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123 Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation I
Hematology Disease Topics & Pathways:
Leukemia, Biological, Diseases, Therapies, Combinations, Lymphoid Malignancies, TKI
Saturday, December 5, 2020: 9:30 AM

William G. Wierda, MD, PhD1*, Constantine S. Tam, MD2, John N. Allan, MD3, Tanya Siddiqi, MD4*, Thomas J. Kipps, MD, PhD5, Stephen Opat, FRACP, FRCPA, MBBS6*, Alessandra Tedeschi, MD7*, Xavier C. Badoux, MBBS, FRACP, FRCPA8, Bryone J. Kuss, MBBS, PhD, FRACP, FRCPA9*, Sharon Jackson, MD10*, Carol Moreno, MD, PhD11*, Ryan Jacobs, MD12*, John M. Pagel, MD, PhD13, Ian W. Flinn, MD, PhD14, Cathy Zhou, MS15*, Edith Szafer-Glusman, PhD15*, Joi Ninomoto, PharmD15*, James P. Dean, MD, PhD15, Danelle F. James, MD, MAS15 and Paolo Ghia, MD, PhD16

1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
2Peter MacCallum Cancer Centre & St. Vincent’s Hospital and the University of Melbourne, Melbourne, VIC, Australia
3Weill Cornell Medicine, New York, NY
4City of Hope National Medical Center, Duarte, CA
5University of California, San Diego, Moores Cancer Center, La Jolla, CA
6Monash University, Clayton, VIC, Australia
7ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
8Ministry of Health, Kogarah, NSW, Australia
9Flinders University and Medical Centre, Bedford Park, SA, Australia
10Middlemore Hospital, Auckland, New Zealand
11Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
12Levine Cancer Institute, Charlotte, NC
13Fred Hutchinson Cancer Research Center, Seattle, WA
14Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
15Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
16Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy

Background: Ibr is an established standard of care in CLL and is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit in randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). The synergistic combination of Ibr + Ven (oral inhibitor of BCL2) has been shown to mobilize and clear CLL cells from multiple disease compartments leading to deep responses, providing a rationale to evaluate time-limited treatment (Jain et al. NEJM 2019). CAPTIVATE (PCYC-1142) is a multicenter phase 2 study (NCT02910583) of first-line Ibr + Ven with 2 cohorts: Minimal Residual Disease (MRD) and Fixed-Duration (FD). For both cohorts, patients (pts) received 3 cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Pts in the MRD cohort were randomized by MRD status to placebo or further treatment. In the pre-randomization phase of the MRD cohort, Ibr + Ven resulted in high rates of undetectable MRD (uMRD) in both peripheral blood (PB; 75%) and bone marrow (BM; 72%), with concordant uMRD results in 93% of pts with matched samples (Tam, ASH 2019). We present primary results from the MRD-guided randomization phase of the MRD cohort, evaluating whether this regimen allows for treatment-free remission in the setting of uMRD.

Methods: Pts <70 years with previously untreated CLL/SLL requiring therapy received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/day PO; Ven ramp-up to 400 mg/day PO). Pts with Confirmed uMRD (defined as uMRD serially over ≥3 cycles, and in both PB and BM) after 12 cycles of Ibr + Ven were randomized 1:1 to receive double-blind treatment with placebo or Ibr; pts who did not meet the definition of Confirmed uMRD were randomized 1:1 to receive open-label treatment with Ibr or continued Ibr + Ven. Primary endpoint was 1-year DFS rate in the Confirmed uMRD pts randomized to placebo vs Ibr; DFS was defined as survival without progression or MRD relapse. Key secondary endpoints were rates of uMRD (<10-4 by 8-color flow cytometry), response per iwCLL, progression-free survival (PFS), and adverse events (AEs).

Results: 164 pts were enrolled in the MRD cohort. Median age was 58 years (range, 28-69); baseline high-risk features included del(17p) in 16% and del(11q) in 17%; del(17p) or TP53 mutation in 20%; complex karyotype in 19%; and unmutated IGHV in 60%. Median time on study was 31.3 mo (range, 15.0-41.0). 90% of pts completed planned treatment with 3 cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Of 149 randomized patients, 86 (58%) with Confirmed uMRD (100% uMRD in PB and BM) were randomized to placebo (n=43) or Ibr (n=43). 63 of 149 pts (42%) did not achieve Confirmed uMRD as defined above and were randomized to Ibr (n=31) or Ibr + Ven (n=32); uMRD rates at randomization in this group were 48% in PB and 32% in BM. In the Confirmed uMRD group, 1-year DFS rate was not significantly different for pts randomized to placebo (95.3%; 95% CI 82.7-98.8) versus Ibr (100%; 95% CI 100-100) (P=0.1475; Figure). In the group without Confirmed uMRD who were randomized to continue Ibr or Ibr + Ven, uMRD rates improved to 57% in PB and 54% in BM during the overall study period. 30-mo PFS rates were >95% across all randomized arms (Table). Full results of endpoints by randomized arms will be presented. The median duration of treatment was 28.6 mo (range, 0.5-39.8) with Ibr and 12.0 mo (range, 0.8-34.1) with Ven. AEs were primarily grade 1/2 and mostly occurred in early cycles of Ibr + Ven, with modest differences by randomized treatment arm. During the overall study period across all-treated pts (with median treatment duration 29 mo), most common grade 3/4 AEs (≥5% of pts) were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%).

Conclusions: First-line Ibr + Ven treatment is an all-oral, once-daily, chemotherapy-free regimen that confers high rates of PB and BM uMRD in pts with CLL, and a 90% reduction in high-risk TLS monitoring (Siddiqi, EHA 2020). The 1-year DFS in pts randomized to placebo after Ibr + Ven combination was similar to that of pts continuing Ibr, supporting a fixed-duration treatment that offers treatment-free remissions in pts with CLL/SLL. The depth of response achieved with this regimen is reflected in the 30-mo PFS rate of ~95% across all treated pts. The safety profile of Ibr + Ven was consistent with known AEs for Ibr and Ven, and no new safety signals emerged.

Disclosures: Wierda: Genzyme Corporation: Consultancy; GlaxoSmithKline, Novartis, AbbVie, Genentech, Karyopharm, Pharmacyclics LLC, an AbbVie Company, Acerta Pharma, Gilead Sciences, Juno Therapeutics, KITE Pharma, Sunesis, Miragen, Oncternal Therapeutics, Cyclacel, Loxo Oncology, Janssen, and Xencor: Research Funding. Tam: BeiGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Allan: AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Janssen, AstraZeneca, and AbbVie: Honoraria. Siddiqi: Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; PCYC: Membership on an entity's Board of Directors or advisory committees; Astrazenca: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; AstraZeneca: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member. Kipps: AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Opat: Amgen: Research Funding; Epizyme: Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; AstraZenca: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tedeschi: Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Badoux: AbbVie: Honoraria, Other: Travel/accommodations/expenses. Kuss: Roche, Janssen, Gilead, and AbbVie: Speakers Bureau; Janssen, AbbVie, Roche, Mundipharma, Takeda, Merck, and Gilead: Consultancy, Honoraria. Jackson: AbbVie: Consultancy; Roche: Other: Travel/accommodations/expenses. Moreno: Janssen: Speakers Bureau; AbbVie and Janssen: Research Funding; Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy. Jacobs: AbbVie, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, and Verastem: Consultancy; TG Therapeutics and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Janssen, Sanofi, and Genentech: Speakers Bureau. Pagel: Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy. Flinn: Curis: Research Funding; Curio Science: Consultancy; Calithera Biosciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Nurix Therapeutics: Consultancy; Celgene: Research Funding; Constellation Pharmaceuticals: Research Funding; MorphoSys: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Merck: Research Funding; Loxo: Research Funding; Forty Seven: Research Funding; Takeda: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Genentech, Inc.: Research Funding; Infinity Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Pfizer: Research Funding; Great Point Partners: Consultancy; IGM Biosciences: Research Funding; F. Hoffmann-La Roche: Research Funding; Kite Pharma: Consultancy, Research Funding; ArQule: Research Funding; Incyte: Research Funding; Agios: Research Funding; Forma Therapeutics: Research Funding; Novartis: Research Funding; Unum Therapeutics: Consultancy, Research Funding. Zhou: AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Szafer-Glusman: Pharmacyclics LLC, an AbbVie Company: Current Employment. Ninomoto: AbbVie, Amgen, and Celgene: Current equity holder in publicly-traded company; AbbVie: Current Employment. Dean: AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. James: Pharmacyclics LLC, an AbbVie Company: Current Employment, Other: Leadership, Patents & Royalties: and other intellectual property; AbbVie: Current equity holder in publicly-traded company. Ghia: ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

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

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