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CONFERENCE UPDATE: EHA 2025

Sustained efficacy of fixed-duration ibrutinib + venetoclax in CLL/SLL: Final analysis of the phase 2 CAPTIVATE study

26 Sep 2025

STUDY DESIGN

The phase 2 CAPTIVATE study evaluated the first-line use of all-oral, once-daily ibrutinib (a BTK inhibitor) + venetoclax (a BCL-2 inhibitor) in patients with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), across two cohorts: a minimal residual disease (MRD)-guided randomized discontinuation cohort and a fixed-duration (FD) cohort.¹ In earlier analyses with up to 5.5 years of follow-up, the FD regimen demonstrated sustained progression-free survival (PFS) at the 5-year landmark, including among patients with high-risk genomic alterations.¹ With up to 7 years of follow-up, the final analysis of this phase 2 trial provides long-term outcomes, with a primary focus on the FD cohort.¹

The study enrolled previously untreated CLL/SLL patients aged ≤70 years (n=202).¹ All participants received a three-cycle lead-in of ibrutinib monotherapy (420mg once daily), followed by twelve cycles of combined ibrutinib (420mg once daily) and venetoclax (oral ramp-up over five weeks to 400mg once daily).¹ Focusing on the FD cohort and the placebo arm of the MRD-guided cohort, all patients in the FD cohort (n=159) completed the planned 15-month regimen and discontinued therapy, while patients in the MRD cohort placebo arm with confirmed undetectable minimal residual disease (uMRD) (n=43) received one additional cycle of ibrutinib + venetoclax during randomization, followed by placebo treatment.¹ Among patients with confirmed progressive disease (PD), a total of 36 who met iwCLL criteria for retreatment received either single-agent ibrutinib (n=25) or fixed-duration ibrutinib + venetoclax (n=11).¹ Notably, in both the total pooled population and the FD cohort, approximately 60% of patients harbored high-risk unmutated IGHV (uIGHV), while del(17p) or TP53 mutations─ also considered high-risk genomic alterations were present in 14% of the total population and 17% of the FD cohort.¹

Key outcomes assessed included PFS, overall survival (OS), impact of del(17p)/mutated TP53 and IGHV status on long-term PFS, and time to next treatment (TTNT) with up to 7 years of follow-up.¹

FINDINGS

Efficacy outcomes :

Key outcomes assessed included PFS, OS, impact of del(17p)/mutated TP53 and IGHV status on long-term PFS, and TTNT with up to 5 years of follow-up¹

Median PFS was not reached in either group. Among the total pooled population (n=202), the 5.5-year PFS rate was 66% (95% CI: 58-72), while in the FD cohort (n=159), the 5.5-year PFS was slightly lower at 60% (95% CI: 52-68)¹

OS rates at 5.5 years were high in both groups, reaching 97% (95% CI: 93-99) in the total population and 96% (95% CI: 91-98) in the FD cohort, with median OS not reached in either¹

Freedom from next-line therapy at 5.5 years was 73% (95% CI: 66-79) overall and 69% (95% CI: 61-76) in the FD cohort¹

uMRD at the end of treatment strongly predicted long-term PFS, regardless of high-risk genomic status¹

In the retreatment analysis, the best overall response, defined as complete response, nodular partial response, or partial response, was achieved in 76% of patients retreated with ibrutinib alone and 82% with the ibrutinib + venetoclax combination. At median follow-up durations of 28.4 months and 15.2 months, respectively, the 2-year PFS and OS rates for single-agent ibrutinib were 91% and 96%, while the combination therapy achieved 100% PFS and OS at 1 year¹

Safety :

No new safety signals were observed during retreatment, relative to the safety profile of first-line treatment with single agent ibrutinib or FD ibrutinib + venetoclax¹

Over the study period, including any retreatment received on study, secondary malignancies occurred in 24 patients; non-melanoma skin cancers occurred in 16 patients ,and other cancers in 14 patients¹

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