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633 Relapse after First-Line Fixed Duration Ibrutinib + Venetoclax: High Response Rates to Ibrutinib Retreatment and Absence of BTK Mutations in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) with up to 5 Years of Follow-up in the Phase 2 Captivate Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Frontline Treatment With Targeted Agents in Patients With Chronic Lymphocytic Leukemia
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, CLL, Clinical Research, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Sunday, December 10, 2023: 5:00 PM

Paolo Ghia, MD, PhD1, William G. Wierda, MD, PhD2, Paul M. Barr, MD3, Thomas J. Kipps, MD, PhD4, Tanya Siddiqi, MD5*, John N. Allan, MD6, Zoë Hunter, PhD7*, Cathy Zhou, MS7*, Anita Szoke, MD7*, James P. Dean, MD, PhD8* and Constantine S. Tam, MD, MBBS9*

1Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
2The University of Texas MD Anderson Cancer Center, Houston, TX
3Wilmot Cancer Institute, University of Rochester, Rochester, NY
4UC San Diego Moores Cancer Center, Duarte, CA
5City of Hope National Medical Center, Duarte, CA
6Weill Cornell Medicine, Long Island City, NY
7AbbVie, North Chicago, IL
8Executive Medical Director and Global Development Lead, IMBRUVICA and Pediatrics (Oncology), AbbVie, North Chicago, IL
9Alfred Hospital and Monash University, Melbourne, VIC, Australia

Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of ibrutinib + venetoclax as first-line treatment for CLL/SLL in 2 cohorts: minimal residual disease (MRD)–guided randomized-discontinuation (MRD cohort) and Fixed Duration (FD cohort). Results from the FD cohort with 4 years of follow-up (Barr, ASCO 2023) showed 4-year progression-free survival (PFS) and overall survival (OS) rates of 79% and 98%, respectively. After completing fixed-duration treatment, ibrutinib-based retreatment was allowed per protocol in patients with an indication for treatment after experiencing progressive disease (PD). Here, we report retreatment outcomes in patients from the FD cohort or the MRD cohort placebo arm, as well as updated results with an additional year of follow-up (up to 5 years) from the FD cohort.

Methods: Patients aged ≤70 years with previously untreated CLL/SLL received 3 cycles of ibrutinib, then 12 cycles of combined ibrutinib + venetoclax (ibrutinib, 420 mg/day orally; venetoclax, standard 5-week ramp up to 400 mg/day orally). Response was assessed by investigators per International Workshop on CLL (iwCLL) 2008 criteria. Duration of response (DOR), PFS, and OS were estimated using Kaplan-Meier methodology. Per protocol, on-study retreatment included single-agent ibrutinib; patients with PD >2 years after treatment completion could be retreated with the FD regimen (3 cycles of ibrutinib + 12 cycles of ibrutinib + venetoclax).

Results: Of 202 patients treated with fixed-duration ibrutinib + venetoclax in the FD cohort (n=159) or the MRD cohort placebo arm (n=43), 53 have had PD to date (Table 1), with PD occurring >2 years after completion of treatment in the majority of patients (33/53 [62%]). Of the 40 patients with available samples at PD, one had an acquired resistance-associated mutation in BCL2 (A113G); no other patient had clinically relevant mutations in BTK, BCL2, or PLCG2. A total of 22 patients have initiated retreatment on study with single-agent ibrutinib. With a median time on retreatment of 17 months (range, 0–45), overall response rate (ORR) in 21 evaluable patients was 86% (with best responses of complete response [CR], n=1 [5%]; partial response [PR], n=17 [81%]; PR with lymphocytosis, n=1 [5%]; stable disease, n=1 [5%]; PD [Richter transformation], n=1 [5%]). The most frequent adverse events (AEs; occurrence ≥10%) during single-agent ibrutinib retreatment were COVID-19 (n=6, all grade 1/2), diarrhea (n=5), hypertension (n=4), and pyrexia (n=3). No dose reductions or discontinuations due to AEs occurred among retreated patients. Eighteen patients have not received subsequent treatment, 7 patients have initiated other subsequent therapies, and 6 patients have started retreatment with ibrutinib + venetoclax (time on retreatment, 5–15 months). Best responses in patients retreated with ibrutinib + venetoclax are CR, n=2; PR, n=3; and SD, n=1. Response data for the patient with BCL2 (A113G) is pending.

To date, with a median time on study of 56 months (range, 1–61) for patients in the FD cohort, the 54-month PFS and OS rates were 70% (95% CI, 62–77) and 97% (95% CI, 93–99), respectively. Best response rates remained unchanged from the 4-year follow-up analysis (CR, including CR with incomplete bone marrow recovery [CRi], 58%; ORR, 96%). In patients who achieved CR/CRi (n=92), median duration of CR/CRi was not reached; 90/92 patients (98%) achieved durable CR/CRi (lasting ≥12 cycles). PFS in patients with high-risk features was promising (Table 2), but it was numerically lower in the subset with del(17p)/mutated TP53 (54-month rate, 45% [95% CI, 25–64]). Serious AEs considered related to study treatment and second malignancies continued to be collected after completion of fixed-duration treatment. One AE of basal cell carcinoma occurred during this additional year of follow-up. In total, second malignancies have occurred in 8% of patients since completion of ibrutinib + venetoclax treatment.

Conclusion: Ibrutinib-based retreatment results in the CAPTIVATE study show promising responses in patients needing subsequent therapy after receiving this all-oral, once-daily fixed-duration regimen for first-line treatment of CLL/SLL. With up to 5 years of follow-up, fixed-duration ibrutinib + venetoclax continues to provide deep remissions with clinically meaningful PFS, including in patients with high-risk genomic features.

Disclosures: Ghia: BeiGene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Lilly/Loxo Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Wierda: Oncternal Therapeutics, Inc.: Research Funding; Genentech: Research Funding; Cyclacel: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssens Biotech: Research Funding; GSK/Novartis: Research Funding; GlaxoSmithKline: Research Funding; Nurix THerapeutics: Research Funding; Numab THerapeutics: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; Accutar Biotechnology: Research Funding; Janssens Biotech Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; KITE Pharma: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources. Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; TG therapeutics: Consultancy, Research Funding; Gilead: Consultancy; MEI Pharma: Consultancy. Kipps: California Institute for Regenerative Medicine (CIRM): Research Funding; Pharmacyclics/AbbVie: Honoraria, Other: Travel, Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Breast Cancer Research Foundation: Research Funding; Dava Oncology: Honoraria, Other: Travel; Curio Bioscience: Honoraria, Other: Travel; Johnson & Johnson: Honoraria, Other: Travel; Nexus Biopharma, inc.: Honoraria, Other: Travel; Janssen: Honoraria, Other: Travel; Genentech/Roche: Research Funding. Siddiqi: Ascentage Pharma: Research Funding; Pharmacyclics, LLC an AbbVie Company: Research Funding; Oncternal: Research Funding; TG therapeutics: Research Funding; Juno therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Allan: Lilly: Consultancy; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Lava Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics SA: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics LLC: Consultancy, Speakers Bureau; TG Therapeutics, Inc: Consultancy, Research Funding. Hunter: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Zhou: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Szoke: Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current holder of stock options in a privately-held company. Dean: Pharmacyclics LLC, an AbbVie Company: Current Employment, Current holder of stock options in a privately-held company. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding.

*signifies non-member of ASH