Updated CAPTIVATE Data Underscore Long-Term Benefits of Fixed-Duration Ibrutinib/Venetoclax in CLL/SLL

Chronic Lymphocytic Leukemia

The fixed-duration, frontline combination comprised of ibrutinib (Imbruvica) and venetoclax (Venclexta) continued to produce deep, durable responses with a clinically meaningful progression-free survival (PFS) benefit in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to 3-year follow-up findings from the FD cohort of the phase 2 CAPTIVATE trial (NCT02910583) presented during the 2022 EHA Congress.¹

At a median follow-up of 38.7 months (range, 0.8-41.4), which included a median follow-up of 24.9 months following fixed-duration treatment, the complete response (CR) rate increased from 55% (95% CI, 48%-63%) at the time of the primary analysis to 57% (95% CI, 50%-65%) among all treated patients (n = 159); the partial response (PR) rate was 39%.

The median duration of CR was not yet reached (n = 91), but the 24-month landmark estimate for CR duration was 94%. Moreover, the median duration of response was also not reached for all 153 patients who responded to treatment.

In the subset of patients with del(17p)/Tp53-mutated disease (n = 27), the CR achieved with the combination was 56%, with a PR rate of 41%; these rates were 64% and 33%, respectively, in the subset of patients with unmutated IGHV (n = 89).

Moreover, the 36-month PFS rate with the fixed-dose regimen was 88% (95% CI, 82%-92%) in all treated patients. In those with del(17p)/Tp53-mutated disease or those with unmutated IGHV, these rates were 80% (95% CI, 58%-91%) and 86% (95% CI, 77%-92%), respectively. Additionally, the 36-month overall survival (OS) rate in all treated patients was 98% (95% CI, 94%-99%); these rates were similar in the subsets of patients with del(17p)/Tp53-mutated disease and unmutated IGHV, at 96% (95% CI, 76%-99%) and 97% (95% CI, 90%-99%), respectively.

“Ibrutinib plus venetoclax represents an efficacious, all-oral, once-daily, chemotherapy-free, fixed-duration regimen for previously untreated patients with CLL/SLL,” Carol Moreno, MD, PhD, of Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, and colleagues, wrote in a poster on the data.

The open-label, single-arm FD cohort of the international, multicenter, phase 2 CAPTIVATE trial enrolled previously untreated patients with CLL/SLL who had active disease that required treatment per International Workshop on Chronic Lymphocytic Leukemia criteria. Patients could not be older than 70 years of age, and they needed to have an ECOG performance status ranging from 0 to 2.

These patients received lead-in treatment with ibrutinib at 420 mg given once daily for the duration of 3 cycles. They then went on to receive ibrutinib at a once-daily dose of 420 mg in combination with venetoclax given via a 5-week ramp-up to 400 mg once daily for 12 cycles. Notably, upon disease progression, patients who had a durable response could be retreated with ibrutinib monotherapy or fixed-duration ibrutinib plus venetoclax.

The primary end point of the trial was investigator-assessed CR rate, which included CRi, in patients without del(17p), and supporting analyses were conducted in the all-treated population. Important secondary end points comprised objective response rate, DOR, undetectable minimal residual disease (uMRD) rates, PFS, OS, reduction in tumor lysis syndrome risk category, and safety.

A total of 159 patients were enrolled to this cohort and received ibrutinib plus venetoclax; 92% (n = 147) completed treatment with the fixed-duration combination. The median age in the all-treated population was 60 years (range, 33-71), 67% were male, and 86% did not have del(17p). Regarding high-risk features, 56% had unmutated IGHV, 17% had del(17p)/TP53 mutation, 13% had del(17p), 18% had del(11q), and 19% had complex karyotype.

The median duration of treatment in this cohort was 13.8 months (range, 0.5-24.9), which is equivalent to the fixed-duration regimen of fifteen 28-day cycles.

Additional data showed that 79% of the 159 patients experienced a best response of uMRD in the peripheral blood or bone marrow with the combination. Of the 85 evaluable patients with uMRD in the peripheral blood at 3 months following treatment, 78% maintained that status through at 12 months post treatment.

In this cohort, a total of 26 patients experienced disease progression; 10 new progressive-disease cases were reported in this longer follow-up report. Among 22 evaluable patients who experienced progression, investigators found no BTK, PLCg2, or BCL-2 mutations linked with resistance to either agent.

As of April 2022, a total of 12 patients who experienced disease progression following fixed-duration ibrutinib plus venetoclax were retreated with ibrutinib monotherapy. The duration of single-agent ibrutinib retreatment in these patients ranged from 6 months to 32 months. Of the 11 patients determined to response evaluable, 9 were found to have a PR to retreatment, 1 had a PR-L, and 1 achieved stable disease.

Regarding safety, 30% of patients experienced treatment-emergent adverse effects (TEAEs) including arthralgia, diarrhea, nausea, and neutropenia. However, these effects were noted to be low grade, to have occurred within 4 months after treatment with the regimen was initiated, and to resolve quickly for most patients.

In post-treatment follow-up, investigators continued to collect data on serious adverse effects associated with study treatment and secondary malignancies. Notably, they have observed no new serious AEs or secondary malignancies since the primary analysis.

Reference

Moreno C, Wierda WG, Barr PM, et al. Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: 3-year follow-up from the FD cohort of the CAPTIVATE study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Accessed June 9, 2022.