Correlation between real-world (RW) progression-free survival (rwPFS) and overall survival (OS) among patients (Pts) with first-line (1L) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) receiving covalent bruton tyrosine kinase inhibitors (cBTKis) or B-cell lymphoma 2 inhibitors (BCL2is)

Abstract

Abstract INTRODUCTION Advances in targeted therapies have resulted in extended survival for many pts with CLL/SLL. OS is a key endpoint in oncology, but in 1st Line CLL studies, it often takes longer to mature due to the disease's indolent nature; therefore, PFS is frequently used as a surrogate. Although clinical trials in 1L CLL/SLL have demonstrated a medium to high correlation between PFS and OS, the application of this relationship, particularly among pts treated with contemporary targeted therapies and in real world settings, remains to be established. This study evaluated the correlation between rwPFS and OS using individual RW pt-level data, focusing on pts receiving 1L cBTKis or BCL2is. METHODS This retrospective observational cohort study included pts with CLL/SLL who initiated 1L treatment with ibrutinib, acalabrutinib, zanubrutinib, or venetoclax between 11/21/2019 – 07/31/2023 in the US community oncology setting. Pts were followed longitudinally through 08/15/2024 using data sourced from the iKnowMed electronic health record. Kaplan-Meier methods were used to estimate OS and rwPFS from initiation of 1L treatment, censoring pts without a death or progression date. Kendall's tau correlation coefficients (τ) were calculated to evaluate the association between rwPFS and OS. A landmark analysis for clinician-document progression at 3- and 6-months after treatment initiation was conducted to minimize lead-time bias. Cox proportional hazards models were used to estimate hazard ratios (HRs), adjusting for age, gender, race, Eastern Cooperative Oncology (ECOG) performance status, Charlson Comorbidity Index (CCI), and Rai stage. RESULTS The median follow-up duration (in months) was 36.2 overall (n=684) and varied by 1L treatment, with 42.3 for acalabrutinib (n=150), 35.6 for ibrutinib (n=384), 16.1 for zanubrutinib (n=50), and 40.4 for venetoclax (n=100). The median age of the study population was 73 years (interquartile range [IQR] 64, 79), with 36.8% female, 74.9% White, and 81.1% non-Hispanic or Latino, 39.9% with a CCI score ≥ 1, and 55.2% with an ECOG score of 0 or 1. Across all 1L treatment subsets, median OS and rwPFS were not reached. Overall, 33.0% (n=226) progressed or died on 1L treatment, and 21.2% (n=145) died. At 24 months, the OS probability was 82.4% (95% confidence interval [CI], 79.2-85.2%) across the study population and, by 1L treatment subset, they were 82.3% (95% CI, 75.1-87.6%) for acalabrutinib, 81.8% (95% CI, 77.4-85.4%) for ibrutinib, 85.2% (95% CI, 71.2-92.7%) for zanubrutinib, and 85.1% (95% CI, 76.1-90.9%) for venetoclax. At 24 months, the rwPFS probability was 73.7% (95% CI, 70.1-76.9%) across the overall study population and, by 1L treatment subset, 71.5% (95% CI, 63.4-78.1%) for acalabrutinib, 72.8% (95% CI, 67.9-77.1%) for ibrutinib, 81.2% (95% CI, 66.9-89.8%) for zanubrutinib, and 78.7% (95% CI, 69.0-85.7%) for venetoclax. Based on the Kendall's tau analysis, a strong correlation between rwPFS and OS was observed in the overall population (τ = 0.79; 95% CI, 0.77–0.80), as well as the 1L treatment subsets: τ = 0.74 (95% CI, 0.68–0.78) for acalabrutinib, τ = 0.78 (95% CI, 0.75–0.80) for ibrutinib, τ = 0.93 (95% CI, 0.90–0.95) for zanubrutinib, and τ = 0.83 (95% CI, 0.78–0.87) for venetoclax. In the 3- and 6-month landmark analyses, pts who had progressed had a higher risk of death, with HRs of 2.328 (95% CI: 1.039–5.215) and 2.617 (95% CI: 1.399–4.896), respectively. CONCLUSIONS This RW analysis found a strong correlation between OS and rwPFS among a community oncology CLL/SLL population receiving 1L cBTKis or BCL2is. While death events contribute to both endpoints, Kendall's tau correlation quantifies the strength of the association across treatments. These findings support the use of rwPFS as an early endpoint outside of clinical trials, particularly when long-term follow-up is not feasible. Landmark analyses remain informative despite the slower accumulation of progression events in this indolent population. Future studies with extended follow-up durations are required to validate the use of rwPFS as a surrogate endpoint for OS in novel targeted therapies and in key subgroups with high unmet needs.