Fixed-Duration Ibrutinib Plus Venetoclax Demonstrates Long-Term Efficacy in Untreated CLL/SLL

Paolo Ghia, MD, PhD

Fixed-duration ibrutinib (Imbruvica) in combination with venetoclax (Venclexta) displayed durable progression-free survival (PFS) and overall survival (OS) results in patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to data from the phase 2 CAPTIVATE study (NCT02910583) presented during the 2025 ASCO Annual Meeting.1

At a median follow-up of 68.9 months (range, 0.8-83.9), findings from the final analysis of CAPTIVATE demonstrated that the median PFS and OS were not reached in the pooled population (n = 202). The 5.5-year PFS and OS rates were 66% (95% CI, 58%-72%) and 97% (95% CI, 93%-99%), respectively.

“[During the 2025 ASCO Annual Meeting], we presented the results from the fixed-duration cohort because that is the way that patients are treated in different countries around the world,” Paolo Ghia, MD, PhD, a full professor in medical oncology at Università Vita-Salute San Raffaele, director of the Strategic Research Program on CLL, and head of the Laboratory of B-Cell Neoplasia at the IRCCS Ospedale San Raffaele in Milan, Italy, said in an interview with OncLive®.

Unpacking the Study Design and Baseline Characteristics

CAPTIVATE was a multicenter study that evaluated minimal residual disease (MRD)–guided discontinuation and fixed-duration treatment with ibrutinib plus venetoclax in patients with treatment-naive CLL/SLL.2 Eligible patients needed to have measurable nodal disease by CT scan, adequate hepatic and renal function, and adequate hematologic function.

In the fixed-duration arm (n = 159), patients who were 70 years old or younger received 3 cycles of ibrutinib at 420 mg daily then 12 cycles of ibrutinib at the same dose plus venetoclax via 5-week ramp-up dosing up to 400 mg per day followed by no further treatment.1 Patients in the MRD-guided cohort (n = 43) who achieved confirmed undetectable MRD received 1 additional cycle of ibrutinib plus venetoclax during the MRD-guided random assignment followed by placebo.

Additionally, patients with confirmed disease progression could receive on-study retreatment with ibrutinib monotherapy. Those in the fixed-duration cohort who experienced disease progression over 2 years after the end of treatment could be retreated with ibrutinib plus venetoclax.

The primary end points were 1-year disease-free survival rate in patients with confirmed undetectable MRD in the MRD cohort and complete response (CR)/CR with incomplete blood count recovery (CRi) rate in the fixed-duration cohort.2 In the MRD cohort, secondary end points included CR/CRi rate, overall response rate (ORR), 42-month duration of response (DOR), MRD-negativity rate, 48-month PFS, tumor lysis syndrome risk reduction, 48-month OS, and safety. Secondary end points in the fixed-duration cohort included ORR, 60-month DOR, MRD-negativity rate, 66-month PFS, 66-month OS, tumor lysis syndrome risk reduction, and safety.

At baseline, the median age in the pooled population was 60.0 years (range, 33-71).1 Most patients had unmutated IGHV (59%); other high-risk genomic features included deletion 17p (del[17p])/TP53 mutations (14%), and at least 3 complex karyotype abnormalities (17%).

Among all patients who were retreated with single-agent ibrutinib (n = 25) or ibrutinib plus venetoclax (n = 11), the median age was 58.5 years (range, 39-71). Most patients were male (67%) and had unmutated IGHV (78%). Additional high-risk genomic features included del17p/TP53 mutations (28%), deletion 11q(22%), at least 3 complex karyotype abnormalities (31%), and at least 5 complex karyotype abnormalities (19%).

Further Efficacy Data and Safety Findings

Additional findings from the fixed-duration cohort of CAPTIVATE showed that the 5.5-year PFS rates among patients with (n = 29) and without (n = 169) del(17p)/TP53 mutations were 36% (95% CI, 17%-55%) and 70% (95% CI, 62%-76%), respectively. The 5.5-year PFS rates in patients with IGHV-unmutated (n = 119) and -mutated (n = 78) disease were 55% (95% CI, 45%-64%) and 79% (95% CI, 68%-87%), respectively.

Patients with undetectable (n = 76) and detectable (n = 72) MRD at cycle 7 achieved 5.5-year PFS rates of 60% (95% CI, 48%-70%) and 60% (95% CI, 47%-71%), respectively. At the end of treatment, patients with undetectable (n = 90) and detectable (n = 60) MRD experienced 5.5-year PFS rates of 71% (95% CI, 60%-80%) and 47% (95% CI, 33%-59%), respectively.

“MRD assessment at the end of therapy is what is correlated with PFS,” Ghia commented. “The value after 7 months is not associated at all with long-term durability, which means that we probably cannot shorten the treatment [duration].”

Notably, MRD status at the end of treatment was predictive of long-term PFS irrespective of IGHV status. Patients with IGHV-unmutated disease who had undetectable (n = 47) and detectable (n = 35) MRD at cycle 7 achieved 5.5-year PFS rates of 46% (95% CI, 31%-59%) and 45% (95% CI, 26%-62%), respectively. These respective rates in patients with undetectable (n = 56) and detectable (n = 26) MRD at the end of treatment were 62% (95% CI, 47%-73%) and 22% (95% CI, 9%-40%).

Patients with IGHV-mutated disease with undetectable (n = 28) and detectable (n = 34) MRD at cycle 7 experienced 5.5-year PFS rates of 84% (95% CI, 63%-94%) and 70% (95% CI, 51%-82%), respectively. At the end of treatment, patients with undetectable (n = 33) and detectable (n = 31) MRD achieved 5.5-year PFS rates of 87% (95% CI, 69%-95%) and 62% (95% CI, 42%-77%), respectively.

The ORR among patients who were retreated with single-agent ibrutinib was 76%, including a CR rate of 4%. The 2-year PFS and OS rates were 91% (95% CI, 68%-98%) and 96% (95% CI, 74%-99%), respectively.

The ORR among patients who were retreated with the combination was 82% with a CR rate of 9%. The 2-year PFS and OS rates were both 100% (95% CI, 100%-100%).

In terms of safety, patients who were retreated with single-agent ibrutinib experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 88%. The most common any-grade TEAEs included COVID-19 (24%), diarrhea (20%), and hypertension (20%). Patients in this cohort also experienced grade 3 or 4 TEAEs (36%) and TEAEs leading to treatment discontinuation (4%). There were no TEAEs leading to dose reduction.

All patients who were retreated with the combination experienced an any-grade TEAE. Grade 3 or 4 TEAEs occurred at a rate of 36%. No patients experienced TEAEs leading to treatment discontinuation or dose reduction. Any-grade COVID-19, diarrhea, and hypertension were reported at respective rates of 18%, 36%, and 45%.

“The next analysis we are going to [perform] will study at a molecular level the differences between patients who did achieve undetectable MRD early and those who did not,” Ghia said. “That is still the element that is predicting long-term response. Therefore, it would be nice to identify these patients earlier, so that we can increase the quantity of therapy and prolong the time on therapy. We have to design alternative strategies for those patients who will eventually not achieve undetectable MRD and durable PFS.”

Disclosures: Ghia received honoraria from AbbVie, AstraZeneca, BeiGene, Galapagos NV, Gilead Sciences, Janssen Oncology, Juno/Celgene/Bristol Myers Squibb, Lilly, MSD, and Roche. He also holds consulting or advisory roles with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb/Celgene/Juno, Galapagos NV, Janssen, Lilly, MSD, and Roche. He has received research funding from AbbVie, AstraZeneca, Bristol Myers Squibb/Celgene/Juno (Inst), Janssen Oncology, and Lilly.

References

1. Ghia P, Barr PM, Allan, JN, et al. Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. J Clin Oncol. 2025,43(suppl 16):7036. doi:10.1200/JCO.2025.43.16_suppl.7036
2. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia /​small lymphocytic lymphoma (CLL/​SLL) (Captivate). ClinicalTrials.gov. Updated December 20, 2024. Accessed July 8, 2025. https://clinicaltrials.gov/study/NCT02910583