Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study.

7036 Background: First-line ibrutinib (Ibr) + venetoclax (Ven) treatment for CLL/SLL was tested in the phase 2 CAPTIVATE study, including minimal residual disease (MRD)–guided randomized discontinuation (MRD cohort) and Fixed Duration (FD) cohorts. We report final analysis results for patients (pts) treated with FD Ibr+Ven in the FD cohort and MRD cohort placebo arm. Methods: Pts ≤70 y with previously untreated CLL/SLL received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/d orally; Ven, 5-wk ramp up to 400 mg/d orally), up to 13 cycles in the MRD cohort placebo arm. On-study retreatment included single-agent Ibr; FD cohort pts with progressive disease (PD) >2 y after end of treatment (EOT) could be retreated with FD Ibr+Ven. Results: 202 pts completed FD Ibr+Ven (FD cohort, n=159; MRD cohort placebo arm, n=43). With median follow-up of 68.9 mo (range, 0.8–83.9), 5.5-y PFS and OS rates (95% CI) were 66% (58–72) and 97% (93–99), respectively. 5.5-y PFS rates (95% CI) in pts without and with del(17p)/mutated TP53 were 70% (62–76) and 36% (17–55), respectively. In pts with unmutated IGHV, 5.5-y PFS was 55% (45–64): 63% (49–74) in pts without, and 44% (28–60) in pts with, concomitant del(17p)/mutated TP53 /complex karyotype. The corresponding rates for pts with mutated IGHV were 79% (68–87), 85% (71–93), and 62% (34–81). Undetectable MRD (uMRD4; <10 –4 by flow cytometry) was achieved in peripheral blood (PB) in 54% of pts at C7 and 69% at EOT, and in bone marrow in 69% of pts at EOT. 5.5-y PFS rates (95% CI) were higher in pts with uMRD4 in PB at EOT (75% [67–82]) vs those with MRD (47% [33–59]). 64 pts had PD after completion of FD Ibr+Ven. 5.5-y freedom from next-line treatment was 73% (95% CI 66–79). Of 40 pts with available samples at PD to date, 1 had an acquired subclonal mutation in BCL2 of unclear significance (A113G, VAF 8.3%); none had acquired resistance-associated mutations in BTK or PLCG2 . 36 pts initiated retreatment with Ibr (n=25) or Ibr+Ven (n=11). With 28.4 mo median follow-up on Ibr retreatment (range, 3.7–59.1), ORR was 76% (best response: 1 CR; 1 nodular PR; 17 PR; 4 SD; 1 PD [Richter transformation]; 1 no assessment); 2-y PFS and OS rates from the start of retreatment were 91% and 96%, respectively. With 15.2 mo median follow-up on Ibr+Ven retreatment (range, 7.4–29.3), ORR was 82% (best response: 1 CR; 8 PR; 2 SD); 1-y PFS and OS rates from the start of retreatment were both 100%. Second malignancies occurred in 24 pts across the entire study period, including 12 initial treatment and 4 retreatment TEAEs. Conclusions: Ibr+Ven is an all-oral, once-daily, chemotherapy-free FD regimen for first-line treatment of CLL/SLL that continues to provide durable PFS and OS with long-term follow-up, including in pts with high-risk genomic features. Ibr-based retreatment provided durable responses in pts needing subsequent therapy after completion of FD Ibr+Ven. Clinical trial information: NCT02910583 .