Initiating First-Line (1L) Fixed-Duration (FD) Ibrutinib and Venetoclax (Ibr+Ven) in Patients (Pts) with Chronic Lymphocytic Leukemia (CLL) Improves Overall Survival (OS) Outcomes to Rates Approximating an Age-Matched General European Population

Introduction: Ibr+Ven is an all-oral, chemotherapy-free, FD treatment option that provides a deep and durable response for treatment-naive (TN) pts with CLL. In the phase 3 GLOW trial, FD Ibr+Ven significantly prolonged OS versus chemoimmunotherapy in pts with TN CLL. With a median follow-up (FU) of up to 5 years, updated results showed a 54-month (mo) OS rate of 84.5% for FD Ibr+Ven compared with 63.7% for chlorambucil plus obinutuzumab, with a hazard ratio (HR) of 0.453 (95% confidence interval [CI], 0.261-0.785). Additionally, in the FD cohort of the phase 2 CAPTIVATE (CAPTIVATE-FD) trial, OS rates at 61.2 mo FU were consistently over 90%, regardless of high-risk features. Here we report OS estimates in pts with CLL treated with 1L FD Ibr+Ven from GLOW and CAPTIVATE-FD versus an age-matched general European population. Aim: OS was assessed for pts with TN CLL receiving FD Ibr+Ven versus a respective age-matched general European population for the following study populations 1) pooled Ibr+Ven-treated pts across GLOW and CAPTIVATE-FD clinical trials; 2) subpopulation of pts aged ≥ 65 years; 3) subpopulation of pts aged < 65 years; 4) subpopulation of pts with mutated IGHV; and 5) subpopulation of pts with unmutated IGHV. Methods: Ibr+Ven data were pooled from 2 clinical trials in pts with TN CLL/small lymphocytic lymphoma: GLOW (NCT03462719; median FU, 55.1 mo) and CAPTIVATE-FD (NCT02910583; median FU, 55.7 mo). Individual trial descriptions and eligibility criteria were reported previously. Post-hoc analysis of IGHV was used for baseline IGHV status for the GLOW study. The OS of pooled pts treated with Ibr+Ven was compared with age-matched simulated survival rates of a general European population using age at randomization. Survival probabilities for the general population by 5-year age intervals from the 2019 World Health Organization life tables were used. To avoid immortal time bias within each age interval, available probabilities were converted to a daily scale. Kaplan-Meier methodology was used for OS analysis, with HRs derived from a Cox proportional-hazards model using trial and simulated data. Results: A total of265 pts (GLOW, n = 106; CAPTIVATE-FD, n = 159) were treated with FD Ibr+Ven in the 1L setting. Median (range) age at randomization was 65 (33-93) years; 135 (50.9%) pts were aged ≥ 65 years. Most (n = 165; 62.3%) pts were male; 248 (93.6%) were White. 145 (54.7%) pts had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 107 (40.4%) pts had an ECOG PS of 1. Among pts treated with Ibr+Ven, 156 (58.9%) had unmutated IGHV, 98 (37.0%) had mutated IGHV, and 11 (4.2%) had an unknown IGHV status. Pts with unknown/missing IGHV were excluded in subpopulation analysis based on IGHV status. Median FU time from randomization was 55.7 mo. OS estimates were compared across Ibr+Ven-treated pts and an age-matched European general population; HRs < 1 favored Ibr+Ven. The OS estimate was comparable in the overall population of 265 FD Ibr+Ven-treated pts (HR 0.999; 95% CI, 0.567-1.761; p = 0.998). The estimated OS rates for the overall Ibr+Ven-treated population were 95%, 93%, and 91% at 36, 48, and 60 mo, respectively. The estimated OS was also comparable for 135 Ibr+Ven-treated pts aged ≥ 65 years (HR 0.828; 95% CI, 0.422-1.623; p = 0.582); the estimated 36-, 48-, and 60-mo OS rates were 92%, 90%, and 88%, respectively. For 130 pts aged < 65 years, the estimated OS was similar to their respective age-matched European population (HR 1.636; 95% CI, 0.549-4.875; p = 0.377), with estimated OS rates of 97%, 96%, and 93% at 36, 48, and 60 mo, respectively. The OS estimate for pts with unmutated IGHV was also similar to an age-matched European population (HR 1.182; 95% CI, 0.594-2.351; p = 0.633). Although the HR estimate was numerically favorable for pts with mutated IGHV treated with Ibr+Ven versus an age-matched general European population (HR 0.396; 95% CI, 0.106-1.489; p = 0.171), there were only 3 observed OS events in the FD Ibr+Ven cohort, and the results were not statistically significant. Conclusion: This pooled analysis demonstrates that OS for pts with CLL treated with Ibr+Ven in the 1L setting was comparable to an age-matched general European population, including in the subpopulations of pts aged ≥ 65 years and < 65 years. This study also showed that estimated OS was similar to an age-matched European population, regardless of IGHV mutational status.