First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study
Authors: Ghia Paolo , Allan John N. , Siddiqi Tanya , Kipps Thomas J. , Kuss Bryone J. , Opat Stephen , Flinn Ian W. , Badoux Xavier C. , Tedeschi Alessandra , Gonzalez-Barca Eva , Pagel John M. , Jacobs Ryan , Barrientos Jacqueline , Szafer-Glusman Edith , Zhou Cathy , Ninomoto Joi , Dean James P. , Tam Constantine S. , Wierda William G. 
Published: November 2021

Abstract
Background : Ibr, an established standard of care in CLL, is a once-daily Bruton tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival benefit shown in multiple randomized phase 3 studies in first-line CLL. Ven, an oral BCL-2 inhibitor approved as a single agent or combined with rituximab or obinutuzumab for CLL treatment, achieves high rates of undetectable MRD (uMRD). Ibr and Ven, with distinct and complementary mechanisms of action, work synergistically to mobilize CLL cells from lymph nodes and lymphoid niches, enhance cell killing, and eliminate distinct CLL cell populations. CAPTIVATE (PCYC-1142; NCT02910583) is an international, multicenter phase 2 study evaluating first-line Ibr + Ven in 2 cohorts: MRD and Fixed-Duration (FD). Patients (pts) first received 3 cycles of Ibr followed by 12 cycles of combined Ibr + Ven. In the primary analysis of the MRD cohort, pts with Confirmed uMRD who after fixed duration treatment were randomized to placebo or continued Ibr had similar post-randomization 1-year DFS rates (95% and 100%, respectively) (Wierda, ASH 2020). Two-year post-randomization results are presented.
Methods : Pts aged &lt;70 years with previously untreated CLL received 3 cycles of Ibr lead-in then 12 cycles of combined Ibr + Ven (oral Ibr 420 mg/day; oral Ven ramp-up to 400 mg/day). During cycle 16, pts with Confirmed uMRD (defined as uMRD serially over ≥2 assessments ≥3 mo apart, and in both peripheral blood [PB] and bone marrow [BM]) were randomized 1:1 to receive double-blind treatment with placebo or single-agent Ibr. Pts who did not meet the definition of Confirmed uMRD were randomized 1:1 to receive open-label treatment with single-agent Ibr or continued Ibr + Ven. Endpoints presented include 2-year DFS rate (defined as survival without progression [PD] or MRD relapse post-randomization) in pts with Confirmed uMRD randomized to placebo vs Ibr, rates of uMRD (&lt;10 -4 by 8-color flow cytometry), investigator-assessed best response per iwCLL, investigator-assessed PFS, and adverse events (AEs).
Results : 164 pts were enrolled. Median age was 58 years (range, 28-69). High-risk features included unmutated IGHV (60% of pts), del(17p)/TP53 mutation (20%), complex karyotype (19%), and del(11q) without del(17p) (17%). After 12 cycles of Ibr + Ven, 149 pts were randomized: Confirmed uMRD to placebo (n=43) or Ibr (n=43); without Confirmed uMRD to Ibr (n=31) or Ibr + Ven (n=32). Median overall follow-up was 38.2 mo (range, 15.0-47.9); median post-randomization follow-up was 24.0 mo (range, 5.8-33.1). In pts with Confirmed uMRD randomized to placebo versus Ibr, no new DFS events occurred since the primary analysis; 2-year DFS rates post-randomization remained unchanged at 95% (placebo) vs 100% (Ibr), for a 4.7% difference (95% CI -1.6-10.9) and overall log-rank P=0.1573 (Figure 1). In the placebo and Ibr arms post-randomization, modest improvements were observed in complete response (CR) rates, including CR with incomplete bone marrow recovery (CRi) (Figure 2). Estimated 36-mo PFS rates were 95% with placebo and 100% with Ibr. In pts without Confirmed uMRD randomized to Ibr vs Ibr + Ven, greater improvements in best uMRD rates and CR/CRi rates were observed with Ibr + Ven than with Ibr post-randomization (Figure 2). Estimated 36-mo PFS rates were 97% with both Ibr and Ibr + Ven. Median treatment duration was 36.8 mo (range, 0.5-47.9) in all pts (N=164). Modest differences in AEs were observed across treatment arms post-randomization. During the overall study period across all-treated pts, the most frequent grade 3/4 AEs were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). With up to 48 mo of treatment, AEs led to discontinuation of Ibr or Ven in 13% of pts; no new safety signals emerged.
Conclusions : First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free regimen that provides deep responses in pts with CLL. With an additional year of follow-up and no new MRD relapses, PDs or deaths in pts with confirmed uMRD, the 2-year DFS rate in the MRD-guided placebo arm remained high at 95% while 3-year PFS rates were ≥95% across all randomized treatment arms. The results in pts with Confirmed uMRD support the potential for treatment-free remission with fixed-duration treatment, including in pts with high-risk features. High rates of uMRD were achieved; the safety profile of Ibr + Ven was consistent with known safety profile for each agent.
Figure 1 Figure 1.

Disclosures
Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding. Allan: Celegene: Research Funding; AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Janssen Biotech Inc, TG Therapeutics Inc.: Research Funding; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; Epizyme: Consultancy; AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Janssen Biotech Inc, Pharmacyclics LLC: Consultancy; AbbVie Inc, Ascentage Pharma, Epizyme, Genentech, a member of the Roche Group, Janssen Biotech Inc, Pharmacyclics LLC: Other: Advisory Committee. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Kipps: Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Kuss: Commonwealth Serum Laboratories: Other: Stock or other ownership; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Roche Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen: Speakers Bureau. Opat: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: 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; Celgene: 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; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Flinn: Portola Pharmaceuticals: Other: All 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; Loxo: Other: All 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; Juno Therapeutics: Consultancy, Other: All consultancy and 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; Seagen: Consultancy, Other: All consultancy and 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; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: 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; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: 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; Novartis: 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; MorphoSys: Consultancy, Other: All consultancy and 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; BeiGene: Consultancy, Other: All consultancy and 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; Acerta Pharma: Other: All 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; IGM Biosciences: Other: All 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; Curis: 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; Karyopharm Therapeutics: Other: All 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; Gilead Sciences: 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Agios: 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; Rhizen Pharmaceuticals: 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; 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; Trillium Therapeutics: 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. Badoux: Janssen: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Tedeschi: Beigene: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Gonzalez-Barca: Kiowa: Consultancy, Speakers Bureau; Eusapharma: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Speakers Bureau; Roche: Other: Travel, Accommodations, Expenses; AbbVie: Other: Travel, Accommodations, Expenses, Speakers Bureau. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Incyte/MorphoSys: Consultancy. Jacobs: AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Verastem: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; Genentech: Consultancy; AbbVie: Consultancy, Speakers Bureau. Szafer-Glusman: AbbVie: Current Employment, Other: Stock or other ownership. Zhou: AbbVie: Current Employment, Other: Stock and other ownership. Ninomoto: AbbVie: Current Employment, Other: Stock or other ownership. Dean: Pharmacyclics: Current Employment, Other: Stock or other ownership; AbbVie: Other: Stock Ownership. Tam: Pharmacyclics: Honoraria; BeiGene: Consultancy, Honoraria; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Wierda: Janssen: Research Funding; AstraZeneca: Research Funding; GSK/Novartis: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Loxo Oncology, Inc.: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Cyclacel: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding.

OffLabel Disclosure:
Ibrutinib in combination with venetoclax is not approved in any indication.