Multinational retrospective study of utility of recurrence-based surrogate endpoints for survival in adjuvant melanoma trials

Surogate endpoints are widely used to support interim analyses and regulatory approval of adjuvant therapies in resected solid tumors, yet many lack formal trial-level validation. A multinational retrospective study at five centers evaluated disease-free survival (DFS) and distant metastasis-free survival (DMFS) as surrogate endpoints for disease-specific survival (DSS) and overall survival (OS) in resected melanoma. A total of 10,379 patients with stage I-III melanoma treated between 2000 and 2023 were analyzed; all underwent sentinel node biopsy. There were 2418 DFS events, 1833 DMFS events, and 1235 melanoma-specific deaths. Trial-level surrogacy for DFS with DSS was strongest at 24 to 36 months (R² up to 0.95). DMFS showed consistently high surrogacy for DSS form 24 to 48 months (R² 0.87-0.91). Correlations with OS were weak at all horizons from 12 to 48 months (R² < 0.40). Surrogacy was stage-dependent, with robust performance in pT-defined IIB-IIC disease and limited surrogacy in IB-IIA disease. The authors conclude that DFS and DMFS are valid surrogate endpoints for DSS in resected melanoma at later time horizons, particularly in higher-risk disease. OS showed attenuated correlation with recurrence-based endpoints.