Frontline Ibrutinib/Venetoclax Combination Induces Responses in CLL/SLL

Paolo Ghia, MD, PhD

Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treated with the combination of ibrutinib (Imbruvica) plus venetoclax (Venclexta) had complete response (CR) and complete response with a 56% incomplete bone marrow recovery (CRi) rate according to data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

The phase 2 CAPTIVATE study (NCT02910583) found similarly high rates of overall survival (OS) and progression-free survival (PFS) with the combination therapy for patients overall and with high-risk features.

“The primary end point was met, with a complete response rate of 56% in patients without deletion(17p),” lead author Paolo Ghia, MD, PhD, of the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele in Milan, Italy, explained in his presentation of the data. “The complete response [rate] was 55% in the all-treated population, and the overall response rate was 96%.”

The primary analysis focused on the fixed-duration cohort of the CAPTIVATE study, with patients receiving 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. A total of 159 previously untreated patients with CLL/SLL aged 70 years or younger with an ECOG performance score of 2 or less were enrolled in the trial.

Of the 159 patients enrolled, 147 (92%) completed the 12 cycles of ibrutinib plus venetoclax. The median time on study was 27.9 months (range, 0.8-33.2) with a median treatment duration of 13.8 months (range, 0.5-24.9). The median follow-up was 14.0 months after treatment completion

In patients without del(17p), the CR rate was 56% (95% CI, 48%-64%) with the all-treated population reporting a 55% CR rate. The only exception was observed in the bulky disease category, where patients with bulky disease had a CR rate of 31% (95% CI, 18%-44%).

Further, for patients with bone marrow or peripheral disease, high rates of undetectable minimal residual disease (uMRD) were observed, including in patients with high-risk disease features.

When examining patients at 24 months, those without del(17p) treated with the combination had a 96% PFS rate (95% CI, 91%-98%). For OS, the 24-month rate was 98% (95% CI, 94%-99%) for this patient cohort. The median follow-up time was 27.9 months (range, 0.8-33.2).

The most common any-grade adverse effects (AEs) for the combination treatment were diarrhea (62%), nausea (43%), neutropenia (42%), and arthralgia (33%). Grade 3 or 4 AEs included neutropenia (33%), infections (8%), hypertension (6%), and neutrophil count decrease (5%). Twenty-three percent of patients experienced serious AEs, with only 1 fatal AE observed.

The primary end point of the research was investigator-assessed CR/CRi for patients without del(17p), with key secondary end points focusing on overall response rate, duration of response, uMRD rates, progression-free survival, overall survival, tumor lysis syndrome reduction, and safety.

“All of these results together support the idea of the combination of ibrutinib plus venetoclax as an all-oral, once daily, chemo[therapy]-free, fixed-duration [treatment] that may achieve deep responses and undetectable MRD in a vast majority of patients,” concluded Ghia in his presentation of the data.

This combination therapy is currently being examined in a complementary older population for the randomized phase 3 GLOW study (NCT03462719), results of which are expected soon.

_Reference

_{Ghia P, Allan JN, Siddiqi T, et al. Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of the FD cohort of the phase 2 captivate study. J Clin Oncol. 2021;39(suppl 15):7502. doi:10.1200/JCO.2021.39.15_suppl.7502}