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Fixed-Dose, First-Line Ibrutinib/Venetoclax Combination Achieves Durable Remissions in CLL


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The combination of fixed-duration, first-line treatment with ibrutinib plus venetoclax achieved complete responses in more than half of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), based on the primary analysis of the fixed-dose cohort of the phase II CAPTIVATE study.1

Similarly high rates of overall survival and progression-free survival, secondary endpoints, were observed in the total study population and in high-risk patients with the fixed-dose combination.

“The primary endpoint was met, with a complete response rate of 56% in patients without deletion (17p). The complete response rate was 55% in the all-treated population, and the overall response rate was 96%,” stated lead author Paolo Ghia, MD, PhD, of Università Vita-Salute San Raffaelle and IRCCS Ospedale San Raffaele, Milan, Italy, at the 2021 ASCO Annual Meeting.

Paolo Ghia, MD, PhD

Paolo Ghia, MD, PhD

CAPTIVATE is a multicenter phase II study of first-line ibrutinib plus venetoclax in CLL. At the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, results from the minimal residual disease (MRD) cohort were presented. Undetectable MRD was achieved in more than two-thirds of patients with a fixed-duration of 12 cycles of treatment with the combination, and progression-free survival rates were greater than 95% regardless of subsequent randomized treatment.2

Study Details

The primary analysis of CAPTIVATE reported on the fixed-duration cohort of 159 patients with untreated CLL/SLL aged 70 or younger who received 3 cycles of the all-oral, once daily regimen of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Median age was 60 years. High-risk features included del(17p)/TP53 mutations in 27; del(17p) in 20; del(11q) in 28; complex karyotype in 31; and unmutated IGHV in 89. There were 139 patients (86%) without del(17p). Among 159 patients, 147 completed 12 cycles of ibrutinib plus venetoclax. The median time on study was 27.9 months, and the median treatment duration was 13.8 months. Median follow-up time after treatment cessation was 14 months.

The complete response rate was 56% in patients without del(17p) and 55% in all treated patients. These rates were consistent among high-risk subgroups, except for those with bulky disease, who had a complete response rate of 31%. The objective response rate in all treated patients and in those without del(17p) was 96%. “These responses represent a 40% improvement over the historical comparator FCR regimen in the CLL10 study,” Dr. Ghia stated.

Secondary Endpoints

Among the 88 patients who achieved complete response, 78 (89%) had durable responses lasting longer than 1 year. Among the 66 patients without del(17p) who achieved complete responses, 76 (87%) were durable lasting longer than 1 year. The rate of undetectable MRD in peripheral blood was 77% in all treated patients and 76% in those without del(17p); the rates of undetectable MRD in the bone marrow were 60% and 62%, respectively.

At 24 months, progression-free survival rate in patients without del(17p) was 96% and 95% in all treated patients. The 24-month overall survival rate was 98%—identical in all treated patients and those without del(17p). Median follow-up was 27.9 months.

“All of these results together support the idea of the combination of ibrutinib plus venetoclax as an all-oral, once daily, chemotherapy-free, fixed-duration treatment that may achieve deep responses and undetectable MRD in a vast majority of patients,” Dr. Ghia stated.

The phase III GLOW study is currently ongoing in an older population and includes a study arm of ibrutinib plus venetoclax. 

DISCLOSURE: The CAPTIVATE phase II study was funded by Pharmacyclics LLC.  Dr. Ghia has received honoraria from Abbvie, Acerta Pharma/AstraZeneca, Adaptive Biotechnologies, ArQule, BeiGene, Dynamo, Gilead Sciences, Janssen Oncology, Juno Therapeutics, Juno/Celgene/Bristol Myers Squibb, Lilly, MEI Pharma, MSD, Roche, and Sunesis Pharmaceuticals; has served in a consulting or advisory role for Abbvie, Acerta Pharma/AstraZeneca, Adaptive Biotechnologies, ArQule, BeiGene, Dynamo, Gilead Sciences, Janssen, Juno Therapeutics, Lilly, MEI Pharma, MSD, Roche, and Sunesis Pharmaceuticals; and has received research funding from Abbvie, AstraZeneca, Gilead Sciences, Janssen Oncology, Novartis, and Sunesis Pharamceuticals.

REFERENCES

1. Ghia P, et al: 2021 ASCO Annual Meeting. Abstract 7501. Presented June 6, 2021.

2. Wierda WG, et al: 2020 ASH Annual Meeting & Exposition. Abstract 123. Presented December 5, 2020.


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Invited discussant Jacqueline C. Barrientos, MD, MS, of Northwell Health Cancer Institute, Zucker School of Medicine at Hofstra/Northwell in Great Neck, New York, noted that, although both ibrutinib and venetoclax have shown superior results to chemotherapy, each drug is associated with toxicity.

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