Fixed-duration treatment with ibrutinib plus venetoclax has shown meaningful survival benefits, durable responses, and an acceptable safety profile in high-risk subgroups of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). These findings come from the 5.5-year follow-up of the phase 2 CAPTIVATE study, presented at the 2024 EHA Congress. The study highlights the potential of this combination therapy, particularly for patients with genomic risk features, including del(17p) and TP53 mutations.
CAPTIVATE Study Details
The CAPTIVATE study enrolled patients with previously untreated CLL/SLL, without restrictions on genomic risk features. Patients received three cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib plus venetoclax. Ibrutinib was administered at 420 mg orally daily, and venetoclax was administered with a 5-week ramp-up to 400 mg orally daily. The median time on study was 61.2 months.
The median progression-free survival (PFS) was not reached in the fixed-duration treatment cohort. The 5-year overall survival (OS) rates were 96% (95% CI, 91%-98%) in all treated patients. In patients with del(17p), TP53 mutations, or complex karyotype, the 5-year OS rate was 90% (95% CI, 77%-96%), while it was 100% (95% CI, 100%-100%) in patients without these high-risk features. The 5-year PFS rates were 67% (95% CI, 59%-74%) in all treated patients and 54% (95% CI, 39%-67%) in patients with del(17p), TP53 mutations, or complex karyotype.
High-Risk Patient Profiles
In the fixed-duration cohort, the median age was 60 years, with 67% of patients being male and 28% presenting with Rai stage III or IV CLL. High-risk genomic features included unmutated IGHV (56%), del(17p)/TP53 mutations (17%), del(11q) (18%), and complex karyotype (23%).
Efficacy and Safety Data
Patients who achieved undetectable minimal residual disease (MRD) had improved 5-year PFS rates. Among patients with unmutated IGHV, the 5-year PFS rate was 56% (95% CI, 45%-66%), compared to 80% (95% CI, 68%-88%) in those with mutated IGHV. The 5-year OS rate was 93% (95% CI, 85%-97%) in patients with unmutated IGHV vs 100% (95%, 100%-100%) in those with mutated IGHV.
Of 61 patients with CLL disease progression following completion of fixed-duration treatment, 52% initiated retreatment with single-agent ibrutinib or combination treatment. The overall response rate (ORR) among evaluable patients who received single-agent ibrutinib retreatment (n = 22) was 86%, while the ORR among those who received retreatment with ibrutinib plus venetoclax (n = 7) was 71%.
No new serious adverse effects (AEs) were reported. Eighteen second malignancies were observed in 13 patients.
Pirtobrutinib Plus Venetoclax Study
In a phase 1b trial, patients with relapsed or refractory (R/R) CLL were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR). Overall response rates were 93.3% for PV and 100% for PVR. Progression-free survival at 18 months was 92.9% for PV patients and 80.0% for PVR patients. The most common grade ≥3 adverse events included neutropenia (52%) and anemia (16%).
