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Introduction : Glofitamab (RG6026) is a novel T-cell-engaging, bispecific, full-length antibody with a 2:1 molecular configuration that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Preclinically, glofitamab had superior potency compared with other tested bispecifics with 1:1 formats (Bacac, et al. Clin Cancer Res 2018). NP30179 (NCT03075696) is an ongoing multicenter, Phase I/Ib, dose-escalation and dose-expansion trial evaluating the safety, tolerability, pharmacokinetics, biomarker responses, and efficacy of glofitamab in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in pts with heavily pre-treated R/R NHL (Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). Step-up dosing of glofitamab was used in addition to Gpt to further reduce the risk of CRS. For the first time, we present clinical data of glofitamab step-up dosing with Gpt in pts with R/R NHL. Methods: Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration. Glofitamab was given intravenously with step-up dosing on Cycle (C) 1 Day (D) 1 and 8 and then at the target dose from C2D1, every 3 weeks for up to 12 cycles (2.5/10/16mg or 2.5/10/30mg). Response rates reported are based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014). Results: As of April 17, 2020, 38 pts received step-up doses of glofitamab; 17 pts received 2.5/10/16mg, and 21 pts received 2.5/10/30mg. Twenty-eight pts (73.7%) had aggressive NHL (aNHL) histologies and ten pts had indolent NHL (iNHL; Table). The median age was 68 years (range 52-85) and median number of prior lines of therapy was 3 (range 1-12). Twenty-seven (71.1%) pts were refractory to their last therapy, and 28 (73.7%) pts were refractory to prior CD20 therapy. After a median follow-up of 2.8 months, across all efficacy-evaluable pts (n=32) the overall response rate (ORR) and complete metabolic response (CMR) rate was 62.5% and 40.6%, respectively. For pts with aNHL (n=24), the ORR was 50.0% with CMR rates of 29.2%. As of the data cut-off date, 17 pts with aNHL (70.8%) had reached the first response assessment only (C3) and remain on treatment; four pts (16.7%) had reached the second response assessment (C6). For pts with iNHL (n=8), the ORR was 100.0% with 75.0% of pts achieving CMR. Across the safety-evaluable population (n=38), the most common AEs were CRS (57.9%), pyrexia (31.6%), neutropenia, thrombocytopenia and hypophosphatemia (28.9% each). No AEs led to treatment discontinuation. Of 22 patients who experienced CRS events, the CRS events only occurred in C1 and C2; 15 had CRS after the 2.5mg dose, 12 after the 10mg dose, and 5 during C2 (16 or 30mg dose; Figure). Eight pts (21.1%) and 13 pts (34.2%) experienced Grade (Gr) 1 and 2 CRS, respectively; none experienced Gr 3 CRS. One pt (2.6%) experienced Gr 4 CRS after the 30mg dose. No CRS events occurred after C2. Tocilizumab was used to manage CRS in six (15.8%) pts: n=2 for 2.5/10/16mg and n=4 for 2.5/10/30mg cohorts. CRS events were manageable and resolved for 21 pts (95.4%) at data cut-off. No Gr ≥3 neurologic adverse events were reported. Consistent with prior biomarker data from fixed-dose regimens (Bröske, et al. EHA 2020), glofitamab administered with step-up dosing induced a transient T-cell redistribution. Conclusions: Step-up dosing of glofitamab allowed escalation up to 30mg to maximize efficacy, while minimizing the risk of increased CRS. High ORR and CMR rates were observed in pts with NHL who had failed several lines of treatment. Toxicity was manageable with the main safety signal being low-grade CRS observed in early cycles. Updated results will be presented at the congress which will include data from at least 50 pts receiving glofitamab step-up dosing with Gpt. Disclosures Hutchings: Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy. Bachy:Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Genentech, Inc.: Consultancy. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Iacoboni:Novartis, Gilead, Celgene, Roche: Honoraria. Sureda Balari:BMS: Speakers Bureau; Roche: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Dixon:Roche Products Limited: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Perez Callejo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Relf:Roche Products Ltd: Current Employment. Carlile:AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Piccione:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Dickinson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) 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: 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: Despite recent advances, prognosis for pts with NHL who undergo multiple lines of therapy remains poor. Novel drugs that provide durable complete responses (CRs) are needed for these pts. Glofitamab (RG6026) is a novel T-cell-engaging, bispecific antibody that binds bivalently to CD20 on B cells, and monovalently to CD3 on T cells. In study NP30179 (NCT03075696), an ongoing Phase I/II dose-escalation and expansion study, glofitamab fixed-dosing (0.6-25mg) with obinutuzumab pre-treatment (Gpt) achieved high, durable CRs with manageable safety in pts with heavily pre-treated R/R NHL (Dickinson et al. EHA 2020). Step-up dosing (SUD) of glofitamab, in addition to Gpt, allowed dose-escalation up to the highest planned dose of 30mg to maximize efficacy, while mitigating cytokine release syndrome (CRS; [Hutchings et al. J Clin Oncol 2021]). We present updated duration of response (DoR) data from the glofitamab monotherapy fixed-dosing and SUD cohorts of study NP30179 in pts with R/R NHL. Methods: Pts received 1000mg obinutuzumab 7 days prior to first dose of glofitamab. Glofitamab was given intravenously at a fixed dose (0.6-25mg) every 2 weeks or every 3 weeks (q3w) or with SUD (2.5/10/16mg or 2.5/10/30mg [recommended Phase II dose; RP2D]) on Cycle (C) 1 Day (D) 1 and 8, and then at the target dose from C2D1 q3w, for up to 12 cycles. Response rates are based on Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 258 pts were enrolled in the previously specified cohorts. Median age was 64.0 (range, 22‒86) years, 62.0% were male, and the median number of prior therapies was 3 (range, 1‒12). A total of 183 (70.9%) pts had aggressive NHL (aNHL), and 75 (29.1%) had indolent NHL (iNHL). Of the pts with aNHL, 98 had diffuse large B-cell lymphoma, 26 had mantle cell lymphoma, 31 had transformed follicular lymphoma (FL), and 11 had Richter's transformation. All pts with iNHL had Grade (Gr) 1‒3a FL. Response rates are reported across all doses investigated. Highest responses were seen with the RP2D (2.5/10/30mg) in pts with aNHL (Table). At the clinical cut-off date (CCOD), median duration of follow-up in pts with aNHL was 13.4 (range: 0‒36) months. In efficacy-evaluable pts with aNHL (n=175), the overall response rate (ORR) was 53.7% and the CR rate was 39.4%. Median duration of CR had not yet been reached (95% confidence interval [CI]: 21.4‒not estimable [NE], n=69; Figure); 72.5% of pts with a CR (50/69) were still in CR at the time of analysis. Median DoR (CR plus partial response) was 29.4 months (95% CI: 6.0‒NE; responders, n=94). In pts with iNHL (n=75), ORR was 81.3% and CR rate was 69.3%; median follow-up was 8.6 (range: 0‒37) months. Median duration of CR had not yet been reached (95% CI: 10.5‒NE, n=52; Figure); 82.7% of pts with a CR (43/52) were still in CR at the time of the analysis. Median DoR had not been reached (95% CI: 10.5‒NE; responders, n=61). A total of 149/258 pts (57.8%) experienced a serious adverse event (AE). CRS was the most prevalent AE, occurring in 152/258 pts (58.9%). The majority of CRS events were mild: Gr 1-2, 139 (53.9%) pts; Gr 3, 9 (3.5%) pts; Gr 4, 4 pts (1.6%). Four pts (1.6%) experienced a glofitamab-related AE that led to withdrawal of the study drug. Ninety-two (35.7%) pts experienced a neurological AE; the majority of events were Gr 1 (56/258; 21.7%) or Gr 2 (33/258; 12.8%). Three pts experienced a Gr 3 neurological AE (facial paralysis, syncope, radiculopathy), which were considered unrelated to glofitamab treatment. Immune effector cell-associated neurotoxicity syndrome (ICANS)-like events related to glofitamab occurred in 9 pts (3.5%); all events were Gr 1 or Gr 2, and all but one (Gr 1 tremor) resolved at CCOD. Conclusions: The current dataset on DoR is the largest presented to date for a CD20xCD3 bispecific antibody, with median follow-up exceeding 13 months for pts with aNHL. Glofitamab, with a fixed treatment duration and 'off-the-shelf' accessibility, has demonstrated high levels of monotherapy activity in heavily pretreated pts with R/R NHL, including those who have received two or more lines of systemic therapy. Glofitamab has shown promising response rates and durable responses a range of different doses for both aNHL and iNHL. Duration of responses in pts with aNHL were in the range of those observed in pts with refractory aNHL from an early chimeric antigen receptor T-cell data set (Neelapu et al. N Engl J Med 2017). Figure 1 Figure 1. Disclosures Dickinson: Amgen: Honoraria; Celgene: Research Funding; 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. Carlo-Stella: 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; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Morschhauser: Epizyme: 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; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Novartis: 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; Roche: Consultancy, Speakers Bureau; Genentech, Inc.: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: 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; Janssen: Honoraria; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees. Patel: BeiGene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Fate Therapeutics: Research Funding; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Kite: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Trillium Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Xencor: Research Funding; Curis, Inc: Research Funding; Abbvie: Consultancy; Millenium/Takeda: Research Funding; Velos Bio: Research Funding; Aptevo Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Khan: Genentech: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Karyopharm: Speakers Bureau; SeaGen: Speakers Bureau; Morphosys: Speakers Bureau; Kite: Speakers Bureau; GSK: Speakers Bureau. Bartlett: 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; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Hertzberg: Roche: Honoraria, Speakers Bureau; MSD: Honoraria; BMS: Honoraria; Takeda: Honoraria; Gilead: Honoraria. Leppä: Genmab: Research Funding; Orion: Consultancy; CHO Pharma USA: Consultancy; Novartis: Honoraria, 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; Incyte: Honoraria, 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; MSD: Membership on an entity's Board of Directors or advisory committees; University of Helsinki and Helsinki University Hospital: Current Employment; Takeda: Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Den Neste: Novartis: Consultancy, Research Funding; Roche: Research Funding; Celgene: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Salar: Beigene: Consultancy; BMS/Celgene: Consultancy, Speakers Bureau; EusaPharma: Consultancy; Janssen: Consultancy, Speakers Bureau; Hospital del Mar: Current Employment; Abbvie: Research Funding. 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: 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; Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Clark: Roche Products Ltd: Current Employment. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hutchings: Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibodywith 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.

Context Glofitamab, a T-cell-engaging, bispecific, full-length antibody, allows bivalent binding to CD20 (B-cells) and monovalent binding to CD3 (T-cells). In NP30179 (NCT03075696), an ongoing multicenter, phase I, dose-escalation and expansion study, glofitamab SUD, in addition to Gpt, allowed dose escalation ≤30 mg to maximize efficacy while mitigating cytokine release syndrome (CRS) (Hutchings et al. J Clin Oncol 2021). Objective To present updated efficacy data from glofitamab monotherapy SUD cohorts. Methods Gpt (1000 mg) was given 7 days pre-glofitamab initial dose. Intravenous glofitamab SUD was given on day (D) 1 and 8 of cycle (C) 1, then at target dose from C2D1 (2.5/10/16 mg or 2.5/10/30 mg); treatment continued for ≤12 cycles, every 21 days. Response rates were based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results As of December 1, 2020, 52 pts received glofitamab SUD; 17 and 35 pts received 2.5/10/16 mg and 2.5/10/30 mg, respectively. Twenty-eight pts (53.8%) had aggressive NHL (aNHL) and 24 pts had indolent NHL (iNHL). Median age: 68 (44–85) years; median 3 (1–12) prior lines of therapy; 40 (76.9%) and 38 (73.1%) pts were refractory to their most recent and any prior CD20 therapy, respectively. Median follow-up duration: 6.3 months. Best overall response (OR) and complete metabolic response (CMR) rates for aNHL cohort: 64.3% and 57.1%, respectively. 4/5 pts (80%) with mantle cell lymphoma (2.5/10/16 mg, n=2; 2.5/10/30 mg, n=2) had CMR. For aNHL, 13/16 CMRs are ongoing, with 8 CMRs lasting >3 months. OR and CMR rates for pts with iNHL: 79.2% and 70.8%, respectively, with 14/17 CMRs ongoing and 10 CMRs lasting >3 months. As of August 3, 2020, common adverse events were CRS (63.5%), neutropenia (38.5%), and pyrexia (32.7%), with CRS mostly confined to C1. Grade (Gr) 1 and 2 CRS was reported in 18 (34.6%) and 12 (23%) pts, respectively; 3 pts had Gr 3 CRS; none had Gr 4/5 events (defined by ASTCT 2019 criteria). Conclusions Updated data for glofitamab monotherapy SUD show higher preliminary response rates than previously reported in pts with R/R NHL who have failed multiple lines of therapy. CRS was mostly manageable, low-grade, and confined to C1.

7519 Background: Glofitamab (RG6026), a T-cell-engaging, bispecific, full-length antibody, allows bivalent binding to CD20 (B-cells), and monovalent binding to CD3 (T-cells). In NP30179 (NCT03075696), an ongoing multicenter, Phase I dose-escalation and expansion study, 0.6–25mg glofitamab fixed-dosing with obinutuzumab pretreatment (Gpt), showed high, durable complete responses and manageable safety in heavily pretreated R/R NHL (Dickinson, et al. EHA 2020). Glofitamab SUD, in addition to Gpt, allowed dose escalation up to 30mg to maximize efficacy, while mitigating cytokine release syndrome (CRS) (Hutchings, et al. JCO 2021). We present updated efficacy data from glofitamab monotherapy SUD cohorts. Methods: Gpt (1000mg) was given to pts 7 days pre-glofitamab initial dose. Intravenous SUD of glofitamab was given on Day (D) 1 and 8 of Cycle (C) 1 and then at the target dose from C2D1 (2.5/10/16mg or 2.5/10/30mg); treatment continued for up to 12 cycles, every 21 days. Response rates were based on the Lugano criteria (Cheson, et al. JCO 2014). Results: Fifty-two pts received glofitamab SUD; 17 and 35 pts received 2.5/10/16mg and 2.5/10/30mg, respectively. Twenty-eight pts (53.8%) had aggressive NHL (aNHL) and 24 pts had indolent NHL (iNHL). Pts had a median age of 68 (44–85) years and received a median of 3 (1–12) prior lines of therapy. Forty (76.9%) and 38 (73.1%) pts were refractory to their most recent and any prior CD20 therapy, respectively. After a median follow-up of 6.3 months, an updated efficacy analysis was conducted on December 1, 2020. For pts with aNHL (N = 28), the best overall response (OR) and complete metabolic response (CMR) rates were 64.3% and 57.1%, respectively; a trend of improved response was observed with increased target dose, with a CMR rate of 71.4% at 2.5/10/30mg (N = 14). Notably, 4/5 pts (80%) with mantle cell lymphoma (2.5/10/16mg, n = 2; 2.5/10/30mg, n = 2) had CMR. For aNHL, 13/16 CMRs are ongoing, with 8 CMRs lasting > 3 months. For pts with iNHL (N = 24), OR and CMR rates were 79.2% and 70.8%, respectively; 14/17 CMRs are ongoing, with 10 CMRs lasting > 3 months. As of August 3, 2020, common adverse events (52 pts) were CRS (63.5%), neutropenia (38.5%), and pyrexia (32.7%). CRS was mostly confined to C1: 24/50 pts had CRS after 2.5mg; 20/49 pts after 10mg; 2/16 and 8/32 pts had CRS after 16 and 30mg (C2D1), respectively. Grade [Gr] 1 and 2 CRS was reported in 18 (34.6%) and 12 (23%) pts, respectively; 3 pts had Gr 3 CRS; none had Gr 4/5 events (ASTCT 2019). Updated data, including biomarker data on baseline CD20 expression and CD8 levels in the tumor, will be presented. Conclusions: Updated data for glofitamab monotherapy SUD show higher preliminary response rates than previously reported in pts with R/R NHL who have failed multiple lines of therapy. CRS was mostly manageable, of low grade, and confined to the first cycle of treatment. Clinical trial information: NCT03075696.