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

Background: Ibr is an established standard of care in CLL and is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit in randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). The synergistic combination of Ibr + Ven (oral inhibitor of BCL2) has been shown to mobilize and clear CLL cells from multiple disease compartments leading to deep responses, providing a rationale to evaluate time-limited treatment (Jain et al. NEJM 2019). CAPTIVATE (PCYC-1142) is a multicenter phase 2 study (NCT02910583) of first-line Ibr + Ven with 2 cohorts: Minimal Residual Disease (MRD) and Fixed-Duration (FD). For both cohorts, patients (pts) received 3 cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Pts in the MRD cohort were randomized by MRD status to placebo or further treatment. In the pre-randomization phase of the MRD cohort, Ibr + Ven resulted in high rates of undetectable MRD (uMRD) in both peripheral blood (PB; 75%) and bone marrow (BM; 72%), with concordant uMRD results in 93% of pts with matched samples (Tam, ASH 2019). We present primary results from the MRD-guided randomization phase of the MRD cohort, evaluating whether this regimen allows for treatment-free remission in the setting of uMRD.

Methods: Pts <70 years with previously untreated CLL/SLL requiring therapy received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/day PO; Ven ramp-up to 400 mg/day PO). Pts with Confirmed uMRD (defined as uMRD serially over ≥3 cycles, and in both PB and BM) after 12 cycles of Ibr + Ven were randomized 1:1 to receive double-blind treatment with placebo or Ibr; pts who did not meet the definition of Confirmed uMRD were randomized 1:1 to receive open-label treatment with Ibr or continued Ibr + Ven. Primary endpoint was 1-year DFS rate in the Confirmed uMRD pts randomized to placebo vs Ibr; DFS was defined as survival without progression or MRD relapse. Key secondary endpoints were rates of uMRD (<10^-4 by 8-color flow cytometry), response per iwCLL, progression-free survival (PFS), and adverse events (AEs).

Results: 164 pts were enrolled in the MRD cohort. Median age was 58 years (range, 28-69); baseline high-risk features included del(17p) in 16% and del(11q) in 17%; del(17p) or TP53 mutation in 20%; complex karyotype in 19%; and unmutated IGHV in 60%. Median time on study was 31.3 mo (range, 15.0-41.0). 90% of pts completed planned treatment with 3 cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Of 149 randomized patients, 86 (58%) with Confirmed uMRD (100% uMRD in PB and BM) were randomized to placebo (n=43) or Ibr (n=43). 63 of 149 pts (42%) did not achieve Confirmed uMRD as defined above and were randomized to Ibr (n=31) or Ibr + Ven (n=32); uMRD rates at randomization in this group were 48% in PB and 32% in BM. In the Confirmed uMRD group, 1-year DFS rate was not significantly different for pts randomized to placebo (95.3%; 95% CI 82.7-98.8) versus Ibr (100%; 95% CI 100-100) (P=0.1475; Figure). In the group without Confirmed uMRD who were randomized to continue Ibr or Ibr + Ven, uMRD rates improved to 57% in PB and 54% in BM during the overall study period. 30-mo PFS rates were >95% across all randomized arms (Table). Full results of endpoints by randomized arms will be presented. The median duration of treatment was 28.6 mo (range, 0.5-39.8) with Ibr and 12.0 mo (range, 0.8-34.1) with Ven. AEs were primarily grade 1/2 and mostly occurred in early cycles of Ibr + Ven, with modest differences by randomized treatment arm. During the overall study period across all-treated pts (with median treatment duration 29 mo), most common grade 3/4 AEs (≥5% of pts) were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%).

Conclusions: First-line Ibr + Ven treatment is an all-oral, once-daily, chemotherapy-free regimen that confers high rates of PB and BM uMRD in pts with CLL, and a 90% reduction in high-risk TLS monitoring (Siddiqi, EHA 2020). The 1-year DFS in pts randomized to placebo after Ibr + Ven combination was similar to that of pts continuing Ibr, supporting a fixed-duration treatment that offers treatment-free remissions in pts with CLL/SLL. The depth of response achieved with this regimen is reflected in the 30-mo PFS rate of ~95% across all treated pts. The safety profile of Ibr + Ven was consistent with known AEs for Ibr and Ven, and no new safety signals emerged.