Similar 1-Year DFS Observed With Continued Ibrutinib, Following Fixed-Duration of Ibrutinib/Venetoclax Vs Placebo in CLL/SLL

William G. Wierda, MD, PhD

Placebo following a fixed-treatment duration of ibrutinib (Imbruvica) combined with venetoclax (Venclexta) achieved similar 1-year disease-free survival (DFS) results compared with patients who remained on ibrutinib following confirmed undetectable minimal residual disease (MRD) in patients with previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, according to a presentation at the 2020 American Society of Hematology Annual Meeting.

The results, according to lead study investigator William G. Wierda, MD, PhD, professor, D.B. Lane Cancer Research Distinguished Professor, section chief of chronic lymphocytic leukemia and center medical director of the department of leukemia at The University of Texas MD Anderson Cancer Center, support a fixed duration treatment of ibrutinib and venetoclax in this patient population.

“The one-year disease-free survival rate of 95% in patients randomized to placebo is similar to the rate for patients randomized to ibrutinib, supporting a fixed duration treatment with 12 cycles of combined ibrutinib plus venetoclax and treatment discontinuation for patients who achieved confirmed undetectable MRD,” said Wierda during a virtual presentation of data from the MRD cohort of the phase 2 CAPTIVATE trial.

Wierda stated that preclinical data supported the use of ibrutinib and venetoclax in this situation, as each treatment alone demonstrated complementary clinical activity and did not have overlapping toxicities.

The aim of this cohort of the CAPTIVATE trial, according to Wierda, was to assess if deep remissions could be achieved following a 1-year fixed duration of ibrutinib plus venetoclax, and if patients could discontinue treatment and reasonably remain off treatment.

The primary goal of the study was to compare 1-year DFS between the continued administration of ibrutinib or a switch to placebo in patients who achieved a confirmed undetectable MRD, which was defined as undetectable serially over 3 or more cycles of therapy, and noticeable in peripheral blood (PB) and bone marrow (BM).

The CAPTIVATE trial is a multicenter, international phase 2 study of first line ibrutinib and venetoclax across 2 cohorts: one involving MRD and the other fixed duration. In this cohort, patients received 3 cycles of ibrutinib followed by 12 cycles of the combination. Patients were then randomized to receive placebo or further ibrutinib treatment depending on their MRD status.

Among 149-evaluable patients (median age, 58 years; range, 28-69), 58% achieved confirmed undetectable MRD and were randomized to either continued ibrutinib alone (n = 43) or placebo (n = 43). The remaining 63 patients who did not reach confirmed undetectable MRD were randomized to continue receiving ibrutinib (n = 31) or the combination (n = 32).

Results showed that continued ibrutinib following a confirmed undetectable MRD resulted in a 1-year DFS of 100% compared with 95.3% in the placebo group (P=.1475).

After a median follow-up of 31.3 months, all evaluable patients achieved a 30-month progression-free survival (PFS) of 95.3% (95% CI, 90.4-97.8). Each randomized arm in both the confirmed undetectable MRD and unconfirmed undetectable MRD group achieved a 30-month PFS of 95% or greater.

Increases in undetectable MRD were greater with continued combination therapy compared with ibrutinib alone in patients who had unconfirmed undetectable MRD following the 12 cycles of the combination. Following additional randomized treatment with ibrutinib, undetectable MRD in BM increased from 32% to 42% compared with 31% to 66% in patients who continued to receive the combination. Moreover, undetectable MRD in PB remained at 45% for patients who received additional ibrutinib and increased from 50% to 69% in patients who received the combination.

Very few patients in each arm required dose reduction or dose discontinuation, according to Wierda. In the group with confirmed undetectable MRD, 4 patients (3 in the ibrutinib arm and 1 in the placebo arm) experienced adverse events (AEs) that led to dose reduction after randomization. Four patients in the unconfirmed undetectable MRD group — 2 each for ibrutinib alone and the combination — experienced AEs that led to dose reduction after randomization. There were no treatment discontinuations as a result of AEs in the confirmed undetectable MRD group compared with 3 (1 for ibrutinib alone and 2 for the combination treatment) in the group with unconfirmed undetectable MRD.

The most common AEs of interest over time, meaning grade 3 or 4, were neutropenia and hypertension. Occurrences varied across the treatment arms.

“There were no safety concerns with this highly active combination of first line ibrutinib and venetoclax an all-oral, once-daily, fixed-duration regimen that achieves undetectable MRD in blood or bone marrow in three quarters of patients after 12 cycles of combined treatment,” concluded Wierda.

_Reference

_{Wierda WG. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study. Presented at: the 2020 ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract #123.}