Fixed-Duration Ibrutinib Plus Venetoclax Shows Long-Term Efficacy in First-Line CLL/SLL Treatment

Fixed-duration, first-line ibrutinib (Imbruvica; Janssen Biotech) plus venetoclax (Venclexta; AbbVie and Genentech) demonstrated durable progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) with high-genomic features. The data from the phase 2 CAPTIVATE study (NCT02910583) were presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹

3D visualization of white blood cells | Image Credit: © stockdevil - stock.adobe.com

Patients 70 years and under received 3 lead-in cycles of ibrutinib at a dose of 420 mg daily followed by 12 cycles of ibrutinib plus venetoclax, with venetoclax administered in a 5-week ramp-up to 400 mg daily. In the minimal residual disease (MRD) cohort placebo arm, patients could receive up to 13 cycles. Retreatment was available with single-agent ibrutinib or ibrutinib plus venetoclax for those with progressive disease (PD) over 2 years after completing initial therapy.²

A total of 202 patients completed the FD ibrutinib plus venetoclax regimen: 159 in the FD cohort and 43 in the MRD cohort placebo arm. At a median follow-up of 68.9 months (range: 0.8-83.9), the data showed a 5.5-year PFS rate of 66% (95% CI, 58-72) and OS of 97% (95% CI, 93-99); however, outcomes varied by genetic risk. Patients without del(17p) or mutated TP53 had a 5.5-year PFS of 70%, compared with just 36% in those with high-risk genomic alterations.²

IGHV mutation status also influenced outcomes. Among patients with unmutated IGHV, 5.5-year PFS was 55% overall, 63% in those without high-risk cytogenetics, and 44% in those with them. For patients with mutated IGHV, PFS reached 79%, increasing to 85% in those without high-risk features and falling to 62% with them.²

MRD status correlated strongly with outcomes. Undetectable MRD (less than 10^-4 by flow cytometry) in peripheral blood was achieved in 54% of patients by cycle 7 and 69% at the end of treatment. Bone marrow undetectable MRD (uMRD) was also 69% at the end of treatment. Patients with uMRD at EOT had a higher 5.5-year PFS rate (75%) than those with detectable MRD (47%).²

Sixty-four patients experienced disease progression after initial treatment. Among 40 with available samples at PD, only 1 had a BCL2 mutation of unclear significance, and no resistance mutations were detected in BTK or PLCG2. Thirty-six patients initiated retreatment with ibrutinib alone (n = 25) and with ibrutinib plus venetoclax (n = 11). After a median follow-up of 28.4 months on ibrutinib retreatment, the overall response rate (ORR) was 76%, with a 2-year PFS and OS of 91% and 96%, respectively. For those retreated with ibrutinib plus venetoclax, ORR was 82%, and both 1-year PFS and OS were 100% with 15.2 months of follow-up.²

Second malignancies were reported in 24 patients over the study period, including 12 during initial treatment and 4 during retreatment.²

These results underscore the long-term efficacy of FD ibrutinib plus venetoclax in first-line CLL/SLL, including for patients with high-risk genomic features. Importantly, ibrutinib-based retreatment yielded durable responses, supporting its use in relapsed settings after initial fixed-duration therapy.²

REFERENCES

1. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia /​small lymphocytic lymphoma (CLL/​SLL) (Captivate). ClinicalTrials.gov identifier: NCT02910583. Updated December 20, 2024. Accessed June 4, 2025. https://clinicaltrials.gov/study/NCT02910583

2. Ghia P, Barr P, Allan J, et al. Abstract 7036 — Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. Presented at: American Society of Clinical Oncology 2025 Annual Meeting. May 30-June 4. Chicago, IL.