Association Between Progression-Free Survival and Overall Survival in Mantle Cell Lymphoma: A Trial-level Surrogate...

Survival outcomes of patients with mantle cell lymphoma (MCL) have substantially improved. In the setting of extended overall survival (OS), progression-free survival (PFS) is typically used as a primary endpoint in MCL clinical trials rather than OS to limit trial duration and cost. However, no prior analysis has assessed whether PFS can reliably predict OS. The aim of this study is to perform a systematic evaluation of PFS as a surrogate endpoint for OS in phase III MCL clinical trials.

A systematic review was conducted to identify phase III MCL trials. A weighted linear regression was carried out to examine the correlation between treatment effects (hazard ratios) for PFS and OS. Surrogacy strength was quantified using the coefficient of determination (R²). The surrogate threshold effect (STE) was additionally calculated to determine the magnitude of PFS benefit required to predict a benefit in OS.

Sixteen trials, encompassing 19 treatment comparisons and 5996 patients, met inclusion criteria. An R² of 0.75 was observed, indicating a moderate association between treatment effects of PFS and OS. The STE for an average-sized trial (n = 334) was 0.59. Statistically significant benefits in both endpoints were observed in 17.6% of treatment comparisons.

PFS demonstrates a moderate correlation with OS in phase III MCL trials. The substantial magnitude of PFS benefit needed to confidently predict improvement in OS limits its reliability as a surrogate endpoint, especially when treatment effect sizes are modest.