Phase 2 CLL, SLL Study: First-Line Fixed-Duration Ibrutinib Plus Venetoclax Promising

The phase 2 CAPTIVATE study assessed ibrutinib plus venetoclax for first-line management of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The study included a cohort that received a fixed-duration regimen of ibrutinib plus venetoclax and a measurable residual disease (MRD)–guided randomized discontinuation cohort, which served as the placebo arm.

“Ibr+Ven [ibrutinib plus venetoclax] is an all-oral, once-daily, chemotherapy-free FD [fixed duration] regimen for first-line treatment of CLL/SLL that continues to provide durable PFS [progression-free survival] and OS [overall survival] with long-term follow-up, including in pts [patients] with high-risk genomic features,” wrote study first author Paolo Ghia, MD, PhD, of Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy, with colleagues.

The authors’ final comparison was released at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois. On site at the Meeting, it was presented by William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

Patients enrolled in the study had previously untreated CLL or SLL and had a maximum age of 70 years. They received three cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax, which consisted of oral ibrutinib at 420 mg daily plus a 5-week ramp-up of oral venetoclax up to 400 mg daily. Patients in the MRD-guided placebo cohort received up to 13 cycles. A total of 202 patients completed fixed-duration ibrutinib plus venetoclax treatment; the fixed-duration cohort included 159 patients, and the MRD-guided placebo cohort included 43 patients.

The total cohort had a median follow-up of 68.9 months. At 5.5 years, the calculated OS rate was 97%, and PFS was 66%.

The calculated PFS at 5.5 years for patients with and without a del(17p) or TP53 mutation was 36% and 70%, respectively. PFS at 5.5 years in patients with unmutated IGHV was 55%. PFS at 5.5 years in patients with unmutated IGHV with and without a concomitant del(17p), TP53 mutation, or complex karyotype was 44% and 63%, respectively. PFS at 5.5 years in patients with mutated IGHV was 79%. PFS at 5.5 years in patients with mutated IGHV with and without a concomitant del(17p), TP53 mutation, or complex karyotype was 62% and 85%, respectively.

By end of treatment, undetectable MRD (uMRD) was achieved in peripheral blood in 69% of patients and in bone marrow in 69% of patients. Comparing patients who had uMRD in peripheral blood at end of treatment with patients who had MRD in peripheral blood at end of treatment, the rate of PFS at 5.5 years was 75% and 47%, respectively.

Sixty-four patients had disease progression after completing the fixed-duration ibrutinib plus venetoclax regimen, and the rate of freedom from next-line treatment at 5.5 years was 73%. Samples from 40 patients with disease progression were available; one sample revealed an acquired subclonal BCL2 mutation of unclear significance. None of the samples exhibited acquired resistance-associated mutations in BTK or PLCG2.

“Ibr [ibrutinib]-based retreatment provided durable responses in pts [patients] needing subsequent therapy after completion of FD Ibr+Ven [fixed duration ibrutinib plus venetoclax],” Dr. Ghia and colleagues wrote.

This on-study retreatment included ibrutinib monotherapy, and patients in the fixed-duration cohort who had disease progression more than 2 years after the end of treatment could be retreated with fixed-duration ibrutinib plus venetoclax.

Retreatment was initiated in 36 patients out of the total cohort, with 25 receiving ibrutinib monotherapy and 11 receiving ibrutinib plus venetoclax. Patients receiving ibrutinib monotherapy had a 28.4-month median follow-up, with an overall response rate (ORR) of 76%; at 2 years from start of retreatment, PFS and OS rates were 91% and 96%, respectively. Patients receiving ibrutinib plus venetoclax had a 15.2-month median follow-up, with an ORR of 82%; at 1 year from the start of retreatment, PFS and OS rates were both 100%.

Over the total study period, second malignancies manifested in 24 patients. Twelve treatment-emergent adverse events occurred during initial treatment, and four occurred during retreatment.