Pooled analysis of endpoint surrogacy in first-line chronic lymphocytic leukemia

Surrogate endpoints are commonly used to estimate efficacy in clinical studies of chronic lymphocytic leukemia (CLL). A patient- and trial-level analysis investigated the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL. Pooled analysis of 12 front-line studies by the German CLL Study Group (4237 patients) found a patient-level correlation of PFS and OS that was strong (Spearman’s Rho > 0.9). A joint-frailty copula model indicated a weak correlation for chemotherapy and chemoimmunotherapy (C/CIT) with a tau of 0.52, while the correlation was strong for targeted therapy (TT, tau 0.91). A meta-analysis of first-line phase III trial in CLL from 2008-2024 included 5198 patients treated with C/CIT and 2867 patients treated with TT. Treatment effect correlation of the hazard ratios for PFS and OS was R = 0.75, while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 and 0.71, respectively. The authors conclude that patient-level correlation was confirmed in the setting of targeted therapies while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data.