PB1878: CROSS-TRIAL ANALYSIS OF FIXED-DURATION IBRUTINIB (I) PLUS VENETOCLAX (V) VS FLUDARABINE (F), CYCLOPHOSPHAMIDE (C), AND RITUXIMAB (R) AS FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Abstract

Background: While continuous single-agent I or I-based therapies are superior to FCR, FCR remains an efficacious fixed-duration regimen for fit patients (pts) with previously untreated CLL. CAPTIVATE (PCYC-1142; NCT02910583) is a multicenter phase 2 study of first-line treatment with the all-oral, once-daily, chemotherapy-free regimen of I+V in fit pts with CLL. Primary analysis of the CAPTIVATE Fixed Duration (FD) cohort demonstrated deep, durable responses with fixed-duration I+V (Ghia et al, ASCO 2021). Aims: We performed a cross-trial analysis to evaluate outcomes with fixed-duration I+V relative to FCR using data from the FD cohort of the CAPTIVATE study and the FCR arm of the recent E1912 study (NCT02048813; Shanafelt et al. NEJM 2019;381:432-43). Methods: This cross-trial analysis included pts with previously untreated CLL or SLL aged ≤70 y who were treated with I+V in the FD cohort of CAPTIVATE or with FCR in E1912. As pts with del(17p) were not enrolled in E1912, pts with del(17p) from CAPTIVATE were excluded from the analysis. In CAPTIVATE, pts received three 28-d cycles of I, followed by 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). In E1912, pts received six 28-d cycles of FCR (F 25 mg/m2 on days 1-3; C 250 mg/m2 on days 1-3; R 50 mg/m2 on day 1 and 325 mg/m2 on day 2 in cycle 1, then 500 mg/m2 on day 1 in cycles 2-6). PFS and OS were estimated by Kaplan-Meier method. Adjusted treatment effects for PFS, OS, and ORR were estimated by inverse probability of treatment weighting (IPTW) using propensity score (PS) which balanced treatment groups for the following baseline prognostic factors: age, sex, ECOG performance status ≥1, CLL/SLL diagnosis, time from diagnosis, advanced Rai stage, absolute lymphocyte count, beta-2 microglobulin >3.5 mg/L, and high-risk genomic features (TP53 mutated, del[11q], unmutated IGHV). AEs were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Analysis included 136 pts without del(17p) treated with fixed-duration I+V in the CAPTIVATE FD cohort and 175 pts treated with FCR in E1912; baseline characteristics were generally well-balanced across groups, with notable differences in the proportions of pts aged ≥65 y and with baseline thrombocytopenia (Table). Median follow-up was 38.7 mo with I+V and 33.7 mo with FCR. After IPTW, PFS was improved with I+V relative to FCR (hazard ratio [HR] 0.42; 95% CI 0.25-0.71; log-rank P=0.0018; 36-mo PFS rate: 89% vs 70%), as was OS (HR 0.19; 95% CI 0.05-0.77; log-rank P=0.0084; 36-mo OS rate: 98% vs 90%). Results were generally similar in unadjusted analyses (Table). Adjusted ORRs were 96% for I+V and 85% for FCR (difference 11.2%; 95% CI 5.1–17.3; Chi-square P=0.0011). Median duration of treatment was 13.8 mo for I+V and 4.7 mo for FCR. Treatment was discontinued due to AEs in 5% and 21% of pts, respectively. Overall, grade ≥3 AEs occurred in 62% of pts with I+V and 90% with FCR. Grade ≥3 AEs in ≥5% of pts with I+V were neutropenia (36%), and with FCR were lymphopenia (67%), neutropenia (45%), leukopenia (41%), lymphocytosis (31%), anemia (18%), thrombocytopenia (18%), febrile neutropenia (16%), hypertension (6%), hyperglycemia (6%), and maculopapular rash (5%). EAIRs for grade ≥3 AEs and AEs of clinical interest of any grade were lower with I+V than with FCR (Table). Image:Summary/Conclusion: Results of this cross-trial analysis suggest superior PFS with fixed-duration I+V relative to FCR in first-line CLL. The safety profile with I+V appeared favorable relative to the safety profile of FCR, with lower AE rates and fewer discontinuations due to AEs.