A framework to evaluate surrogate endpoints at the trial level: Analysis in colorectal cancer

Surrogate endpoints are increasingly used as the basis of cancer drug approvals. A strong association between treatment effects on the surrogate and true endpoint is essential for their validation as reliable endpoints. We assess the current evidence of trial-level surrogacy for colorectal cancer (CRC) endpoints through a novel framework.

We developed a framework to grade the quality of oncology surrogate endpoints in 7 domains of the surrogate relationship Data source quality (A-B); disease setting homogeneity (0 to 3); uniformness of surrogate and true endpoint definitions (0 to 3); number of trials evaluated (0 to 4); individual (0 to 2) and trial-level associations (0 to 8). We screened PubMed using keywords and MeSH terms for meta-analyses published before 07/06/2024 validating surrogate endpoint associations across CRC trials. Two reviewers blindly assessed each article before reaching a consensus score. The main outcomes were framework-derived evidence scores and reported trial-level associations (R2) with overall survival (OS).

Eighteen articles were identified, containing 39 evaluations of 12 unique surrogate endpoints for OS. Evidence scores ranged from B6-A23. Only disease-free survival (DFS) consistently demonstrated high-quality evidence of trial-level surrogacy (≥A18, median R2 = 0.92). Progression-free survival (PFS) and objective response rate (ORR) were low-quality surrogates in metastatic CRC (PFS B6-A15, median R2 = 0.55; ORR: B6-A13, median R2 = 0.33). Other evaluated endpoints demonstrated as unreliable surrogates.

DFS shows high-quality surrogacy in stage II/III colon cancer. Endpoints identified in the metastatic setting demonstrate inconsistent surrogacy evidence. Re-assessment and identification of new endpoints is warranted, particularly with immunotherapy.