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Altres ajuts: Pharmacyclics LLC; AbbVie Company. Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features. Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).

Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK) approved in the United States and European Union for adult patients with CLL [1], has helped shift the treatment par...

iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinutuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P0.0001). The best overall rate of undetectable minimal residual disease (0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of progression- free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574.

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

Objective: Report RESONATE-2 phase 3 study extended long-term follow-up of first-line ibrutinib vs chlorambucil in older patients with CLL/SLL. Methods: Patients (≥65 years [y]) with previously untreated CLL/SLL (without del[17p]) were randomly assigned 1:1 to once-daily ibrutinib 420 mg, until disease progression (PD) or unacceptable toxicity (n=136); or chlorambucil 0.5–0.8 mg/kg, up to 12 cycles (n=133). Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for patients treated with ibrutinib vs chlorambucil (HR 0.160 [95% CI: 0.111–0.230]). At 6.5y, PFS was 61% vs 9% for ibrutinib vs chlorambucil. PFS benefit was observed consistently, including ibrutinib-treated patients with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). With ibrutinib, 6.5y OS was 78%; ORR was 92%, and complete response (CR/CRi) rate increased to 34%. Ongoing rates of grade ≥3 AEs of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage in 5–7y. One patient (1%) had dose reduction due to grade ≥3 AEs during years 5–6/6–7. Of 31 patients with dose reductions due to any-grade AEs over full follow-up, 22 (71%) had AE resolution/improvement. Primary reason for discontinuation was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were 3% (n=2) in 5–6y and none in 6–7y. With up to 7y of follow-up, 47% of patients remain on single-agent ibrutinib. Conclusions: Long-term RESONATE-2 data demonstrate sustained PFS and OS benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. Responses continued to deepen over time. Rates of grade ≥3 AEs of interest continued to be low with rare further discontinuations and dose reductions due to AEs; most AEs leading to dose reduction resolved/improved. Ibrutinib remains well tolerated with no new safety signals. Funding: Pharmacyclics LLC, an AbbVie Company.

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.

7523 Background: Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 studies versus established therapies in patients (pts) with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Extended long-term follow-up data for the RESONATE-2 study of first-line ibrutinib vs chlorambucil in older pts with CLL/SLL are reported. Methods: In the phase 3 RESONATE-2 study, older pts (≥65 years [y]) with previously untreated CLL/SLL and without del(17p) (N=269) were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression (PD) or unacceptable toxicity (n=136) or chlorambucil 0.5–0.8 mg/kg up to 12 cycles (n=133). Outcomes included PFS, OS, overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for pts treated with ibrutinib vs chlorambucil (hazard ratio [HR] 0.160 [95% confidence interval (CI): 0.111–0.230]). At 6.5y, PFS was 61% in pts treated with ibrutinib vs 9% in pts treated with chlorambucil. This PFS benefit was observed across all subgroups, including in ibrutinib-treated pts with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). OS at 6.5y was 78% with ibrutinib treatment. ORR was 92% for ibrutinib-treated pts with complete response (CR/CRi) rate increasing to 34% with this follow-up. Ongoing rates of grade ≥3 adverse events (AEs) of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage occurred in 5–7y. Dose reductions due to grade ≥3 AEs occurred in 1% (n=1) of pts during the 5–6y and 6–7y intervals. Across full follow-up, 31 pts had dose reductions due to any-grade AEs of whom 22/31 (71%) had resolution or improvement the AE. Primary reason for discontinuations in 5–7y was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were seen in 3% (n=2) of pts from 5–6y and none in 6–7y. With over 7y of follow-up, 47% of pts remain on single-agent ibrutinib. Conclusions: Extended long-term data from RESONATE-2 demonstrate the sustained PFS and OS benefit of first-line ibrutinib treatment for pts with CLL, including for pts with high-risk genomic features. Responses continue to deepen over time. Rates of grade ≥3 AEs of interest continued to be low at up to 7y follow-up and further discontinuations and dose reductions due to AEs were rare; most AEs leading to dose reduction resolved or improved. Ibrutinib remains well tolerated with no new safety signals observed. Clinical trial information: NCT01722487, NCT01724346.

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.

7510 Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr >4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.

7510 Background: Ibr, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is FDA-approved for all pts with CLL/SLL. We report updated safety and efficacy results with up to 4 y follow-up from the ph III RESONATE trial of ibr vs ofatumumab (ofa). Methods: Pts had ≥1 prior therapy. Pts received 420 mg ibr PO until PD or ofa up to 24 wks. At interim analysis (median 9 mo follow-up), the DMC declared superiority of ibr vs ofa for PFS and OS, and ibr access was recommended for all ofa pts. Long-term follow-up efficacy endpoints are per investigator assessment. Ofa pts were censored at crossover for OS. Results: 391 pts were randomized to receive ibr (n = 195) or ofa (n = 196). Median age was 67 y (40% ≥70 y); 57% had Rai stage III/IV. With median follow-up of 44 mo (53 mo max) for ibr arm, PFS was significantly longer for ibr vs ofa (median NR vs 8 mo, [HR 0.133; P< 0.0001]; 3-y PFS 59% vs 3%) with significant benefit across subgroups. PFS with ibr for del11q subgroup trended to have the most favorable outcome; however, PFS was not statistically different for pts with del17p or del11q or without these FISH abnormalities. At analysis, with the majority of pts (68%) randomized to ofa crossing over to ibr, OS was longer for ibr vs ofa (median OS NR for either arm). The OS rate for ibr at 3 y was 74%. ORR for ibr was 91% with CR/CRi rates (now 9%) increasing over time. Baseline cytopenias improved with extended ibr therapy for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). AE profile of ibr was consistent with previous reports. Major hemorrhage, Gr ≥3 atrial fibrillation, and Gr ≥3 hypertension occurred in 6%, 6%, and 8% of pts, respectively, over a follow-up of up to 4 y. Incidence of most Gr ≥3 AEs decreased from y 1 vs y 2-3: neutropenia- 18% vs 8%; pneumonia- 11% vs 4%; atrial fibrillation- 4% vs 2%, respectively. Discontinuations were most frequently PD (27%) and AE (12%). At analysis, 90 ibr pts (46%) continue ibr on study. Conclusions: Long-term treatment with ibr in this international ph III RESONATE study is tolerable and continues to show sustained PFS and OS regardless of high-risk cytogenetics. Ph III results in relapsed del17p and del11q pts compare favorably to prior ph II reports. Clinical trial information: NCT01578707.