41 Background: Surrogate endpoints of overall survival (OS) are increasingly used as the basis of cancer drug approvals, but a strong association between their treatment effects is essential for validation as appropriate surrogates. We summarize the current evidence landscape for meta-analytic validation of surrogate endpoints in colorectal cancer (CRC) and assess surrogacy evaluation quality through a novel framework to inform the selection of primary endpoints in future trials. Methods: We developed a framework to grade the quality of surrogate endpoints in oncology. We then searched MEDLINE to identify meta-analytic validation studies of endpoints in CRC at the trial level. We consulted a research librarian to develop a search strategy in PubMed using keywords and MeSH terms. Articles published before 07/06/2024 were included and two reviewers independently evaluated each. Grades were assessed according to seven evidence domains: data source (A-B), disease population (0-3), surrogate and true endpoint definitions (0-3), number of trials evaluated (0-4), quality and strength of individual (0-2) and trial-level associations (0-8). Discordance in blinded assessments was resolved by consensus decision. Results: Eighteen articles were identified containing 39 evaluations of 12 unique endpoints. Results are presented for disease-free survival (DFS), Progression-free survival (PFS), overall response rate (ORR), time to progression (TTP) and disease control rate (DCR). PFS was most frequently assessed (n=11). Surrogates were primarily evaluated in stage IV disease (n=34) and analyses of biologic agents (n=29). Individual patient data (IPD) was used in 13 evaluations. A23 was the highest endpoint quality score assigned using IPD and B6 was the lowest using summary trial data (SD). Only DFS consistently demonstrated high-quality surrogacy for OS at the trial level using IPD (≥A18, R 2 ≥ 0.70). Conclusions: DFS consistently shows high quality of surrogacy, whereas other endpoints show inconsistent surrogacy evaluation ranging from low to moderate quality in contemporary CRC trials. Standardizing the methodology of endpoint validation using IPD may improve surrogacy estimates. Assessment of new, or revision of prior surrogate endpoints may be warranted, particularly in the context of metastatic disease. Endpoint Data source (frequency) Treatment setting (frequency) Treatment era (frequency) Trial-level association, R 2 (range) Surrogate quality score (range) DFS (n=5) IPD: 5 Adjuvant Pre-biologics: 4Post-biologics: 1 0.70-0.93 A18-23 PFS (n=11) IPD: 3SD: 8 Metastatic Pre-biologics: 2Post-biologics: 9 0.34-0.99 B6-A22 ORR (n=9) IPD: 1SD: 8 Metastatic Pre-biologics: 1Post-biologics: 8 0.03-0.74 B6-A13 TTP (n=5) SD: 5 Metastatic Post-biologics: 5 0.27-0.65 B7-11 DCR (n=2) SD: 2 Metastatic Post-biologics: 2 0.82-0.89 B7-8
Chia et al. (Sat,) studied this question.