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Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with

Background Genomic abnormalities such as del(17p)/TP53 mutation, del(11q), and unmutated IGHV are risk factors that predict inferior outcomes with chemoimmunotherapy (CIT) in patients (pts) with CLL/SLL (Byrd J Clin Oncol 2006). Mutations in BIRC3, NOTCH1, SF3B1, and XPO1 have also been associated with poor outcomes with CIT in pts with CLL (Foa Haematologica 2013; Jain Am J Hematol 2016). Ibrutinib (ibr) is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival (OS) benefit shown in multiple randomized phase 3 studies versus established therapies in pts with previously untreated or relapsed/refractory CLL/SLL. Superior outcomes were demonstrated with ibr-based therapy versus comparators in the overall population, and in pts with high-risk disease features, such as TP53 aberrations, del(11q), and/or unmutated IGHV in the RESONATE-2 study of first-line single-agent ibr (Burger Leukemia 2020) and in the iLLUMINATE study of first-line ibr-obinutuzumab (Moreno Lancet Oncol 2019). In pts with relapsed/refractory CLL/SLL who were treated with ibr, mutations in BIRC3, NOTCH1, SF3B1, or XPO1 had no significant impact on the PFS benefit conferred by ibr (Byrd Blood 2019). To better understand outcomes in pts with previously untreated CLL with various high-risk genomic features, including integrated FISH cytogenetics and single gene mutations, we performed a pooled analysis of two phase 3 studies of ibr-based therapy in the first-line treatment of CLL/SLL (RESONATE-2 and iLLUMINATE). Methods In RESONATE-2 (NCT01722487), pts aged ≥65 years without del(17p) were randomized to single-agent ibr or chlorambucil (clb). In iLLUMINATE (NCT02264574), pts aged ≥65 years, or Results The pooled analysis included 498 pts treated with first-line ibr-based or clb-based therapy (n=249 each) with median follow-up of 49.1 mos (range, 0.1-78.7). Ibr-based therapy significantly improved ORR and PFS vs comparator (clb-based) therapy. At 42 mo, PFS rates were significantly higher across high-risk genomic subgroups in ibr-treated pts (63-82%) compared with clb-treated pts (6-34%), and consistent PFS benefit with ibr was observed across all high-risk genomic subgroups (Figure). When comparing ibr-treated pts with specified high-risk genomic features vs those without, PFS and ORR were comparable in the different subgroups, including pts with unmutated vs mutated IGHV (PFS HR, 1.79, 95% CI 0.99-3.24) or mutated vs not mutated NOTCH1 (PFS HR, 1.05, 95% CI 0.65-1.69) (Table). Improved outcome was also noted for pts with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category per Rossi 2013 (HR 1.05, 95% CI 0.54-2.04). At a median duration of ibr treatment of 35.7-43.8 mo across these high-risk subgroups, there were no meaningful differences in the rates of treatment-emergent adverse events (AEs) of any grade or grade ≥3 AEs compared to those of the overall population. Conclusions This integrated analysis of pts undergoing first-line ibr-based treatment, with up to 79 mo follow up, demonstrated similar PFS and ORR for ibr-treated pts with or without high-risk genomic features, and confirmed significant PFS and ORR benefits with ibr-based therapy versus clb (± obinutuzumab). This analysis across two phase 3 studies demonstrated the efficacy of first-line ibr-based treatment irrespective of cytogenetic and mutational risk features, including those with unmutated IGHV, NOTCH1 mutation, and those with the highest risk classification of del(17p)/TP53 mutation/BIRC3 mutation. Disclosures Burger: Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Other: Travel/accomodations/expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BeiGene, Gilead, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Robak:BioGene: Honoraria, Research Funding; UCB: Honoraria, Research Funding; UTX-TGR: Research Funding; Bristol Meyers Squibb: Research Funding; Momenta: Consultancy; Medical University of Lodz: Current Employment; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; Pfizer: Research Funding; GSK: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Demirkan:AbbVie, Amgen, AstraZeneca, and Roche: Consultancy; AbbVie, AstraZeneca, Janssen, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Amgen, and Janssen: Speakers Bureau; AbbVie, Amgen, Janssen, and Pfizer: Other: Travel/accommodations/expenses. Bairey:AbbVie: Consultancy; Janssen: Consultancy, Research Funding. Moreno:Janssen: Speakers Bureau; AbbVie and Janssen: Research Funding; Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy. Simpson:BeiGene: Current Employment, Current equity holder in publicly-traded company; AbbVie and Janssen: Honoraria, Other: Travel/accommodations/expenses; AbbVie, Acerta, Amgen, BeiGene, Celgene, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, Sanofi, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Dai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie, Bristol-Myers Squibb, Exelixis, Gilead, GlaxoSmithKline, and Revance: Current equity holder in publicly-traded company. Cheung:Pharmacyclics LLC, an AbbVie Company: Current Employment, Patents & Royalties: and other intellectual property; AbbVie and Eli Lilly: Current equity holder in publicly-traded company. Kwei:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Gilead: Current equity holder in publicly-traded company. Lal:Pharmacyclics LLC, an AbbVie Company: Current Employment; The Permanente Medical Group (spouse): Current Employment; AbbVie, Clovis, Gilead Sciences, Infinity, Reviva Pharmaceuticals, and The Permanente Medical Group: Current equity holder in publicly-traded company. Hsu:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Kipps:AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company: Consultancy. Tedeschi: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; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AbbVie: Consultancy, 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.

Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) benefit demonstrated in 5 randomized phase 3 studies in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) compared with standard-of-care chemotherapy and/or immunotherapy (RESONATE, RESONATE-2, iLLUMINATE, Alliance 041202, and ECOG 1912), and significant overall survival (OS) benefit in 3 of these studies. To understand how treatment with single-agent ibrutinib in earlier lines impacts patient outcomes, we evaluated long-term follow-up data from RESONATE and RESONATE-2 to compare efficacy and safety by number of prior lines of therapy. Methods : This integrated analysis included patients treated with single-agent ibrutinib in the first-line (RESONATE-2, NCT01722487) and relapsed/refractory (R/R; RESONATE, NCT01578707) settings. R/R patients were grouped by number of prior lines of therapy (1-2 vs ≥3). Patients with del(17p) were excluded from this analysis given their exclusion from RESONATE-2. Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV. Outcomes included investigator-assessed PFS and objective response rate (ORR), OS, and safety. Results : This analysis of 271 patients included 136 patients in the first-line and 135 patients in the R/R groups (1-2 prior: n=68; ≥3 prior: n=67). Patients in the first-line group were older (median age [range], 73 years [65-89]) than those with 1-2 prior lines (65 years [30-86]) and ≥3 prior lines (67 years [44-83]). The proportion of patients with high-risk prognostic features was lower in the first-line group (first-line: 54%; 1-2 prior: 81%; ≥3 prior: 76%). Median follow-up was 59.8 months for first-line, 66.2 months for 1-2 prior, and 65.1 for ≥3 prior. Median PFS was not reached (NR) for first-line or 1-2 prior lines and was 40.1 months for ≥3 prior lines (Figure 1A). A greater proportion of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (first-line: 70%; 1-2 prior: 60%; ≥3 prior: 33%). First-line treatment resulted in a 34% reduction in risk of disease progression or death compared to 1-2 prior lines (HR: 0.66 [95% CI, 0.40-1.09]). PFS was significantly prolonged for first-line vs ≥3 prior lines (HR: 0.32 [95% CI, 0.21-0.49]) and 1-2 prior vs ≥3 prior lines (HR: 0.48 [95% CI, 0.30-0.77]). For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87]). Median OS for the overall population was NR (range, 0.10+-66.04+) for first-line, NR (5.98-71.56+) for 1-2 prior, and 67.4 months (1.15-69.78+) for ≥3 prior lines. The ORR was 91%, 94%, and 82% for first-line, 1-2 prior, and ≥3 prior lines, respectively. The CR rate (CR+CR with incomplete marrow recovery) was highest for the first-line group (first-line: 30%; 1-2 prior: 12%; ≥3 prior: 10%). At the time of analysis, 58% of patients remain on ibrutinib treatment in the first-line group. Prior to study closure, 38% of patients with 1-2 prior and 18% of patients with ≥3 prior lines remained on ibrutinib treatment. In the overall population, 8 patients (6%) in the first-line group discontinued due to progressive disease while it was the most common reason for discontinuation for patients with 1-2 (n=15, 22%) and ≥3 prior lines (n=25, 37%). Across all three groups, 52 patients (19%) discontinued due to adverse events (AEs) (first-line: n=29, 21%; 1-2 prior: n=13, 19%; ≥3 prior: n=10, 15%). AEs leading to dose reduction occurred in 20% of first-line, 13% of 1-2 prior, and 22% of ≥3 prior lines. Conclusions : Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs. Disclosures Barr: Gilead: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, 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; BeiGene: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy. Mulligan:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Clinical Trial participant, Research Funding, Speakers Bureau; Commonwealth Serum Laboratories (CSL): Other: Clinical Trial participant; Sanofi-Aventis: Other: Clinical Trial participant; Acerta: Other: Clinical Trial participant. Dai:AbbVie: Equity Ownership; Celgene: Equity Ownership; Exelixis: Equity Ownership; Gilead: Equity Ownership; GSK: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Amaya-Chanaga:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Dean:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. o'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy.