Updated Study Results Show Durable Responses in CLL After Fixed-Duration Ibrutinib-Venetoclax Based on Undetectable MRD

Paolo Ghia, MD, PhD

The use of ibrutinib (Imbruvica) plus venetoclax (Venclexta) in the first-line setting for patients with previously untreated chronic lymphocytic leukemia (CLL) continues to provide deep, durable responses similar to placebo, according to updated results from the MRD cohort of the phase 2 CAPTIVATE trial presented at the 2021 ASH Annual Meeting.

“These results in patients with confirmed [undetectable MRD] receiving fix duration treatment (randomized to placebo), support the potential for treatment-free remission with first-line, fixed duration ibrutinib plus venetoclax, an all-oral, once daily, chemotherapy free-regimen that provides deep, durable responses in patients with CLL,” the study authors wrote in the presentation.

The phase 2 CAPTIVATE trial (NCT02910583) comprised 164 patients younger than 70 years of age (median age, 58 years; range, 28-69) with previously untreated CLL to receive 3 cycles of ibrutinib followed by 12 cycles of combined ibrutinib plus venetoclax (oral ibrutinib at 420 mg/day; oral venetoclax ramp-up to 400 mg/day). The median time on study was 38.2 months (range, 15-47.9) and median post-randomization follow-up was 24 months (range, 5.8-33.1).

After the 12 cycles, patients with confirmed undetectable MRD (uMRD) were randomized to placebo (n = 43) or ibrutinib (n = 43) and those without uMRD to either ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32).

Notably, most patients included in the study had high-risk factors such as unmutated IGHV (60%), del (17p)/TP53 mutation (20%), complex karyotype (19%) and del (11q) without del (17p) (17%).

No new disease-free survival (DFS) events have occurred since the primary analysis among patients with confirmed uMRD randomized to placebo or ibrutinib. In patients with confirmed uMRD post-randomization, 2-year disease-free survival (DFS) rates remained unchanged at 95% in the placebo arm and 100% with ibrutinib, for a 4.7% difference (95% CI, -1.6-10.9; overall log-rank, P = .1573. Additionally, modest improvements in complete response (CR) rates were observed in both the placebo and ibrutinib arms, including CR with incomplete bone marrow recovery (CRi).

At a median follow-up of 38 months, the 36-month PFS in the confirmed uMRD population was 95.3% (95% CI, 82.7-98.8) in patients who received placebo and 100% in those assigned to ibrutinib (95% CI, 100-100).

In patients without confirmed uMRD, improvements in uMRD rates, CR/CRi rates were greater with ibrutinib plus venetoclax compared with ibrutinib alone post-randomization. And, the 36-month PFS rates among those patients following randomization were 96.7% in both the ibrutinib (n = 31) and ibrutinib plus venetoclax (n = 32) arm.

The study authors noted that as of Aug. 4 ,2021, 12 patients whose disease progressed after fixed-duration treatment with the combination have been retreated with ibrutinib alone. At a median follow-up of 4.9 months, 9 patients had a PR, and 3 have pending responses.

“Early data suggest that patients who progress after fixed duration treatment with ibrutinib + venetoclax can be successfully retreated with single-agent ibrutinib,” the researchers wrote.

Grade ≥3 adverse events were infrequent across randomized arms with the exception of neutropenia. With median study follow-up of 38 months, adverse events remained consistent with known profiles for single-agent ibrutinib and venetoclax With up to 48 months of treatment, 13% of patients discontinued ibrutinib or venetoclax due to adverse events with no new safety signals emerging in the additional follow-up.

“With an additional year of follow-up since the primary analysis, there were no new MRD relapses, PD, or deaths in patients with confirmed uMRD treated with placebo or ibrutinib,” wrote in the presentation.

The authors concluded noting that there are still several ongoing global phase 2/3 studies assessing time-limited treatment with the combination of ibrutinib plus venetoclax.

Reference

1. Ghia, P, Allan, J, Siddiqi, T, et al. First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Virtual. Abstract #68.