previously treated B-cell malignancies. CITADEL-204 (NCT03144674) is a multicenter, open-label phase 2 study of parsaclisib in patients with relapsed or refractory (R/R) MZL. Here, we report preliminary results for patients who were not previously treated with a Bruton's tyrosine kinase inhibitor (BTKi-naïve). Methods: Eligible patients were ≥18 years of age with histologically confirmed MZL who received ≥1 prior line of systemic therapy, including anti-CD20 therapy, but were BTKi-naïve. Patients had documented disease progression or lack of response to the most recent regimen, had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were assessed by an independent review committee (IRC). Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients who had a follow-up of ≥9 weeks, had at least 1 post-baseline assessment, or discontinued study participation prematurely. Results: From December 2017 to January 17, 2020 (data cut-off), 99 patients (WG, n = 28; DG, n = 71) were treated. Median age was 71 years; 52.5% of the patients were male, 94.9% had an ECOG PS ≤1, and 31.3%, 33.3%, and 35.4% had nodal, extranodal, and splenic MZL, respectively. The median number of prior systemic therapies was 2. At cut-off, 40 (40.4%) patients had discontinued treatment, including 20 (20.2%) for disease progression. The median parsaclisib exposure (range) was 7.5 months (0.4−22.4). At the data cut-off, 94 patients were evaluable for response, including 66 in DG (Table). Median (range) follow-up for the efficacy evaluable population was 11.1 months (1.2−25.0) overall and 9.5 months (1.2−25.0) in DG. The ORR (95% confidence interval [CI]) was 54.3% (43.7−64.6) overall and 57.6% (44.8−69.7) in DG; the ORR (95% CI) was 48.3% (29.4−67.5), 50.0% (31.9−68.1), and 63.6% (45.1−79.6) for patients with nodal, extranodal, and splenic MZL, respectively (Table). The median time to response was 8 weeks. The median DOR (95% CI) was 9.3 months (6.2−not evaluable [NE]) among all responders and 9.4 months (6.0-NE) in DG. The median PFS (95% CI) was 13.8 months (8.8−NE) overall and 11.5 months (8.3-NE) in DG. Among the 99 treated patients, the most common treatment-emergent AEs (TEAEs) were diarrhea (36.4% of patients), cough (18.2%), and rash (14.1%). The most common TEAEs grade ≥3 were neutropenia and diarrhea (8.1%, each). The most common serious TEAEs were febrile neutropenia and pneumonia (5.1%, each). TEAEs leading to dose interruption or dose reduction occurred in 47.5% and 14.1% of patients, respectively. TEAEs leading to discontinuation occurred in 15.2% of patients; the most common events were diarrhea (5.1%) and colitis (3.0%). TEAEs leading to death occurred in 4 patients, with 2 events, febrile neutropenia (n = 1) and sepsis (n = 1), deemed treatment related. New or worsening grade ≥3 laboratory test values of clinical interest included increase in alanine/aspartate amino transferase (2.0%/1.0% of patients), and decrease in neutrophil count (13.1%), platelet count (3.0%), and hemoglobin (3.0%). Conclusion: BTKi-naïve patients with R/R MZL achieved rapid and durable responses with single-agent parsaclisib. Comparable efficacy was observed in patients diagnosed with nodal, extranodal, or splenic MZL. Treatment with parsaclisib was generally well tolerated without unexpected toxicities. Updated data will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy; Cardinal Health: Consultancy. Corradini:KiowaKirin: Consultancy, Honoraria; Incyte: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Gurion:Medison: Consultancy; Gilead Sciences: Consultancy; Takeda Pharmaceuticals: Consultancy; JC Health CARE: Honoraria; Roche: Honoraria. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Jurczak:MorphoSys: Research Funding; European Medicines Agency,: Consultancy; Sandoz-Novartis: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; MEI Pharma: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Afimed: Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics, Inc.: Research Funding; Acerta: Consultancy, Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; AstraZeneca: Consultancy. Mehta:Affimed: Research Funding; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Innate Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; fortyseven Inc/Gilead: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Research Funding; Juno Parmaceuticals/BMS: Research Funding. Zinzani:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Incyte: Honoraria; Bayer: Honoraria; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. Rappold:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhao:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Johnson:Incyte: Honoraria; Kite Pharma: Honoraria; Kymera: Honoraria; Boehringer Ingelheim: Consultancy; MorphoSys: Honoraria; Oncimmune: Consultancy; Takeda: Honoraria; Novartis: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Honoraria; Bristol-Myers: Honoraria; Genmab: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Oncimmune: Consultancy.

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL per modified iwCLL criteria (Blood 2008;112:5259; J Clin Oncol. 2012;30:2820) and for SLL per Lugano criteria (J Clin Oncol. 2014;32:3059). Results : As of 15 Apr 2020 (data cutoff), median follow-up was 18.2 mo (range, 5.0-26.3) for the 109 pts enrolled; 97 pts (89.0%) remained on treatment with zanubrutinib. The best overall response rate (ORR) was 94.5% (3.7% complete response [CR] or CR with incomplete bone marrow recovery, 87.2% partial response [PR], 3.7% PR with lymphocytosis, 4.6% stable disease, 0.9% progressive disease). Five pts (4.6%) met clinical CR criteria but did not undergo bone marrow biopsy. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not reached. Estimated 18-mo PFS (Figure), 18-mo DoR, and 18-mo OS were 88.6% (95% CI, 79.0-94.0), 84.0% (95% CI, 67.5-92.6), and 95.1% (95% CI, 88.4-97.9), respectively. Investigator-reported transformation occurred in 5 pts (4.6%), of whom 4 had histologic confirmation. Median time to transformation was 13.6 mo (time to transformation for each pt: 3.9, 7.0, 13.6, 13.8, and 15.7 mo). In an exploratory analysis, 37.2% and 26.7% of pts with evaluable karyotypes had at least 3 or 5 distinct karyotypic abnormalities, respectively; no differences in ORR or PFS were observed between pts with or without complex karyotype. With extended follow-up, adverse events (AEs) reported in ≥10% of treated pts included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%). Grade ≥3 AEs occurring in >2% of pts included neutropenia/neutrophil count decreased (12.9%) and pneumonia (3.7%). AEs of interest (pooled terms) included infections (64.2%), bleeding (47.7%; 5.5% grade ≥3 or serious), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Skin tumors were reported in 9.2%, and non-skin second malignancies were reported in 4.6% of pts. Three pts (2.8%) reported an AE of atrial fibrillation or flutter of which 2 events occurred in the setting of sepsis. Four pts (3.7%) discontinued zanubrutinib due to AEs (including pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury [in the context of disease progression]), of which 2 pts have died. Three additional pts died, 2 due to disease progression and 1 from sepsis after progression. No sudden or unknown deaths were reported. Conclusions : Extended follow-up of zanubrutinib monotherapy in TN CLL/SLL pts with del(17p) showed the durability of responses in this high-risk cohort, with an estimated 18-mo PFS of 88.6% and estimated 18-mo OS of 95.1%. Zanubrutinib was generally well tolerated, with low rates of discontinuation due to AEs. These data support the potential utility of zanubrutinib in the frontline management of pts with high-risk disease. Disclosures Brown: TG Therapeutics: Consultancy; Sunesis: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Verastem: Consultancy, Research Funding; Kite: Consultancy; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Sun: Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy; Juno/Celgene: Consultancy. Robak:Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Pfizer: Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; GSK: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; UTX-TGR: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Ghia:Novartis: Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Walker:Alfred health: Current Employment; Peninsula Health: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Janowski:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Chan:Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Shadman:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta Pharma: Ended employment in the past 24 months; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding. Laurenti:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opat:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Ciepluch:Copernicus Wojewodzkie centrum Onkologii: Current Employment. Verner:Cilag Pty Ltd: Research Funding; Concord Repatriation General Hospital: Current Employment; Janssen: Research Funding. Šimkovič:University Hospital Hradec Kralove: Current Employment; Acerta Pharma: Consultancy; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Österborg:Sanofi: Consultancy; Kancera: Current equity holder in publicly-traded company, Research Funding; BeiGene: Research Funding; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Trněný:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Blombery:Invivoscribe: Honoraria; Janssen: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Yin:BeiGene: Current Employment, Current equity holder in publicly-traded company; Arcus Biosciences: Current equity holder in publicly-traded company; Cornell University: Patents & Royalties: A genetically modified mouse model, licensed to pharmaceutical companies. Feng:BeiGene: Current Employment, Current equity holder in publicly-traded company. Ramakrishnan:BeiGene: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Background: Twenty percent of patients (pts) with high-tumor burden follicular lymphoma (FL) develop progression/relapse of disease within 24 months of frontline immune-chemotherapy (POD24). Those ultra-high-risk cases are at 50% risk of dying within 5-years since the POD event. Unmet need is to identify such pts at the time of initial treatment. The traditional approach used for building predictive scores (such as FLIPI, PRIMA-PI) is multivariable logistic regression (LR). LR is the tool of choice in case of many predictors (continuous or categorical) and a single binary (yes/no) outcome. Bayesian network (BN) offer an alternative strategy which may overcome several drawbacks of LR (risk of overfitting, missing data handling, problems of odds ratio interpretation), brings more insight into the complex relations among the variables, and offer an individualized prediction. Aim: The goal was to build a model to predict the risk of POD24 from the parameters known at diagnosis and compare LR to BN approach. Methods: The study (ClinicalTrials.gov No NCT03199066) comprised 1394 FL (grade I-IIIA) patients from the Czech Lymphoma Study Group registry treated with frontline rituximab-containing regimen and diagnosed between 10. 4. 2000 and 28. 12. 2016. The following parameters were analyzed: gender, age at diagnosis, clinical stage, lymphoma grade, no. of LNs regions, bone marrow involvement, no. of extranodal localizations, longest tumor diameter, systemic symptoms, performance status, LDH, beta-2-microglobulin, hemoglobin, and leucocyte, lymphocyte, and thrombocyte counts, induction regime, radiotherapy, ASCT, maintenance application, response to treatment, and OS, PFS and POD24 as outcome parameters. POD24 was defined as relapse, progression, change of therapy for 24 months since the induction started. Only parameters known at diagnosis were used for the prediction of POD24. Results: The median age was 59 yrs (range 26-89 yrs) with female predominance (59.2%), advanced disease stage (III/IV) was seen in 85.9% of the cases and FLIPI risk groups distribution was as follows: low (18.8%), intermediate (30.9%) and high (50.3%). The most frequent regime used was R-CHOP (76.8%), followed by R-CVP (12.4%), R-bendamustine (4.7%), intensive protocols (3.3), and fludarabine-based (2.8%). Consolidative IF-radiotherapy was applied in 5.1% and up-front ASCT in 2.9% of the pts. Maintenance immunotherapy was given in 67.1% of the pts. Response to therapy was known in all but 28 pts (98%) with CR/CRu 67.9%, PR 26.6%, SD 1.8%, and PD in 3.2% of the cases. After a median follow-up of 7.64 yrs, 484 (34.7%) of the pts progressed or relapsed and 316 (22.6%) have died. POD24 was recorded in 266 (19.0%) of the pts. The 5-year OS reached 86.4% and 5-year PFS 64.2%. LR model (PFS) building strategy included testing for significance as this model performed better than the model with all parameters. Overfitting was prevented by splitting the data into training (75%) and testing (25%) set. The performance of the model was assessed using the AUC criterion computed on the ROC curve. The LR model reached AUC of 0.69, and at 80% specificity, it reached about 51% sensitivity. Next, the BN (Augmented Naïve Bayes Classifier) was trained. Links of all predictors to POD24 were forced and all links to age and gender were forbidden, otherwise the network structure was inferred from the data. The performance of the BN was similar to the LR - AUC of 0.67 and about 50% sensitivity at the specificity of 80%. Both these models were compared to the standard PRIMA-PI risk classifier and were found to better stratify the population into risk groups (Table 1). An example of a patient is presented who was low-risk according to PRIMA-PI but actually experienced the POD24 event. The BN estimated the probability of the event to 91% (Figure 1). Conclusion: Lymphoma-related death following POD24 remains the most frequent cause of mortality in FL patients. BN modelling is a non-inferior prognostic tool compared to LR in term of POD24 prediction. Unlike LR, it also allows visualisation of complex relations among the predictors and individualized prediction of the patient's POD24 risk, even if some of the predictors are unknown. Both "ad hoc" trained LR and BN were found to better stratify the population into risk groups with respect to POD24 event than the traditional PRIMA-PI score. Acknowledgement: MZ Czech Republic DRO grant (FNOL, 00098892). Disclosures Procházka: F. Hoffmann-La Roche AG: Consultancy, Honoraria; Takeda Pharmaceuticals, Inc: Consultancy, Research Funding. Belada:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Trněný:Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy.

Introduction: Venetoclax (Ven) is an orally administered, highly selective inhibitor of B-cell lymphoma-2 (BCL-2). Fixed-duration VenR improved outcomes versus standard bendamustine-rituximab (BR) in the randomized Phase III MURANO study (NCT02005471; Seymour et al. N Engl J Med 2018) and is now a standard of care for the treatment of pts with R/R CLL. There are currently limited data to guide subsequent therapies when relapse occurs after fixed-duration VenR and uncertainty regarding the efficacy of repeated VenR treatment. Here, we report the response rates to follow-up therapy with Ven and Ven-based regimens, or exposure to Bruton tyrosine kinase inhibitor (BTKi) salvage therapy, following pts' participation in the MURANO trial. Methods: Pts were randomized to VenR (Ven 400 mg daily for 2 years [yrs] plus monthly R for the first 6 months [mo]) or BR (6 mo). The primary endpoint was investigator-assessed progression-free survival (PFS). Pts in either arm with disease progression were followed for overall survival (OS) and disease response to any subsequent anti-CLL therapeutic regimens. Pts who initiated new anti-CLL therapy, but who had not had a response assessment reported by the principal investigator, were considered unevaluable. Results: 389 pts were enrolled in MURANO (VenR, n=194; BR, n=195). At a clinical cutoff date of May 8, 2020, all main study pts had ceased treatment with a median follow-up of 59 mo (range 0-71.5). PFS and OS benefits were maintained at the 5-yr follow-up (Kater et al. Submitted to ASH 2020). Following disease progression, 67/87 (77.0%) VenR pts and 123/148 (83.1%) BR pts had received subsequent anti-CLL therapy. The time to next therapy (TTNT) from study entry was longer following VenR versus BR, with a median TTNT of 57.8 (95% CI: 55.1-NE) mo versus 23.9 (95% CI: 20.7-29.5) mo (HR, 0.26 [95% CI: 0.20-0.35]; p Of the BR pts receiving subsequent therapy; 99/123 (80.5%) pts received novel targeted therapy alone or in combination with other agents (BTKi, n=72; phosphoinositide 3-kinase inhibitors [PI3Ki], n=10; Ven, n=15; or other investigational medicinal products [IMP], n=2) while the remaining 24 pts received chemoimmunotherapy. Of pts previously treated with BR, the BOR rate to novel targeted agents was 84.4% among evaluable pts (83.9% for BTKi and 80.0% for Ven-based therapy; Table 1). Fifty two of 67 pts in the VenR arm received subsequent novel therapy (BTKi, n=18; PI3Ki, n=1; Ven [alone or in combination], n=32; IMP, n=1). The BOR rate to these targeted agents was 79.4% among evaluable pts. After a median treatment-free interval of 13.5 (range 0.0-41.3) mo, 18 VenR pts received a BTKi as their next line of therapy (all were BTKi naïve). These pts achieved high overall response rates (ORR): 14/14 (100% of pts with an evaluable assessment) at a median treatment duration of 21.9 (range 5.6-59.2) mo, with 10 pts continuing on BTKi therapy at this follow-up. After a median treatment-free interval of 23.7 (range 3.3-43.8) mo, 32 VenR pts were re-treated with Ven-based regimens; 21 were enrolled in the re-treatment arm of the MURANO sub-study and 11 were treated outside of the sub-study. The BOR to re-treatment with Ven or Ven-containing therapies was 72.2% of evaluable pts (Table 1). Among these pts, initial response to VenR at the main study end of combination treatment response visit was 100% (6 complete response [CR]/CR with incomplete hematologic recovery; 12 partial response), with 77.8% (14/18) achieving undetectable minimal residual disease and 15/18 completing the initial 2 yrs of Ven therapy without progression. Median treatment duration in evaluable pts re-treated with Ven-based regimens was 11.4 (range 0.7-37.6) mo with 50% of pts continuing on therapy. Conclusions: Five-yr data from MURANO demonstrated sustained TTNT benefit with VenR versus BR. Despite >80% of relapsed BR pts receiving salvage therapy with a novel agent, OS rates remain superior with VenR therapy. Relapsed VenR pts demonstrated high ORR to either subsequent BTKi therapy or re-exposure to Ven-based regimens. These data show early use of fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response or OS. Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. D'Rozario:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; Takeda: Consultancy; UCB: Honoraria, Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; UTX-TGR: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; BioGene: Honoraria, Research Funding. Kater:Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Honoraria; Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Research Funding. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria. de la Serna:Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Janssen: Speakers Bureau; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding. Trněný:Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Bataillard:Imperial College Healthcare NHS Trust: Ended employment in the past 24 months; Roche Products Limited (temporary clinical fellowship as a fixed-term sabbatical from Hematology specialty training fellowship at Imperial College Healthcare NHS Trust): Current Employment. Lefebure:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Seymour:Mei Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding.

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Methods : The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either ≥ 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Results : In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C (complete accrual). As of 19 April 2019 (data cutoff), all patients had received ≥1 dose of zanubrutinib and were included in the safety analysis. Median age was 70.0 y (range, 42-86) and median follow-up in the safety analysis set was 6.3 mo (Table 1). At data cutoff, 106 patients remained on study treatment. Adverse events (AEs) reported in ≥10% of treated patients included contusion (20.2%), rash (11.0%), upper respiratory tract infection (10.1%), and nausea (10.1%). Grade ≥3 AEs were reported in 33 patients (30.3%). Grade ≥3 AEs that occurred in >1 patient included neutropenia/decreased neutrophil count (n = 10), anemia, pneumonia, nephrolithiasis, and hypertension (each n = 2). One patient died due to grade 5 pneumonia that occurred 8 days after the last dose of zanubrutinib. AEs of interest (pooled terms) included infections (39.4%), bruising (24.8%), minor bleeding (18.3%), neutropenia (13.8%), arthralgia/myalgia (8.3%), diarrhea (8.3%), anemia (6.4%), hypertension (6.4%), thrombocytopenia (5.5%), fatigue (5.5%), headache (4.6%), petechiae (4.6%), second primary malignancy (2.8%), and major bleeding (2.8%). To date, no AEs of atrial fibrillation have been reported. At data cutoff, 90 patients were evaluable for efficacy with median follow-up of 7.0 mo; of these, 87 patients remained on study treatment. The overall response rate was 92.2% (Table 2). Two patients had disease progression due to Richter transformation and 1 patient died due to grade 5 pneumonia. No patient had progressed with CLL/SLL. Conclusions : In this study, we have completed enrollment of one of the largest prospective cohorts of TN patients with del(17p) CLL/SLL. Preliminary results suggested that zanubrutinib was active and generally well tolerated. Clinical trial information: NCT03336333. Disclosures Tam: Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Robak:Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Morphosys AG: Research Funding. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Walker:Alfred Health: Employment; Peninsula Health: Employment. Janowski:AstraZeneca: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Simpson:GSK: Research Funding; Sanofi: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Research Funding; Amgen: Research Funding; Jannsen: Honoraria. Shadman:AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; TG Therapeutic: Research Funding; Acerta Pharma: Research Funding; Atara Biotherapeutics: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy; Astra Zeneca: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Research Funding; Sound Biologics: Consultancy; BeiGene: Research Funding. Ganly:Canterbury District Health Board: Employment. Opat:Takeda: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ciepluch:Copernicus Wojewodzkie Centrum Onkologii Gdansk: Employment. Verner:Janssen-Cilag Pty Ltd: Research Funding. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Österborg:Abbvie: Research Funding; Kancera AB: Research Funding; BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding. Trněný:Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Paik:BeiGene: Employment, Equity Ownership. Marimpietri:BeiGene: Employment, Equity Ownership. Feng:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Teva: Honoraria; TG Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Pharmacyclics: Consultancy; Sun Pharmaceuticals: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Introduction: Multiple response criteria have been proposed for the assessment of treatment response in lymphoma patients (pts). The Lugano 2014 criteria have been adopted as the current standard for response assessment in lymphoma (Cheson et al. J Clin Oncol 2014), incorporating 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas. For non-FDG avid lymphomas, and when PET is not available, Lugano criteria use bi-dimensional tumor measurements of up to six CT target lesions. The more recently proposed Response Evaluation Criteria in Lymphoma (RECIL) (Younes et al. Annals Oncol 2017) were developed based on the hypothesis that uni-dimensional measurements of up to three target lesions could be used to assess response at a similar level of accuracy to the Lugano criteria. The prognostic value of Lugano 2014 versus RECIL 2017 criteria has not yet been assessed in large clinical trials. We compared the prognostic performance of Lugano and RECIL criteria in pts from the Phase III GOYA study (NCT01287741), which compared the efficacy of obinutuzumab (GA101, G) and rituximab (R) in combination with CHOP (G-CHOP vs R-CHOP) in previously untreated pts with CD20-positive DLBCL. Methods: In the GOYA study, pts were randomized 1:1 to receive either G-CHOP or R-CHOP (stratification factors: number of planned chemotherapy cycles, International Prognostic Index [IPI], and geographic region). FDG-PET scans were mandatory at sites where a PET scanner was available and were performed at screening and 6-8 weeks after the last study treatment. Response was assessed prospectively based on Cheson 2007 criteria and retrospectively according to standard Lugano 2014 criteria. A retrospective analysis based on RECIL 2017 criteria was also performed. Response categories by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. The impact of covariates on PFS and OS were analyzed using a multivariate Cox model. Landmark analyses of PFS and OS according to end of treatment (EoT) complete response (CR)/non-CR status were performed, and the prognostic value of response at EoT was compared for the two methods. Results: Of the 1418 pts (intention-to-treat [ITT] population) in the GOYA study, 1334 had PET data and were evaluable for this analysis. Good agreement between Lugano and RECIL criteria was observed for EoT CR status, with 894/966 (92.5%) pts with a complete metabolic response (CMR) by Lugano classified as CR by RECIL (Table). However, 40/63 (63.5%) pts with progressive metabolic disease (PMD) at EoT according to Lugano criteria had a partial response (PR) or minor response (MR) by RECIL criteria, showing poor agreement for these variables. Of the 43 pts with PMD by Lugano and non-PD by RECIL at EoT, 15 pts had no PFS event by Lugano as assessed by CT and could be considered false positives. Concordance for PFS by CT was high between the two criteria, with a kappa estimate of 0.77 (95% CI: 0.74, 0.80). EoT CR status by RECIL was highly prognostic for PFS (stratified HR, 0.32; 95% CI: 0.25, 0.43; p Conclusions: EoT CR status according to RECIL 2017 criteria showed a high concordance with CMR status by Lugano 2014 criteria and was highly prognostic for PFS and OS in previously untreated DLBCL; however, discordance was seen for the identification of PD by RECIL compared with Lugano criteria. PFS as assessed by CT by RECIL, based on uni-dimensional size measurements of up to three target lesions, showed high concordance with PFS by Lugano criteria, based on bi-dimensional size measurements of up to six target lesions. Table Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria. Trněný:Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Knapp:F. Hoffmann-La Roche Ltd: Employment. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam:Roche: Employment, Equity Ownership. Ward:Hoffmann La Roche: Employment, Equity Ownership. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated for the following: in combination with chlorambucil, for the treatment of patients with previously untreated CLL; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV FL.

Introduction: For patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL) who develop resistance to rituximab, treatment options are limited and the prognosis is poor. The open-label, randomized, Phase III GADOLIN (NCT01059630) study compared the efficacy and safety of obinutuzumab (GA101; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (B arm; standard of care) in rituximab-refractory iNHL. The primary analysis in 396 pts (data cutoff: September 1, 2014; median observation time, 21.0 months) showed that Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was significantly longer with G-B (median not reached [NR]) vs B (14.9 months), corresponding to a 45% reduction in risk of progression or death (hazard ratio [HR], 0.55; 95% confidence interval [CI]: 0.40, 0.74; p=0.0001; Sehn et al. Lancet Oncol 2016). The safety profile of G-B was manageable. Here, we report the final analysis of efficacy and safety for GADOLIN (when safety follow-up for all pts had been completed [2 years' safety follow-up from last dose]; data cutoff: November 30, 2018). Methods: Enrolled pts were aged ≥18 years with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg intravenously (i.v.) (Days [D] 1, 8, and 15 of Cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6) or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6) in 28-day cycles. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 months for 2 years or until disease progression). Final analysis endpoints included investigator (INV)-assessed PFS, overall survival (OS), time to new anti-lymphoma treatment (TTNT), and safety. The safety population included pts who received ≥1 dose of study treatment, excluding two pts crossing over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had follicular lymphoma (FL). Median (range) observation time was 57.5 (0.4-97.6) months for the G-B arm and 47.9 (0-100.9) months for the B arm (i.e. 27.6 and 35.6 months additional follow-up since the primary analysis). Median INV-assessed PFS was 25.8 months for the G-B arm vs 14.1 months for the B arm (HR, 0.57; 95% CI: 0.45, 0.73; p Conclusions: Final analysis of the GADOLIN study showed that G-B was associated with a 43% reduction in the risk of progression or death compared with B in pts with rituximab-refractory iNHL and a 49% reduction in pts with FL, with a sustained and clinically relevant OS benefit in pts with FL. There were no new safety signals with longer follow-up. Acknowledgments: The GADOLIN study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Sehn: TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Trněný:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Bouabdallah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dueck:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Roche: Research Funding. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Lugtenburg:Celgene: Honoraria; Janssen-Cilag: Honoraria; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Genmab: Honoraria. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Liu:Roche Pharma Development, Shanghai, China: Employment. Cheson:Seattle Genetics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the standard of care for newly diagnosed DLBCL, with cure rates of 60-70%. However, more effective front-line options are needed to further improve outcomes, particularly in high-risk patients (Sehn LH, Gascoyne RD. Blood 2015;125:22). Approximately 15-20% of treatment-naïve patients with DLBCL have CD20-low expressing tumors, while CD19 is expressed in >90% of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. Blood 2009;113:3773; Prevodnik VK, et al. Diagnostic Pathol 2011;6:33). CD19 is a B-lymphocyte lineage-specific surface antigen that is widely expressed in mature B-cell malignancies, including DLBCL. CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation, and is, therefore, an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized anti-CD19 monoclonal antibody with an engineered constant region (Fc) that enhances Fc-γ receptor binding affinity on effector cells, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Preliminary data in DLBCL cell lines suggest that combined targeting of CD19 and CD20 with tafasitamab and rituximab, respectively, could have synergistic cytotoxic effects. Monotherapy with tafasitamab has shown clinical activity and acceptable safety in a Phase I study in relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT01161511) and in a Phase IIa study in R/R NHL (NCT01685008). In patients with R/R DLBCL, treatment with single agent tafasitamab until progression led to a 26% objective response rate (ORR) with several long-term responses (Jurczak W, et al. Ann Oncol 2018; 29:1266). Preclinical in vitro and in vivo data have demonstrated increased combinatorial antitumor effects with tafasitamab and the immunomodulatory agent lenalidomide (LEN). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, treatment with tafasitamab/LEN achieved an ORR of 60%, a complete response (CR) rate of 42.5% and a median progression-free survival (PFS) of 12.1 months (Salles GA, et al. ICML 2019; Abstr 124). This combination received breakthrough therapy designation by the US Food and Drug Administration. Study design and methods First-MIND is a Phase Ib, open-label, multicenter, randomized trial of tafasitamab/R-CHOP or tafasitamab/LEN/R-CHOP in patients with newly diagnosed DLBCL (Figure 1). Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index 2-5). Key exclusion criteria include known double- or triple-hit lymphoma, and transformed or composite lymphoma. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Days [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) and LEN (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). The trial includes a safety run-in phase and a main phase. In the safety run-in phase, 12 patients will be enrolled in each arm. If no unexpected safety signals suspected to be related to the addition of tafasitamab ± LEN to R-CHOP are observed, an additional 18 patients will be enrolled in each arm in the main phase. The primary objective of the trial is to assess safety; secondary objectives include evaluation of efficacy (ORR and PET-assessed CR rate at end of treatment, PFS, overall survival, event-free survival, time to next anti-lymphoma treatment), long-term safety and pharmacokinetics, and immunogenicity of tafasitamab in each arm. Exploratory objectives will include the assessment of biomarkers in peripheral blood (natural killer [NK] cell count, cell-free circulating tumor DNA) and tumor tissue (DLBCL cell of origin, NK cell or macrophage count/gene expression profile, CD19 and CD20 expression) that may be relevant to the mechanism of action and/or response to study treatment. As this is a Phase Ib study to primarily explore safety, no formal statistical hypothesis is considered for the sample size calculation; approximately 60 patients will be recruited across Europe and the US. Disclosures Burke: Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Consultancy, Research Funding; Kite: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Rosenwald:MorphoSys: Consultancy. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Staber:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria. Westin:Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Fingerle-Rowson:MorphoSys AG: Employment. Klanova:MorphoSys AG: Employment. Würth:MorphoSys AG: Employment. Truemper:Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Roche: Research Funding; Mundipharma: Research Funding.

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impairment of platelet production, leading to downstream thrombocytopenia, a predisposition to bleeding, and adverse impact on patient quality of life. Unmet needs in relapsed or refractory ITP are to improve remission rates and durability through targeting underlying disease mechanisms. PRN1008 is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that modulates immune-mediated processes in ITP. Preclinical PRN1008 data showed inhibition of B-cell receptor-mediated activation of human B cells, Fc receptor (Fc-gamma and Fc-epsilon)-mediated activation of immune cells, and dose-dependent reduction in platelet loss in a mouse ITP model. In platelets from normal healthy volunteer and ITP patients, clinically-relevant concentrations of PRN1008 showed no platelet aggregation or interference with other platelet agonists, in contrast to ibrutinib (Langrish et al. ASH 2017:1052). Methods: This is an ongoing open-label, adaptive, intra-patient dose-escalation, phase I/II study of PRN1008 in adult patients with relapsed or refractory ITP (primary or secondary) who previously responded to ≥ 1 prior ITP therapy and have no available therapeutic options (NCT03395210). Eligible patients have two platelet counts < 30,000/µL within 15 days prior to treatment. Oral PRN1008 starting doses were 200 mg QD, 400 mg QD, 300 mg BID (total 600 mg daily), and 400 mg BID (total 800 mg daily), with intra-patient dose escalation allowed every 4 weeks (maximum 400 mg BID) as needed for efficacy. Stable doses of concomitant corticosteroids and thrombopoietin-receptor agonists (TPO-RA) are permitted. The primary end point is the proportion of patients with ≥ 2 consecutive platelet counts (separated by ≥ 5 days) of ≥ 50,000/µL and increased by ≥ 20,000/µL from baseline without requiring rescue medication. Results: A total of 21 patients have been enrolled to date at starting doses of 200 mg QD (n=9), 400 mg QD (n=1), 300 mg BID (n=5), and 400 mg BID (n=6). As of 15 July 2019 data cut-off, 11 patients were receiving ongoing treatment, 4 completed the study, and 6 patients withdrew (2 due to patient decision, 2 from non-treatment-related adverse events [AEs], 1 erroneously enrolled, and 1 because of rescue medication use). Patients had a median age of 54 y (range, 30-65), 4 (19%) had a prior splenectomy, 19 (90%) were diagnosed with primary ITP, and 2 (10%) with secondary ITP. Patients had ITP for a median of 8.3 years (range, 0.5-42.4) and had received a median of 4 prior ITP therapies. Median platelet count at study entry was 14,173/µL (range, 2,670-27,000/µL). During the study, 6 (29%) patients received PRN1008 monotherapy; 15 (71%) patients were on ≥ 1 concomitant ITP medication. Related treatment-emergent AEs (TEAEs) were reported by 4 (19%) patients; all were grade 1 or 2. The most frequent related TEAEs were nausea, diarrhea, and abdominal distension. There were no treatment-related bleeding or thrombotic events, and no significant changes in the ITP-BAT bleeding scale between baseline and the last visit. There were no dose limiting toxicities (DLT). Patients had received treatment for a median of 10.1 weeks (range, 0.1-31.0). Overall, 7 (33%) patients achieved the primary endpoint across all doses (Table). Patient responses were improved at the 2 higher doses. In 10 patients who had reached ≥ 12 weeks of treatment, ≥ 50% of patients had platelet counts of ≥ 50,000/µL and ≥ 20,000/µL increases from baseline. Conclusion: Overall, PRN1008 was active in 33% of ITP patients who were refractory to multiple treatments with no alternative therapeutic options. This result was demonstrated despite the limited duration of treatment and including patients at all dose levels. In addition, patients treated for longer periods of time have substantially improved response rates that support continued interest in this ongoing study. The safety profile was tolerable at all studied doses whether given as a monotherapy or with allowed concomitant ITP therapy. Importantly, TEAEs were grade 1 or 2 with no thrombotic events. The dose-escalation portion of the study is complete; enrollment is expanding at the 400 mg BID starting dose for a duration of 24 weeks to further characterize treatment benefit and for continued treatment beyond 24 weeks in patients who have responded. Disclosures Kuter: Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Boccia:AstraZeneca: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AMAG: Consultancy; Genentech: Speakers Bureau; DSI: Speakers Bureau. Lee:Weill Cornell Medical College: Employment. Tzvetkov:UMHAT Georgi Stranski: Employment; DCC Pleven: Consultancy. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kostal:Novartis: Honoraria; AOP: Honoraria; University Hospital in Hradec Kralove, Czech Republic: Employment. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; PharmaMar: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. McDonald:Bayer: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Employment, Equity Ownership, Patents & Royalties: Institutional with Incyte and Portola, no royalties. Burns:Principia BioPharma: Employment. Neale:Principia BioPharma: Employment, Equity Ownership. Thomas:Principia Biopharma: Employment, Equity Ownership; BMS: Equity Ownership; Pfizer: Equity Ownership. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Disclosure: Yes, this was an investigational clinical phase I/II study of PRN1008 in patients with relapsed/refractory ITP. Phase I dose escalation phase is now complete and expanded phase II studies ongoing.

Introduction: Our objective was to develop a prognostic model that predicts progression-free survival (PFS) and overall survival (OS) to enable risk-adapted strategies in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We retrospectively investigated the value of quantitative image texture features (i.e. 'radiomics' evaluating tumor heterogeneity) using FDG PET/CT data sets in a large, prospective Phase III trial, GOYA (NCT01287741). Methods: In the GOYA trial, which compared obinutuzumab versus rituximab both in combination with CHOP chemotherapy, there was no significant treatment effect between the two arms, thus the two arms were combined for this study. Baseline PET/CT images with regions of interests (ROIs) defined by qualified physicians were analyzed for radiomics features. Image texture features (ITF) were computed using the open-source and validated PET Oncology Radiomics Test Suite (PORTS). The clinical risk factors (International Prognostic Index [IPI], Ann Arbor stage, extranodal disease, bulky disease), cell of origin (COO), standard PET-derived metrics (standard uptake value [SUV]-mean, SUV-max, total metabolic tumor volume [TMTV], total lesion glycolysis [TLG]), SUV histogram metrics (variance, skewness, and kurtosis), and ITF were evaluated for prediction of PFS and OS. TMTV was estimated using adaptive thresholding. Prognostic models were generated by means of multivariate Cox regression analysis, modeling PFS, and OS. In the absence of an independent patient cohort for external model validation, an internal validation, based on c-index and Brier score, was carried out using bootstrap resampling methods. Stratification of patients into risk groups was achieved through maximally selected rank statistics. Multivariate analysis was also carried out on a subgroup of patients with available COO information. Results: The median follow-ups for PFS and OS were 46 and 50 months, respectively. Baseline PET scans were available for 1334 patients with detectable lesions, and 1077 baseline scans were evaluable for calculating ITFs. In the univariate analysis, high TMTV, histogram mean, histogram variance, and the ITFs gray-tone spatial dependence matrices (GTSDM) difference entropy and low gray-level zone length matrix (GLSZM) small zone high gray emphasis were risk factors for PFS, while high TMTV, histogram mean, and the ITF GTSDM inverse difference moment were risk factors for OS (Table 1, showing 95% CI, HR, and p-values for both univariate and multivariate analyses). In multivariate analysis, the risk factors included IPI, Ann Arbor stage, high TMTV, histogram mean, and GTSDM inverse difference moment; results were generally consistent in the multivariate subgroup analysis on patients with COO data available (Table 1). Based on the multivariate model, the probabilities for PFS and OS at 2 and 4 years for individual patients were established (Table 2). By combining TMTV (four categorical groups) with ITF, COO, and predictive clinical factors, three prognostic subgroups of treatment failure risk were identified: low (55% of patients), intermediate (34%), and high (11%). Hazard ratios for high and intermediate risk compared with low risk were 2.16 (p Conclusion: A model including PET-derived quantitative ITF, in addition to significant clinical features, was able to predict survival probability for untreated DLBCL patients with good precision. The proposed PET-based prognostic model may help identify patients who could benefit from risk-adapted treatment modifications or novel approaches. Acknowledgments: GOYA was sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial assistance, under the direction of Lale Kostakoglu, was provided by Katie Smith of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Dalmasso:I-See s.r.l.: Employment. Pierce:Precision Sensing LLC: Equity Ownership. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Sehn:Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria. Trněný:Takeda: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bolen:Genentech, Inc.: Employment; F. Hoffmann-La Roche: Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lee:Genentech: Employment; F. Hoffman-La Roche: Equity Ownership. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Kinahan:Co-founded PET/X LLC: Equity Ownership; Philips Medical: Research Funding; GE Healthcare: Research Funding; F. Hoffmann-La Roche: Consultancy. Chauvie:International Agency on Atomic Energy (IAEA): Consultancy; Co-owner of Dixit srl (spin-off University of Torino): Equity Ownership; F. Hoffmann-La Roche: Research Funding; Fondazione Cassa di Risparmio di Cuneo (CRC): Research Funding; Italian Foundation on Lymphoma (FIL): Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; SIRTEX: Speakers Bureau.

Background: The combination of lenalidomide+rituximab (R2) recently showed superior efficacy vs R-placebo in patients (pts) with R/R iNHL (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved by the US FDA for treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Advanced age at diagnosis is a risk factor in pts with iNHL. We performed post-hoc subgroup analyses by age from AUGMENT and data here focus on pts age ≥ 70 y. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs R-placebo in pts with FL grade 1-3a or MZL previously treated with ≥ 1 systemic therapy with R/R disease but not refractory to rituximab. Pts were randomized 1:1 to R2 or R-placebo. R2 was oral lenalidomide 20 mg/d, d1-21/28 for 12c plus rituximab IV 375 mg/m2 weekly in c1 and d1 of c2-5. R-placebo was rituximab+placebo on the same schedule. The primary endpoint was progression-free survival (PFS) per 2007 IWG response criteria (without PET) as assessed by IRC (central review). Secondary endpoints included overall response rate (ORR), complete response (CR), time to next anti-lymphoma treatment (TTNLT) and safety. Post-hoc analyses were performed by dividing pts into age < 70 y and ≥ 70 y subgroups, the latter group considered unfit for chemotherapy. Results: Of 358 pts randomized (R2, n = 178; R-placebo, n = 180), 267 pts were age < 70 y (R2, n = 131; R-placebo, n = 136), and 91 pts were age ≥ 70 y (R2, n = 47; R-placebo, n = 44). Baseline characteristics including histology, disease status, and prior treatments are shown in the table and were similar across treatment arms in pts ≥ 70 y. At a median follow-up of 28.3 mo, the study met its primary endpoint of PFS, with a hazard ratio (HR) of 0.46 (95% CI, 0.34-0.62; P < 0.0001) in the overall population. R2 had superior PFS vs R-placebo in both < 70 and ≥ 70 y subgroups, with HR of 0.41 (95% CI, 0.29-0.59) and HR of 0.66 (95% CI, 0.37-1.18), respectively. In pts ≥ 70 y, median PFS with R2 vs R-placebo was 24.9 vs 14.3 mo; ORR/CR was 81%/26% vs 59%/16%; and TTNLT was not reached in either arm. Efficacy results for all pts and those < 70 y are reported in the table; notably in pts receiving R2, mPFS was longer in pts < 70 y vs ≥ 70 y (39.4 mo [95% CI, 22.9-NE] vs 24.9 mo [95% CI, 16.4-NE]). In pts ≥ 70 y, any-grade adverse events (AEs) with a ≥ 10 % difference between R2 vs R-placebo included neutropenia (63% vs 11%), constipation (33% vs 16%), cough (33% vs 16%), leukopenia (26% vs 2%), anemia (24% vs 9%), pyrexia (24% vs 9%), pruritus/pruritus generalized (24% vs 2%), muscle spasms (22% vs 11%), rash/rash maculopapular (22% vs 5%), headache (20% vs 9%), thrombocytopenia (17% vs 2%), dyspepsia (13% vs 2%), influenza (13% vs 2%), back pain (7% vs 18%), and nasopharyngitis (4% vs 16%). Also, tumor flare was reported in 9% vs 0% of pts, respectively. In pts ≥ 70 y, 75% of R2 pts vs 36% of R-placebo pts had ≥ 1 grade 3/4 AE, mainly due to neutropenia (50% vs 7%). All other grade 3/4 AEs occurred in < 10% of pts ≥ 70 y in both treatment arms. One grade 5 AE occurred in pts ≥ 70 y (R-placebo arm). In the R2 arm, the median number of treatment cycles was 12 for both the < 70 y vs ≥ 70 y subgroups; however, fewer older pts completed 12 cycles of lenalidomide (76% vs 57%), and more started lenalidomide at the lower dose of 10 mg (6% vs 35%) because of low creatinine clearance, respectively. In the R2 < 70 y and ≥ 70 y subgroups, the average daily dose of lenalidomide was 17.9 mg/d (range, 5.6-20.0) and 14.4 mg/d (range 4.2-20.0), and median relative dose intensity was 95% and 86%, respectively. Conclusions: Similar to the results in the original population, R2 showed superior efficacy vs rituximab monotherapy (plus placebo) as measured by the primary end point of PFS and secondary end points of ORR and CR in pts with R/R FL grade 1-3a and MZL irrespective of age. The efficacy and safety profiles of R2 and R-placebo in pts ≥ 70 y were similar to those reported in the overall population. Older pts treated with R2 vs R-placebo had superior mPFS (24.9 vs 14.3 mo). They were more likely to start lenalidomide at a lower dose and had lower median dose intensity which may have contributed to their shorter mPFS vs younger pts receiving R2. These data show that R2 maintained efficacy improvements vs R-placebo in pts ≥ 70 y, despite higher unfit status and lower overall lenalidomide treatment/exposure. Thus, R2 is an effective and available treatment option for pts with iNHL, including those with advanced age. Disclosures Trněný: Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Leonard:Nordic Nanovector: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Kalambakas:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Fustier:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Gribben:Janssen: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Introduction: The use of PET-CR as a surrogate endpoint would expedite the development of novel therapies and enable better estimates of sample size based on early outcomes of a trial. Previous studies have reported an association between end-of-therapy (EOT) PET results and long-term progression-free (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemoimmunotherapy. We have also previously shown that the overall predictability of PET-CR for PFS and OS in these trials is similar to that in 18 literature-based studies. (15-ICML 2019, P195). To assess the potential for PET-CR as a surrogate endpoint in registration trials, we conducted a prospectively designed individual patient-level-data meta-analysis of available clinical trials. Methods: We synthesized patient-level data from three prospective phase II and III trials (GOYA [NCT01287741], GATHER [NCT01414855], MAYO [NCT00670358]) conducted in previously untreated DLBCL patients, using a Bayesian hierarchical model. We considered the two treatment arms in GOYA (GOYA-R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and GOYA-G-CHOP [obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) separate; hence a total of four arms, excluding patients without baseline PET scans. We investigated the relationship between PET-CR and long-term survival outcomes overall and within patient subgroups. We used Kaplan-Meier plots to compare survival endpoints by PET-CR status. We considered hypothetical RCTs that have PET-CR and PFS as endpoints to show how our model of the relationship between PET-CR and PFS can be used to predict the trial outcome. Results: We included 1496 patients (GOYA-R, GOYA-G, GATHER, MAYO, respectively: 665, 669, 100, 62). EOT PET-CR status was determined by the Lugano criteria in GOYA and by IHP in the other two studies. The overall rate of PET-CR was 72%; respectively 72%, 73%, 62% and 74% per arm. Panel A of the Figure shows Kaplan-Meier plots of PFS by PET-CR status. The Bayesian modeled hazard ratio (HR) comparing PET-CR versus nonCR was 0.13 (95% CI: 0.10, 0.15). The model can be used in planning a clinical trial as follows. Suppose a new therapy improves the PET-CR rate from 70% to 85%. Based on our model the expected HR for PFS treatment effect would be 0.71 (95% CI: 0.58, 0.84). The trial sample size required to demonstrate such an improvement with 90% power is about 650 patients, assuming an accrual rate of 50 patients per month and a minimum follow-up time of 12 months. Panel B of the Figure shows the model-based PFS HR and its CI (shaded) as it depends on the PET-CR rate of the new therapy. This plot also shows the estimated total trial sample size (in red), again assuming the relationship between PET-CR and PFS in our model. However, our model may not apply for the new therapy; and the trial could have an adaptive design with final sample size tailored to the accruing information about PET-CR and PFS and their relationship for the therapies in the trial. Conclusions: Achieving an EOT PET-CR in newly diagnosed DLBCL is highly predictive of favorable outcome in the populations we considered. The estimated HR is 0.13 for PFS, PET-CR versus nonCR, and it is 0.10 for OS. Based on our model, a treatment that improves PET-CR rate could be reasonably expected to have a benefit on PFS and OS, for the populations we considered. Whether a new therapy, with a different mechanism of action, that improves PET-CR rate will extend PFS in a clinical trial is less clear. An adaptive trial could be initiated based on our model as a hypothesis. This hypothesis can be verified or updated using accruing information in the trial itself. Our model can also help in planning clinical trials for re-estimating sample size during the trial and considering early stopping for futility. Further work should investigate the applicability of PET-CR in predicting PFS and/or OS for treatments that have different mechanisms of action and for other populations of patients. Acknowledgements: This work was funded by Genentech/Roche. Disclosures Berry: Berry Consultants, LLC: Consultancy, Employment, Equity Ownership, Other: Berry Consultants, LLC is a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia. Broglio:Berry Consultants LLC: Employment. Ward:Hoffmann La Roche: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McGlothlin:Berry Consultants, LLC: Consultancy, Employment. Elliott:Berry Consultants, LLC: Employment. Sehn:Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Vitolo:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding.

Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus CHOP (R-CHOP). However, approximately 35-40% of patients (pts) relapse following such treatment, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 monoclonal antibody. It has demonstrated greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R, and has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in first-line treatment of pts with advanced DLBCL (Sharman et al. Leuk Lymphoma 2019). GOYA (NCT01287741) was a randomized, open-label, multicenter Phase III study that compared the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. In the primary analysis (median observation period: 29 months), G-CHOP did not significantly improve investigator (INV)-assessed progression-free survival (PFS) compared with R-CHOP (Vitolo et al. J Clin Oncol 2017). Here, we present results from the final analysis of GOYA. Methods: Pts were aged ≥18 years, had histologically documented, previously untreated, CD20-positive DLBCL, with adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status of ≤2, and were classified as being in an International Prognostic Index (IPI) risk group of high, high-intermediate, or low-intermediate risk. Low-risk pts with an IPI score of 1 (not due to age alone) or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts were randomized (1:1) to 8 (21-day) cycles of G (1000mg i.v. on Days [D]1, 8 and 15, Cycle [C]1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was INV-assessed PFS. Secondary endpoints included independent review committee-assessed PFS (primary analysis only); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (according to modified Cheson 2007 criteria); event-free survival; disease-free survival; duration of response; time to next anti-lymphoma treatment; PFS according to cell of origin (COO; germinal center B cell [GCB] or activated B cell [ABC]), as an exploratory endpoint; and safety. Results: In total, 1418 pts were randomized in GOYA; of these, 704 pts who received G-CHOP and 710 who received R-CHOP were included in this final analysis (clinical cut-off date: January 31, 2018). Overall median follow-up was 47.7 months. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms. INV-assessed PFS was similar between G-CHOP and R-CHOP (5-year PFS, 63.8% vs 62.6%; stratified HR, 0.94; 95% CI: 0.78, 1.12; p=0.48; Table). There was no significant difference in 5-year OS between the G-CHOP and R-CHOP groups (77.0% vs 77.7%) or in CR or ORR (Table). In the subgroup analysis of pts with ABC, GCB and unclassified DLBCL, no significant reductions in risk of disease progression were observed (stratified HR for INV-PFS, 0.91 [95% CI: 0.61, 1.36], 0.80 [95% CI: 0.58, 1.12] and 1.10 [95% CI: 0.65, 1.88], respectively). No new safety signals were identified. Grade ≥3 adverse events (AEs; 75% vs 66%) and serious AEs (44% vs 38%) were more common with G-CHOP than R-CHOP. Grade ≥3 AEs of particular interest (≥2% of pts in either treatment arm) were more frequent in the G-CHOP arm: infusion-related reactions (10% vs 3%), neutropenia (57% vs 47%), infections (20% vs 16%), cardiac events (5% vs 3%), thrombocytopenia (6% vs 2%), and hemorrhagic events (3% vs 1%); secondary malignancies occurred in 3% and 2% of the R-CHOP and G-CHOP arms, respectively. AEs resulting in treatment withdrawal (12% [87/702] G-CHOP; 8% [58/701] R-CHOP) and AEs with fatal outcome (6% [43/702] G-CHOP; 4% [31/701] R-CHOP) were slightly more common with G-CHOP. The most common grade 5 AEs were pneumonia (n=5 both arms) and sepsis/septic shock (G-CHOP, n=7; R-CHOP, n=3). Conclusions: Consistent with the primary analysis, G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. Furthermore, there was no significant difference in 5-year OS between the treatment arms. No unexpected safety signals were identified. Further investigation of outcomes is ongoing, including the prognostic value of COO and BCL2 positivity. Disclosures Sehn: F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Trněný:Gilead Sciences: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Liu:Roche Pharma Development, Shanghai, China: Employment. Bolen:Genentech, Inc.: Employment; F. Hoffmann-La Roche: Equity Ownership. Knapp:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam:Roche: Employment, Equity Ownership. Vitolo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated for the following: in combination with chlorambucil, for the treatment of patients with previously untreated CLL; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV FL.

Introduction: Fc gamma receptors (FCGR) are critical mediators of anti-CD20 monoclonal antibody-mediated cell-killing in lymphoma patients (pts). Previous studies have investigated the impact of FCGR genetics on pts' responses to treatment with rituximab (R). In particular, Single Nucleotide Polymorphisms (SNPs) in FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501) have been shown to affect either affinity for IgG (H131R; F158V) or receptor activity (I232T) (reviewed in Hargreaves et al. Immunol Rev 2015). Although the impact of these SNPs on effector function has been demonstrated in vitro, their influence on overall pt response is less clear, with multiple small cohort studies reporting inconsistent effects, likely due to their limited size. Therefore, we assessed the clinical importance of FCGR genotypes in two large, international, randomized Phase III clinical trials, assessing their potential impact on the efficacy of R or obinutuzumab (GA101; G) in combination with chemotherapy in pts with untreated advanced follicular lymphoma (FL) (GALLIUM; NCT01332968) and untreated diffuse large B-cell lymphoma (DLBCL) (GOYA; NCT01287741). Methods: Genomic DNA was extracted from peripheral blood mononuclear cells in 2465 pts enrolled in GALLIUM (R-chemo vs G-chemo; n=1144 of 1202 enrolled) and GOYA (R-CHOP vs G-CHOP; n=1321 of 1418 enrolled). The key SNPs, FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped in all samples using TaqMan™ discrimination assays, with confirmatory Sanger sequencing employing FCGR-gene-specific polymerase chain reaction primers in 10% of cases. For both trials, our analysis of progression-free survival (PFS) included a univariate Cox regression analysis adjusted for treatment arm, and multivariate Cox regression analysis adjusted for stratification factors (GALLIUM: FLIPI and chemotherapy regimen; GOYA: IPI, cell of origin [COO], number of CHOP cycles, and BCL2;). In GOYA, we also adjusted for COO and BCL2 protein expression as we have previously shown these to be prognostically significant (Vitolo et al. J Clin Oncol 2017; McCord et al. Blood 2017). Multiple test correction was performed using Benjamini and Hochberg methodology. Results: The demographic and clinical characteristics of the FL and DLBCL pts included were comparable to those previously reported for the entire GALLIUM and GOYA trials, respectively. The prevalence of each FCGR genotype was comparable across trials, observed in both cohorts as: FCGR2A: R131R, 21.2% (523/2465 pts); H131R, 46.5% (1146/2465 pts); and H131H, 32.3% (796/2465 pts); FCGR3A: F158F, 43.6% (1073/2462); V158F, 44.5% (1096/2462); and V158V, 11.9% (293/2462); FCGR2B: I232I, 74.5% (1596/2143); I232T, 23.5% (503/2143); and T232T, 2.1% (44/2143). In FL, only FCGR2B was associated with PFS in univariate analyses comparing I232T to I232I genotype (Figure), with a more modest association for R treated pts (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.54─1.14; p=0.21) compared to G treated pts (HR 0.56; 95% CI 0.34─0.91; p=0.02). However, neither observation retained statistical significance in stratified analyses. In DLBCL, there was no evidence of a univariate prognostic effect of FCGR genotype. However, in multivariate analysis, we observed an association in the R treatment arm of GOYA with the FCGR2B T232T SNP (HR 4.37; 95% CI: 1.69-11.30; p=0.002 and multiple testing adjusted p=0.03) compared to the I232I pts. However, this observation should be interpreted with caution, given the low prevalence of this genotype (n=13) and limited number of PFS events (n=6). Conclusions: We analyzed FCGR genotype status in 2465 pts with indolent and aggressive lymphoma treated with chemotherapy in combination with R or G and identified no clear prognostic impact of the three key FCGR SNPs. In conclusion, this study, the largest performed to date, provides further conclusive evidence that FCGR genotype does not confer differential responsiveness to R or G in treatment naive pts with advanced FL or aggressive DLBCL. JCS, MN and CH share first authorship, MCC and MZO share senior authorship. Disclosures Strefford: University of Southampton: Employment; F.Hoffman-La Roche: Research Funding. Nowicka:F.Hoffman-La Roche: Employment. Parker:Kay Kendall Leukaemia Fund: Research Funding; University of Southampton: Employment. Knapp:Roche: Employment. Mir:F.Hoffman-La Roche Ltd: Employment. Rose-Zerilli:Leuka Charity: Research Funding. Burton:NHS: Employment; Takeda: Honoraria; Roche: Honoraria; Takeda: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Consultancy. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding. Sehn:Morphosys: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Celgene: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Davies:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite: Consultancy; GSK: Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cragg:Bioinvent: Consultancy, Patents & Royalties: Patent licenced to Bioinvent around CD32b blockade; Boehringer Ingleheim: Consultancy. Oestergaard:Roche: Employment, Other: Ownership interests PLC.

Introduction: Clinical trial response assessments for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) typically mandate bone marrow biopsies (BMBs) at baseline and for confirmation of complete response (CR) as assessed by computed tomography (CT) imaging according to International Working Group (IWG) criteria. BMBs are painful and expensive, and can deter patients (pts) from clinical trial participation. Rutherford et al. (Br J Haematol 2017) suggested that confirmatory BMBs do not impact response assessment in the majority of FL pts treated in clinical trials. We describe the impact of confirmatory BMBs on response in the GALLIUM study (NCT01332968), which randomized previously untreated FL pts to obinutuzumab (G)- or rituximab (R)-chemotherapy (CHOP, CVP, or bendamustine) followed by maintenance with the same antibody in responders, and in the GOYA study (NCT01287741), which randomized previously untreated DLBCL pts to G-CHOP or R-CHOP. Methods: We conducted a retrospective analysis of GALLIUM and GOYA to evaluate the percentage of pts with CR as assessed by CT but with a positive BMB at end of induction (EOI), and the percentage of pts with complete metabolic response (CMR) on positron emission tomography (PET) by Lugano 2014 criteria but with a positive BMB at EOI. Response by PET was an exploratory endpoint and not mandatory. Results: Of 1202 randomized FL pts in GALLIUM, 633 (52.7%) had a positive (613 pts, 51.0%) or indeterminate (20 pts, 1.7%) baseline BMB (data missing for 12 pts, 1.0%). Bone marrow involvement was not prognostic for progression-free survival (PFS; investigator (INV)-assessed PFS: HR 0.99 [95% CI 0.80, 1.23] for pts with positive vs non-positive BMB). At EOI, 209/633 (33%) pts had a CR on CT by IWG criteria, 179 of whom had a follow-up BMB to confirm response; 174/179 (97.2%) had a negative BMB that confirmed CR, 1/179 (0.6%) was positive, and 4/179 (2.2%) were indeterminate. Overall, only 5/179 (2.8%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 5/1202 (0.4%) pts enrolled in the trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (determined by Independent Review Committee; IRC) were used for response assessment in 282/633 (44.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 251/282 (89.0%) pts had a CMR, and 213/251 (84.9%) underwent confirmatory BMBs at EOI (203 [95.3%] negative, 5 [2.3%] positive, and 5 [2.3%] indeterminate). Thus, BMB results only affected response by Lugano 2014 in 4.7% of pts having a repeat BMB (0.8% of all enrolled pts). Of 1418 randomized DLBCL pts in GOYA, 167 (11.8%) had a positive (154 pts, 10.9%) or indeterminate (13 pts, 0.9%) baseline BMB; information was missing for 14 pts (1.0%). Bone marrow involvement was prognostic for PFS (INV-assessed PFS: HR 0.75 [95% CI: 0.56, 0.99]; 3-year PFS rate 55.3% vs 69.8% for pts with positive vs non-positive BMBs, respectively). At EOI, 69/167 (41.3%) pts had a CR on CT by IWG criteria, 49 of whom had a follow-up BMB to confirm response; 47/49 (95.9%) had a negative BMB and 2/49 (4.0%) were positive. Therefore, only 2/49 (4.0%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 2/1418 (0.1%) pts enrolled in the GOYA trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (by IRC) were used for response assessment in 121/167 (72.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 96/121 (79.3%) pts had a CMR, and 70/96 (72.9%) underwent confirmatory BMB. Of these, 65/70 (92.9%) were negative. Thus, BMB results only affected response by Lugano 2014 in 7.1% of pts having a repeat BMB (0.4% of all enrolled pts). Conclusions: In previously untreated FL and DLBCL pts in the GALLIUM and GOYA studies, post-induction BMB results impacted the CR rate by IWG criteria in only a minority of pts ( Disclosures Hiddemann: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Kostakoglu:Roche: Consultancy, Honoraria; Norvatis: Consultancy, Honoraria. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Martelli:F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Sehn:Roche/Genentech: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; PCYC: Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Speakers Bureau. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Mattiello:Roche: Employment. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Sellam:Roche: Employment. Martin:Seattle Genetics: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy.

Introduction: Genetic alterations at 9p24.1 resulting in overexpression of programmed death-1 (PD-1) ligands are near-universal in cHL (Roemer et al, J Clin Oncol 2016); cHL may thus be uniquely sensitive to PD-1 blockade. Nivolumab (nivo), an anti-PD-1 monoclonal antibody, was associated with an objective response rate (ORR) of 69% in relapsed/refractory (R/R) cHL after auto-HCT and irrespective of prior brentuximab vedotin (BV) in the phase 2 CheckMate 205 study (Armand et al, J Clin Oncol 2018; NCT02181738). Whether some patient (pts) can derive very long clinical benefit, whether depth of response predicts long-term outcome, whether treatment (Tx) can be interrupted in complete remission (CR), and whether the safety profile of nivo in R/R cHL changes with prolonged Tx all remain unclear. We therefore present an updated analysis of CheckMate 205, focusing on long-term efficacy and safety. Methods: This international, single-arm, multi-cohort study enrolled pts aged ≥18 y with R/R cHL after auto-HCT. Pts were BV naïve (Cohort A), had prior BV failure after auto-HCT (Cohort B), or had received BV before and/or after auto-HCT (Cohort C). Pts received nivo 3 mg/kg every 2 wk until disease progression (PD)/unacceptable toxicity. Pts in Cohort C discontinued nivo after 1 y in CR and could resume if they relapsed within 2 y of the last dose. Primary endpoint was ORR per independent radiology review committee (IRC); additional endpoints included duration of response (DOR) per IRC, progression-free survival (PFS) per IRC, overall survival (OS), and safety. Time to next Tx (TTNT: time from first dose to next systemic Tx or death) was an exploratory post-hoc analysis. Responses were assessed using International Working Group 2007 criteria. Results: In total, 243 pts were enrolled to Cohorts A (n=63), B (n=80), and C (n=100). Baseline characteristics have been previously described (Armand et al, J Clin Oncol 2018). At data cut-off, minimum follow-up was 31 mo and 49 pts (20%) were still on Tx; the most common reason for discontinuation was PD (35%). Median duration of Tx was 14 mo. ORR per IRC was 71% (65%, 71%, 75% in Cohorts A, B, C, respectively) with a best overall response (BOR) of CR in 21% (32%, 14%, 20% in Cohorts A, B, C, respectively). Among 51 pts who achieved CR, 20 had CR as the first response and 31 improved from partial remission (PR), mostly (n=28/31) within 1 year of first PR. Median time to response was 2 mo, and to CR was 4 mo. Within the first 6, 12, and 18 mo, 68%, 71%, and 71% of pts, respectively, achieved a response. Median DOR was 18 mo overall, and was 32 and 13 mo in pts with a BOR of CR and PR, respectively. Among responders, 64%, 44%, 31%, and 21% of pts had a DOR of at least 6, 12, 18, and 24 mo, respectively. Overall, 11 pts in Cohort C discontinued with persistent investigator-assessed CR; 2 reinitiated nivo due to PD. Median (95% CI) PFS per IRC among all pts was 15 (11-19) mo (Figure A), and was 17, 12 and 15 mo in Cohorts A, B, and C, respectively. Median OS was not reached in any cohort; 24-mo OS rates were 90%, 86%, and 86% in Cohorts A, B, and C, respectively, and were similar among pts in CR, PR, or with stable disease (SD; Figure B). Median TTNT was 29, 27, and 20 mo in Cohorts A, B, and C, respectively. The most common Tx-related adverse events (AEs) of any grade (G) were fatigue (24%), diarrhea (16%), and rash (12%), each Conclusions: With the longest phase 2-3 study follow-up of a checkpoint inhibitor in R/R cHL to date, nivo was associated with frequent and durable responses regardless of BV Tx history. More than 1 in 5 responders remained in response ≥2 years later. With extended follow-up, additional pts achieved CR in all cohorts. Pts with CR had longer PFS than pts with PR or SD. However, pts with both PR and SD had prolonged OS, unlike pts with PD, which may suggest that clinical benefit duration is not well predicted by conventional response criteria. Nivo continued to be well tolerated, with no new safety signals. Characteristics of long-term responders will be presented. Study support: BMS. Medical writing: A Gill, Caudex, funded by BMS Figure. Figure. Disclosures Armand: Infinity: Consultancy; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Younes:Celgene: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Research Funding; J&J: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria; Incyte: Honoraria; Curis: Research Funding; Pharmacyclics: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Boer:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; EISA: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Sandoz: Honoraria; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Shipp:Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Ansell:Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding.

Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates (ORRs), durable efficacy, prolonged overall survival (OS), and an acceptable safety profile in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) irrespective of prior brentuximab vedotin (BV) treatment (Armand et al, J Clin Oncol 2018). Atypical response patterns have been observed with checkpoint inhibitors, and clinical benefits may be experienced by pts who are treated beyond progression (TBP) as defined by conventional criteria (Cheson et al, Blood 2016; Younes et al, Ann Oncol 2017). Stable reductions in tumor burden without symptoms of active disease were seen in pts TBP in CheckMate 205, suggesting that pts might continue to derive clinical benefits from nivo beyond disease progression. As TBP was an option for some pts in CheckMate 205, we report here updated outcomes of those pts. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 cohorts (A: BV naïve; B: BV after auto-HCT; C: BV before and/or after auto-HCT). Nivo was administered at 3 mg/kg IV every 2 wk until disease progression or unacceptable toxicity (or after 1 year in complete response [CR] for cohort C). Response was assessed by 2007 International Working Group (IWG) criteria. A protocol amendment allowed pts with stable performance status and perceived clinical benefit to be TBP per investigator assessment. Tumor burden after initial progression was assessed; exploratory analyses included OS and time to next therapy (TTNT). Pts TBP were further categorized as PD-1 resistant (failure to achieve CR/partial response [PR] during initial treatment with nivo or CR/PR with subsequent progressive disease [PD] ≤90 d of response) and non-resistant pts (CR/PR followed by PD >90 d from response). Results: At data cutoff, 130 pts had PD, among whom 80 (62%) were TBP, and 50 (38%) were not (non-TBP). Demographics of pts TBP and non-TBP were similar to the overall study population, although more pts TBP had ECOG performance status of 0 at baseline (59% vs 36%) and stage IV disease at diagnosis (30% vs 22%), but fewer had B symptoms at baseline (23% vs 30%). In pts TBP vs non-TBP, the cause of initial progression was new lesions in 50 (63%) vs 23 (46%), increased total tumor burden in 17 (21%) vs 11 (22%), and non-target lesion progression in 19 (24%) vs 4 (8%) (pts could have multiple reasons for progression). ORR prior to progression was similar between TBP (54%) and non-TBP (64%) pts. At data cutoff, the median (range) doses of nivo given beyond progression was 11 (1-64) and median TBP duration was 5 (95% CI: 3, 7) mo. Nine (11%) pts TBP remained on treatment compared with 2 (4%) non-TBP. The most common reason for discontinuation was further disease progression in 55 (69%) and 28 (56%) pts TBP and non-TBP, respectively. The majority of pts TBP (37/67 evaluable pts) had stable or reduced target lesion tumor burden and most had sustained further reduction compared with the burden presented at the time of disease progression (Figure). There was no discernible difference in the response to TBP between PD-1 resistant vs non-resistant pts. Median OS for pts TBP was not reached; 1- and 2-yr OS (95% CI) was 94% (85, 97) and 87% (77, 93), respectively. Median TTNT was 20 (95% CI: 14, 24) mo for all pts TBP. Treatment-related adverse events (TRAEs) occurred in 50% of pts after progression vs 68% prior to progression. The most common TRAEs reported after progression were fatigue (8%) and increased lipase (6%). Treatment-related serious AEs after progression were reported in 2 (3%) pts: aspartate aminotransferase increase (n=1) and hypercalcemia (n=1). No deaths occurred in pts TBP. Conclusions: Among pts treated beyond investigator-assessed progression, most commonly due to development of new lesions, continued reductions in tumor burden were observed in a majority with further nivo treatment irrespective of prior PD-1 resistance status. Nivo continued to be well tolerated during TBP with no new safety signals. Pts who have stable performance status despite progression according to conventional criteria may derive continued clinical benefit from TBP. Future work will focus on identifying subsets of pts TBP who may benefit the most from continued nivo treatment. Study support: BMS. Disclosures Cohen: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Leukemia and Lymphoma Society Canada: Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria. Ansell:Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding. Younes:Abbvie: Honoraria; J&J: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Curis: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Astra Zeneca: Research Funding; Incyte: Honoraria; Genentech: Research Funding. Trněný:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ramchandren:Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Collins:BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Zinzani:Astra Zeneca: Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer:EISA: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shipp:Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bayer: Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Infinity: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding.

Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus 6-8 cycles of CHOP (R-CHOP). While the RICOVER trial (Pfreundschuh et al. Lancet Oncol 2008) showed no benefit of 6 versus 8 cycles of R-CHOP administered at 2-weekly intervals, this has not been assessed with the standard 3-weekly regimen, and many centers continue to administer 8 cycles. GOYA (NCT01287741) was an open-label, randomized, Phase III study of the efficacy and safety of R-CHOP versus obinutuzumab (GA101; G) plus CHOP in previously untreated pts with DLBCL. The current exploratory analysis compared investigator (INV)-assessed progression-free survival (PFS) and overall survival (OS) in pts receiving 6 or 8 cycles of CHOP in combination with 8 cycles of R in GOYA. Methods: Eligible pts were aged ≥18 years with histologically documented, CD20-positive DLBCL and ≥1 bi-dimensionally measurable lesion, ECOG PS 0-2, IPI score ≥2, and adequate hematologic function. Low-risk pts with IPI score 1 not due to age alone or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts who were randomized to R-CHOP received 8 cycles of R (375mg/m2) in combination with 6 (CHOP6) or 8 (CHOP8) cycles of CHOP. Centers elected upfront to administer either 6 or 8 CHOP cycles to all pts enrolled at that site. Efficacy was evaluated in all pts who were randomized to R-CHOP (intent-to-treat population; data cut-off: January 31, 2018). Safety was assessed in all pts who completed the 6th treatment cycle and received R in the 7th cycle (CHOP6 safety population: no additional CHOP cycles; CHOP8 safety population: at least 7 or 8 CHOP cycles received). Only AEs starting during or after the 7th cycle were considered. Statistical analyses included Kaplan-Meier estimates and Cox-regression, with and without propensity score adjustment to correct for baseline imbalances. Results: Results are reported for 712 pts who were randomized to R-CHOP (CHOP6, n=526; CHOP8, n=186; safety population: CHOP6, n=461; CHOP8, n=144). In the CHOP6 group, 55% were male and median age was 62 years (range 54-70). In CHOP8, 49% were male and median age was 60 years (range 47-67). Baseline characteristics were broadly comparable across treatment groups, except for geographic region (CHOP6 vs CHOP8: Asia, 32% vs 49%, respectively; Eastern Europe, 10% vs 24%; Western Europe, 36% vs 13%; North America, 18% vs 8%; other, 4% vs 5%). In CHOP6, 89% completed 6 cycles of R-CHOP, while in CHOP8, 76% completed 8 cycles. Three-year INV-assessed PFS rates were comparable between groups: 68.7% in CHOP6 versus 66.8% in CHOP8 (HR 0.92; 95% CI: 0.69, 1.23; Figure 1a). Three-year OS rates appeared higher in the CHOP6 group (83.2% vs 76.2% in CHOP8; HR 0.65; 95% CI: 0.46, 0.91; Figure 1b). PFS and OS comparisons were unchanged after propensity score adjustment for the prespecified baseline characteristics, including age, gender, disease stage, geographic region, IPI score, extranodal sites, body surface area, bulky disease, LDH, and COO (PFS: HR 0.96, 95% CI: 0.70, 1.32; OS: HR 0.66, 95% CI: 0.45, 0.97). Interim treatment response (by CT) did not influence these findings. Model-based subgroup analysis according to baseline pt characteristics did not identify any pt subgroups benefitting from 8 versus 6 cycles of CHOP (Figure 1c). Incidence of grade 3-5 adverse events (AEs) was lower in the CHOP6 group than in the CHOP8 group (17.8% vs 38.9%, respectively); cardiac AEs (all grade: 2.4% vs 6.3%; grade 3-5: 1.3% vs 3.5%) and infections (all grade: 10.6% vs 23.6%) were also less common. In support of these findings, similar results were achieved after repeating the same efficacy analysis in pts who received 6 or 8 cycles of CHOP in combination with 8 cycles of obinutuzumab. Conclusions: In this exploratory analysis of 712 previously untreated DLBCL pts in GOYA, in which the number of CHOP cycles was selected upfront by each site, no additional PFS benefit was observed with 8 cycles of R-CHOP compared with 6 cycles of R-CHOP plus 2 cycles of R, even after adjusting for baseline differences, including COO and IPI. Slow response, assessed by interim CT, did not influence these findings. Furthermore, incidence of grade 3-5 AEs (including cardiac) and any grade infections was markedly higher in pts receiving 8 cycles of CHOP versus 6 cycles. These results suggest that rituximab with 6 cycles of 3-weekly CHOP should be considered standard of care. Disclosures Sehn: Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Culligan:JAZZ: Honoraria; Celgene: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; Abbvie: Other: Support to attend conferences; Pfizer: Honoraria; Merck Sharp & Dohme (MSD): Honoraria. Ogura:Cellgene: Honoraria; Celltrion: Research Funding; Takeda: Honoraria; SymBio: Research Funding. Launonen:Roche: Employment, Other: Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sellam:Roche: Employment. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Vitolo:Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau. Martelli:Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees.

Introduction Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2 and good sensitivity to a small molecule BCL2 inhibitor venetoclax. In the present study we analyzed molecular mechanisms of venetoclax resistance in MCL cells, and tested strategies to overcome it based on concurrent targeting of BCL2 a MCL1. Methods Cell death was determined by flow cytometry using Annexin-V/PI staining. Establishment of MCL cell clones with knock-down or transgenic overexpression of MCL1, BIM and NOXA, western blotting, immunohistochemistry of formalin-fixed paraffin-embedded tissue sections, and immunoprecipitation experiments were carried out as previously described (Klanova et al, Clin Cancer Res, 2016). All PDXs were derived in our laboratory from patients with relapsed MCL. All PDX were confirmed by NGS to keep majority of somatic mutations with the primary MCL cells from which they were derived. Samples were sequenced using SureSelectXT Human All Exon V6+UTR (Agilent Technologies, Santa Clara, CA) on the NextSeq 500 (Illumina, San Diego, CA) instrument according to manufacturer's protocols. Experimental therapies were implemented using NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice purchased from Jackson Laboratory (Bar Harbor, Maine, USA). Therapy was initiated when all mice developed palpable subcutaneous tumors (= day 1, D1). Venetoclax (VTX) and S63845 were from MedchemExpress, carfilzomib (CFZ) was from Charles University General hospital pharmacy. Carfilzomib (4 mg / kg) was administered intravenously (IV) on days 1 and 6. Venetoclax (40 mg / kg) was given by oral gavage on days 1, 2, 3, 6 and 7. S63845 (25 mg / kg) was administered IV on days 1, 2, 3, 6 and 7. Tumor volumes were calculated using the following formula: π / 6 × tumor length × width × height. Results By transgenic overexpression or shRNA-mediated knock-down we confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. We demonstrated that both BIM and NOXA are differentially expressed between MCL cell lines on one side, and primary MCL cells and patient-derived xenograft (PDX) cells on the other side. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, biallelic deletions of BIM harbored by three commonly used MCL cell lines (JEKO-1, MINO and Z138), and previously reported to be present in approx. 30% of MCL patients, were not found in primary MCL cells. As a consequence, vast majority of the in vitro data was implemented on venetoclax-sensitive cell lines HBL2 and MAVER-1, whose patterns of expression of BCL2, MCL1, BIM and NOXA are similar to primary MCL cells. We demonstrated that MCL1, another key anti-apoptotic protein, plays an essential role in mediating resistance to venetoclax. First, MCL1 functions as a buffer for BIM released from BCL2 upon binding of venetoclax thereby preventing activation of BAX and induction of apoptosis. Second, marked upregulation of MCL1 protein was associated with acquired resistance to venetoclax in two most sensitive MCL cell lines HBL2 and MAVER-1. Based on the in vitro data we proposed two experimental treatment strategies that co-targeted MCL1 (along with inhibition of BCL2 with venetoclax): a direct blockage with a highly specific small molecule MCL1 inhibitor S63845, and an indirect blockage achieved by proteasome inhibitor carfilzomib that upregulates the proapoptotic protein NOXA that specifically binds and blocks MCL1. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo inducing the longest "remissions" of MCL bearing mice (i.e. temporary disappearance of subcutaneous MCL tumors) using a panel of four different PDXs derived from patients with relapsed / refractory MCL with complex karyotype changes (Figure 1). The combination of carfilzomib and venetoclax was far less effective, and at the same time more toxic suggesting functional blockage of MCL1 induced by overexpressed NOXA is either incomplete or insufficient. Conclusions Our data strongly support investigation of venetoclax in combination with S63845 as an innovative proapoptotic treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds. Figure 1 Figure 1. Disclosures Trněný: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board.

Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50% of patients (pts) overexpress BCL2 protein, 30% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study. Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion >1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety. Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50% medium/high expression), MYC IHC assay (cutoff 40% signal), BCL2 and MYC FISH, and COO assay (Nanostring). Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4% vs 47.1%) and BCL2 IHC-positive pts (57.7% vs 50.0%). The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0% vs 47.5%) and DH (71.4% vs 25.0%) pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1). Grade 3-4 adverse events (AEs) occurred in 85% (176/208) of pts in CAVALLI versus 66% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1% (3/208) of AEs were fatal versus 5% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61% of pts had >90% relative dose intensity (RDI) of Ven; 73.2% of CAVALLI pts had >90% RDI of each of doxorubicin and cyclophosphamide versus 76.4% for doxorubicin and 77.6% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered. Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts. Disclosures Morschhauser: Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Agios: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Curis: Research Funding; Genentech: Research Funding; Forma: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Trillium: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Kite: Research Funding; Takeda: Research Funding. Gasiorowski:Novartis: Honoraria; MSD: Honoraria. Greil:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Johnson:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Lugtenburg:Genmab: Consultancy; Squibb: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Sandoz: Consultancy; Bristol-Meyers: Consultancy; Servier: Consultancy, Research Funding; Roche: Consultancy. Salles:BMS: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Mir:F. Hoffmann-La Roche: Employment. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Zelenetz:Celgene: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis/Sandoz: Consultancy; Amgen: Consultancy.

Background: Indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is typically responsive to initial chemoimmunotherapy, but relapse is expected. Single-agent rituximab is FDA approved and frequently administered for patients with relapsed/refractory (R/R) low-grade or follicular CD20-positive B-cell NHL. Lenalidomide is an immunomodulatory agent with preclinical and clinical antilymphoma activity alone and in combination with rituximab. We compared the efficacy and safety of lenalidomide plus rituximab (R2) to rituximab (plus placebo) in patients with R/R iNHL. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo (control) in patients with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 months after last rituximab dose). Patients were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 years), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 year. R2 patients received oral lenalidomide 20 mg/day (d), d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control patients received rituximab and placebo on the same schedule. Dose modifications were pre-specified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). Secondary endpoints included overall response rate (ORR), complete response (CR), duration of response (DOR), time-to-next antilymphoma treatment (TTNLT), overall survival (OS), and safety. Results: A total of 358 patients were randomized (n = 178 R2; n = 180 control), median age was 63 years (range, 26 - 88), 34% FLIPI score ≥ 3, and histologies of 82% FL/18% MZL. Median number of prior systemic treatments was 1 (range, 1 - 12); 84% received prior rituximab and 51% had prior antilymphoma therapy within 2 years of enrollment. At median follow-up of 28.3 months, the study met its primary endpoint of PFS with HR = 0.46 (95% CI, 0.34 - 0.62; P < 0.0001) (Figure 1). Median PFS was 39.4 months for R2 vs 14.1 months for control. IRC-assessed ORR for R2 was 78% vs 53% for control (P < 0.0001). CR was 34% for R2 vs 18% for control (P = 0.001). Median DOR was 36.6 and 21.7 months for R2 and control arms, respectively. TTNLT was improved for R2 vs control with HR = 0.54 (95% CI, 0.38 - 0.78; P = 0.0007). OS data were not mature with 16 deaths reported in the R2 arm vs 26 deaths in control (HR = 0.61 [95% CI, 0.33 - 1.13]). Selected all-grade treatment-emergent adverse events (TEAEs) of interest more common in the R2 vs control arm (≥ 10% difference) were infections (63% vs 49%), cutaneous reactions (32% vs 12%), constipation (26% vs 14%), thrombocytopenia (15% vs 4%), and tumor flare reaction (11% vs 1%). Grade 3/4 TEAEs were reported in 69% R2 and 32% control patients. More frequent grade 3/4 TEAEs in the R2 vs control arm were primarily attributable to increased neutropenia (50% vs 13%) and leukopenia (7% vs 2%). Grade 5 TEAEs were reported in 2 patients in each arm. TEAEs leading to discontinuation of lenalidomide occurred in 9% of patients vs 5% for rituximab + placebo. Neutropenia was the only TEAE leading to discontinuation of lenalidomide in > 1 patient (n = 5). Seventy-one percent of R2 patients completed all 12 cycles of planned treatment vs 61% of control. Disease progression was the leading reason for discontinuation of lenalidomide/placebo (n = 21 R2, n = 54 control). Conclusions: R2 demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as secondary endpoints of ORR, CR, DOR, and TTNLT in patients with R/R FL grade 1-3a and MZL. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer early progressions) allowed more patients to complete the planned therapy and delayed the need for subsequent treatment. R2 represents an important new treatment option in patients with previously treated FL/MZL, with meaningful advantages over single-agent rituximab. Disclosures Leonard: Celgene: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; BMS: Consultancy. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria. Izutsu:Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Nihon Medi-Physics: Honoraria; Novartis: Honoraria; Mundhi: Honoraria; HUYA Bioscience International: Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Zenyaku: Research Funding; Celltrion: Research Funding; MSD: Honoraria; Ono: Honoraria, Research Funding; Symbio: Research Funding; Celgene: Consultancy, Research Funding; Solasia: Research Funding; Sanofi: Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Scheliga:INCA - Instituto Nacional Do Cancer, Brazil: Employment. Pinto:Servier: Consultancy; BMS: Honoraria, Research Funding; MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Flinn:Trillium: Research Funding; Takeda: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Verastem: Research Funding; ArQule: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; BeiGene: Research Funding; Kite: Research Funding; Portola: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forma: Research Funding; Merck: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Moreira:Instituto Português de Oncologia do Porto FG, EPE, Porto, Portugal: Employment. Liu:Celgene: Employment, Equity Ownership. Kalambakas:Celgene: Employment, Equity Ownership. Fustier:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Gribben:Cancer Research UK: Research Funding; Unum: Equity Ownership; Novartis: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; NIH: Research Funding; Roche: Honoraria; Janssen: Honoraria, Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria.

Introduction: Natural killer (NK) cells are key elements of the innate immune system. Obinutuzumab (GA101; G) is an anti-CD20 monoclonal antibody with enhanced direct cell death activity and antibody-dependent cellular cytotoxicity (ADCC) vs rituximab (R). Upon binding CD20-bound G/R, NK cells are activated and attack the target cell. Therefore, low pre-treatment NK cell count (NKCC) may be associated with worse outcomes in G/R-treated patients (pts). This exploratory post hoc analysis evaluated the prognostic impact of baseline (BL) NKCC in FL pts treated with G/R plus chemo in the Phase 3 GALLIUM trial (NCT01332968) and DLBCL pts treated with G/R plus CHOP in the Phase 3 GOYA trial (NCT01287741). Methods: BL peripheral blood (PB) NKCCs, assessed by flow cytometry (CD3-CD56+CD16+ cells; normal range [central lab]: 95-640 cells/µL), were available in 1064/1202 (88.6%) FL pts and 1287/1418 (90.8%) DLBCL pts. Cell-of-origin (COO) was determined in 933/1418 DLBCL pts using the Nanostring Research Use Only Lymphoma Subtyping Test (LST). COO and BL NKCC were available in 857/1418 pts. Whole transcriptome gene expression was analyzed using TruSeq RNA sequencing in tumor tissue from 552/1418 DLBCL pts. A 57-gene signature designed to reflect NK cell tumor infiltration was applied to RNA sequencing data from 552 pts; median score was used to define high/low subgroups. Kaplan-Meier methodology was used to estimate progression-free (PFS) and overall survival (OS), and a Cox regression univariate model was used to estimate corresponding HR and CI. The relative importance of BL variables (NKCC, gender, geographic region, treatment arm, chemo backbone/no. of planned chemo cycles, FLIPI/IPI, extranodal/bone marrow involvement, sum of products of diameter, Ann Arbor stage) was evaluated using multivariate (MV) Cox regression models with a stepwise approach. Results: Median (range) BL NKCCs were 220 cells/μL (0-3300) in FL and 200 cells/μL (0-1900) in DLBCL pts. Overall, 108/1064 (10.2%) FL pts and 255/1287 (19.8%) DLBCL pts had low BL NKCC ( On univariate analysis low BL NKCC was associated with shorter PFS in FL (HR 1.57, 95% CI 1.10-2.25, p=0.01; 3-yr PFS 71.6% vs 80.1%) and DLBCL (HR 1.36, 95% CI 1.07-1.72, p=0.01; 3-yr PFS 62.8% vs 70.0%; Figure 1), and shorter OS in FL (HR 2.58, 95% CI 1.51-4.42, p=0.0003; 3-yr OS 87.6% vs 94.3%). DLBCL pts with low NKCC had a trend to worse OS vs pts with normal NKCC (HR 1.35, 95% CI 1.00-1.82, p=0.052; 3-yr OS 77.6% vs 82.3%). On MV analysis, low BL NKCC was independently associated with PFS in FL (HR 1.48, 95% CI 1.02-2.14, p=0.04) and DLBCL (HR 1.36, 95% CI 1.01-1.83, p=0.04). The DLBCL result appeared to be driven by COO subtype, with the highest estimated HR in GCB (HR 1.58, 95% CI 1.0-2.5, p=0.05), and no effect in unclassified and ABC. Interestingly, in line with the enhanced ADCC of G, the impact of low BL NKCC on PFS was stronger in G-treated FL pts (HR 2.06, 95% CI 1.24-3.41, p Although there was no correlation between PB NKCC and tumor NK cell gene expression among biomarker-evaluable pts in GOYA, low tumor NK cell gene expression was associated with shorter PFS in G-treated DLBCL pts (all COO subtypes; HR 1.95, 95% CI 1.2-3.1, p Conclusions: In this largest prospective collection of PB NK cells to date in FL and DLBCL, substantial numbers of pts had reduced NKCCs at BL, which was associated with advanced disease. Univariate and MV analyses may suggest that low PB NKCC is independently associated with shorter PFS in FL and DLBCL and shorter OS in FL. Likewise, low NK cell gene expression in tumor tissue was associated with shorter PFS in G-treated DLBCL pts. Collectively, our results from this exploratory analysis indicate that the number of NK cells in PB and tumor tissue may impact clinical outcome of non-Hodgkin lymphoma pts treated with anti-CD20 antibodies. Disclosures Klanova: F. Hoffmann-La Roche Ltd: Employment, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Magdalena Klanova, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Oestergaard: F. Hoffmann-La Roche Ltd: Employment. Trněný: Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Marcus: Celgene: Other: Support for meeting attendance ; Roche: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Sehn: Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Vitolo: Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bazeos: Roche: Other: • A year-long academic collaboration contract with Roche (no financial gain).. Goede: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Zeuner: Roche: Employment. Knapp: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Danesi: Roche: Employment. Bolen: Genentech: Employment, Equity Ownership. Robson: F. Hoffmann la Roche: Employment. Venstrom: Genentech, Inc.: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.

Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Introduction: Nivolumab (nivo), an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, augments T-cell activation and restores antitumor T-cell function. In the phase 2 CheckMate 205 study (NCT02181738), nivo demonstrated frequent (65-73%) and durable objective responses across 3 cohorts of patients (pts) with relapsed/refractory (R/R) cHL after failure of autologous hematopoietic cell transplantation (Fanale M et al. ICML 2017 [oral 125]). While most pts with cHL are cured with first-line therapy, those with advanced-stage disease are more likely to relapse or progress. More aggressive regimens (eg, BEACOPPesc., Borchmann P et al. Lancet Oncol 2017) are associated with improved progression-free survival (PFS) but are hampered by excessive toxicities and have limited applicability in elderly pts.PD-1 ligand gene amplification has been linked to poorer outcomes in cHL pts treated with standard induction regimens (Roemer MG et al. J Clin Oncol 2016) but is associated with improved responses to nivo in R/R cHL (Younes A et al. Lancet Oncol 2016), suggesting that PD-1 blockade may benefit pts in the frontline setting. We therefore assessed the safety and efficacy of nivo as a single-agent lead-in treatment followed by nivo in combination with chemotherapy, excluding bleomycin due to potential overlapping pulmonary toxicity, for pts with previously untreated advanced-stage cHL. Methods: Cohort D of CheckMate 205 enrolled untreated pts (aged ≥18 y) with advanced-stage newly diagnosed cHL (stage III, IV, or II with B symptoms and extranodal or bulky disease) and ECOG score 0-1. Pts received 4 biweekly doses of nivo monotherapy (240 mg IV flat dose) followed by nivo plus chemotherapy (nivo 240 mg IV, doxorubicin, vinblastine, dacarbazine [N-AVD]) for 6 cycles (12 doses). The primary endpoint was safety and tolerability: proportion of pts with ≥1 grade (G) 3-5 treatment-related adverse event (TRAE) ≤30 d after last dose. Additional endpoints included rates of discontinuation and of independent radiologic review committee-assessed complete remission (CR). Results: At database lock (June 2017), 51 pts had been treated, with a median (range) follow-up of 8 (1-11) mo. Median (range) age was 37 (18-87) y; 29 (57%) pts had stage IV disease, and 41 (80%) had B symptoms. At baseline, 7 (14%) pts had bulky disease and 17 (33%) had extranodal involvement. International prognostic score was ≥3 in 25 (49%) pts. At analysis, 49 (96%) pts had completed nivo monotherapy treatment, receiving all 4 doses; 1 pt discontinued due to disease progression and 1 due to study drug toxicity (G1-2 hyperthyroidism), subsequently receiving AVD only. TRAEs for both treatment phases are shown in the Table. During nivo monotherapy, 2 pts had 1 dose delay each due to an AE; 2 (4%) pts had serious AEs (SAEs; 1 G1-2 hyperthyroidism; 1 G1-2 polyneuropathy); an immune-mediated AE (IMAE), G1-2 hyperthyroidism, was reported in 2 (4%) pts. Fifty pts started combination therapy; at database lock, 35 (70%) had completed therapy, with 34 (69%) receiving 12 N-AVD doses. With N-AVD, 10 (20%) pts had SAEs, 6 G3-4; the most common G3-4 SAE was febrile neutropenia in 2 (4%) pts; IMAEs occurring in >1 pt were hypothyroidism in 8 (16%) pts and increased ALT in 2 (4%). AEs leading to discontinuation of N-AVD occurred in 2 pts: G1-2 hepatic abnormality, and G3-4 febrile neutropenia (FN) and Klebsiella bacteremia. The pt who developed FN and Klebsiella bacteremia died 38 d after the first dose of his fifth cycle of N-AVD due to study drug toxicity of acute respiratory insufficiency. Important primary, secondary, and exploratory endpoints (including CR and objective response rates at end of monotherapy, after 2 combocycles and end of therapy, and PFS) will be presented at the meeting. Conclusions: Nivo monotherapy followed by N-AVD combination therapy was well-tolerated in pts with newly diagnosed, untreated, advanced-stage cHL. Nearly all pts completed nivo monotherapy treatment and started combination therapy with N-AVD. The safety profile was consistent with historical experience of nivo and AVD separately, with no new safety signals. Nivo followed by N-AVD may provide a tolerable alternative treatment option to standard-of-care multi-agent chemotherapy for pts with newly diagnosed advanced-stage cHL. Study support: BMS. Writing support: Matthew Thomas, PhD, Caudex, funded by BMS. Disclosures Ramchandren: Janssen: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy. Fanale: CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC THERAPEUTICS: Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding. Rueda: Bristol-Myers Squibb: Consultancy. Armand: Roche: Research Funding; Genmab: Consultancy; Infinity: Consultancy; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Otsuka: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding. Trněný: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Speakers Bureau. Ansell: Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; LAM Therapeutics, Inc: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Willenbacher: Bristol-Myers Squibb: Consultancy, Honoraria. Sacchi: Bristol-Myers Squibb: Employment. Sumbul: Bristol-Myers Squibb: Employment.

Background: Immunochemotherapy induction followed by maintenance with rituximab (R) is the standard of care (SoC) for pts with advanced-stage symptomatic follicular lymphoma (FL), achieving a median PFS of 6-8 yrs and a median survival of 12-15 yrs. However, FL is incurable and most pts eventually relapse. Relapse occurs in 30% of pts within 3 yrs, and is associated with a poor prognosis. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered type II anti-CD20 monoclonal antibody with enhanced direct cell killing and antibody-dependent cellular cytotoxicity that has promising activity and manageable toxicity when combined with chemotherapy in relapsed indolent non-Hodgkin lymphoma (iNHL). We report the results of GALLIUM (NCT01332968), a global, open-label, randomized Phase 3 study comparing the efficacy and safety of R or G with chemotherapy followed by maintenance as first-line treatment in iNHL. Methods: Pts entered were aged ≥18 yrs with previously untreated FL (grades 1-3a) or chemotherapy-naïve marginal zone lymphoma (MZL), stage III/IV disease or stage II with tumor diameter ≥7cm, ECOG PS 0-2, and requiring treatment according to GELF criteria. CHOP, CVP, or bendamustine (B) were allocated according to center (FL) or pt (MZL). Pts were randomized 1:1 and stratified by chemotherapy, FLIPI or IPI group, and geographic region to R 375mg/m2 on Day (D) 1 of each cycle or G 1000mg on D1, 8 and 15 of Cycle 1 and D1 of subsequent cycles, for either 8 x 21-day cycles (CHOP and CVP) or 6 x 28-day cycles (B). Pts with a CR or PR at the end of induction (EOI) as per modified Cheson criteria received R or G every 2 mo for 2 yrs or until disease progression. The primary endpoint was investigator (INV)-assessed PFS in FL pts. At final analysis, based on 370 PFS events having occurred, the study would have 80% power to detect a HR of 0.741. The current data are from a planned interim efficacy analysis done when 67% of the 370 PFS events had occurred (cut-off date: January 31, 2016) after which the study was unblinded on IDMC recommendation. Efficacy was assessed in all randomized FL pts. Safety was assessed in all FL pts who received any study treatment. Results: Results are reported for 1202 FL pts (R-chemo, 601; G-chemo, 601) with a median age of 59 yrs (53.2% female); data for 195 MZL pts will be reported elsewhere. Treatment arms were well balanced by disease stage (Ann Arbor: I, 1.5%; II, 7.1%; III, 34.9%; IV, 56.5%) and prognostic factors (FLIPI: 0+1, 21.0%; 2, 37.2%; ≥3, 41.8%; FLIPI-2: 0, 9.1%; 1+2, 50.3%; ≥3, 40.6%). Chemotherapy received was B in 57.1% of pts, CHOP in 33.1%, and CVP in 9.8%. CR and ORR at EOI based on CT/NMR imaging were similar for the two arms (Table 1). After a median follow-up of 34.5 mo (range, 0-54.5), there was a 34% reduction in the risk of progression or death (HR, 0.66; 95% CI, 0.51, 0.85; p=0.001; Figure; Table 1). Although medians have not been reached in GALLIUM or PRIMA, the observed HR of 0.66 would translate to a 1.5x longer median PFS for G-chemo than R-chemo, and to an estimated 3 yr improvement in the G arm if a median PFS of 6 yrs was assumed in the R arm. Three-yr INV-assessed PFS rates were: G-chemo, 80.0% (95% CI, 75.9%, 83.6%); R-chemo, 73.3% (95% CI, 68.8%, 77.2%). A consistent benefit in favor of G-chemo was also seen for PFS assessed by Independent Review Committee (IRC), as well as other time-to-event endpoints (Table 1). Subgroup analyses were broadly consistent with the primary analysis. At the time of the analysis, 35 pts (G-chemo; 5.5%) and 46 pts (R-chemo; 8.7%) had died (HR for overall survival, 0.75; 95% CI, 0.49, 1.17; p=0.210; Table 1). G-chemo pts had a higher frequency of grade 3-5 AEs (74.6%) and SAEs (46.1%) than R-chemo pts (67.8% and 39.9%, respectively). The frequency of fatal AEs was similar (G-chemo, 4.0%; R-chemo, 3.4%). AEs led to treatment discontinuation in 16.3% pts (G-chemo) and 14.2% pts (R-chemo) in the absence of disease progression. Safety results are summarized in Table 2. The median decrease in IgG levels at the EOI treatment was similar in the two arms (Table 2). Conclusion: In pts with previously-untreated FL, G-based immunochemotherapy and maintenance resulted in a clinically meaningful improvement in PFS, with a 34% reduction in the risk of a PFS event relative to R-based therapy. Frequency of some AEs, e.g. infusion-related reactions (IRRs), cytopenias, and infections, was higher with G. These data support G-chemo becoming a new SoC in previously untreated pts with FL. Disclosures Marcus: Roche: Consultancy, Honoraria; Takeda: Other: Travel support . Davies:Pfizer: Research Funding; Karyopharma: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; GSK: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Owen:Roche: Consultancy, Honoraria, Research Funding; Lundbeck: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria; Celgene: Honoraria; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Phillips:Roche: Consultancy. Sangha:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Seymour:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Roche, Celgene: Research Funding; Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Genentech: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Rufibach:Roche: Employment, Equity Ownership. Moore:Roche: Employment, Equity Ownership. Herold:Gilead: Other: Personal fees from member advisory board; Celgene: Honoraria; Genentech: Other: Grants; Roche: Honoraria, Other: Grants. Hiddemann:Genentech: Other: Grants; Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Grants.

Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

Background: Treatment options for patients (pts) with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) are limited. GADOLIN (NCT01059630) is an open-label, randomized, Phase 3 trial comparing the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (standard of care) in rituximab-refractory iNHL pts. In the primary analysis, which involved all pts enrolled as of September 1, 2014 (n=396; median observation time, 21.0 months [mo]), median Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was longer in the G-B arm (194 pts; median not reached) than in the B arm (202 pts; 14.9 mo), with a 45% reduction in risk of progression or death (HR 0.55; 95% CI 0.40, 0.74; p=0.0001). Investigator (INV)-assessed PFS was also significantly longer in the G-B arm, but overall survival (OS) data were immature. Safety profiles were comparable. The most common grade ≥3 adverse events (AEs) were neutropenia, thrombocytopenia, anemia, and infusion-related reactions (IRRs). Seventeen additional pts were enrolled after the data cut-off for the primary analysis. Here, we report updated time-to-event and safety results from a planned analysis of all pts (n=413) using a data cut-off of April 1, 2016. Methods: Enrolled pts were aged ≥18 years (yrs) with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg i.v. (days [D] 1, 8, and 15 of cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6), or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6); each cycle was 28 days. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 mo for 2 yrs or until disease progression, whichever occurred first). In the current analysis, assessments included INV-assessed PFS, OS, time to new anti-lymphoma treatment (TTNT), and safety. Efficacy assessment was performed on the intent-to-treat (ITT) population. Safety analysis included all pts who received any study treatment, excluding 2 pts who crossed over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had FL. Baseline characteristics of the ITT population were balanced between arms. Median number of prior regimens was 2 in both arms (pts with ≤2 prior regimens: G-B, 80.4%; B, 77.5%). Most pts were refractory to their last regimen (G-B, 92.2%; B, 92.3%). After 31.8 mo median follow-up, median INV-assessed PFS was 25.8 mo in the G-B arm and 14.1 mo in the B arm; HR was 0.57 (95% CI 0.44, 0.73; p Conclusions: Updated analysis of the GADOLIN study with ~10 mo additional follow-up confirms the previously reported PFS benefit of G-B over B in pts with rituximab-refractory iNHL, and demonstrates a significant improvement in OS in the G-B arm. No new safety signals were detected. Figure 1. OS results: A) ITT population; B) FL pts Figure 1. OS results: A) ITT population; B) FL pts Disclosures Cheson: Roche-Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astra Zeneca: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Teva: Research Funding. Trněný:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Roche: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Research Funding; Lundbeck: Honoraria, Research Funding. Lugtenburg:Celgene: Consultancy; Mundipharma: Consultancy; Servier: Consultancy; Roche: Consultancy; Takeda: Consultancy. Salles:Mundipharma: Honoraria; Gilead: Honoraria, Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Wassner-Fritsch:elisabeth.wassner_fritsch@roche.com: Employment. Sehn:Roche/Genentech: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Lundbeck: Consultancy.