Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma

Yuan Fang Li, Yun Wang, Jie Zhou, Yi Cheng Wei, Jun Lin, Yi Xin Yin, Guo Ming Chen, Fei Yang Zhang, Shi Chen, Zhi Wei Zhou, Ying Bo Chen, Run Cong Nie


Background: We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma.

Methods: Randomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model.

Results: Seventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73.

Conclusions: PFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ? 0.73 has the potential to predict a significant improvement in OS.

World J Oncol. 2022;13(3):126-135


PD-1; PD-L1; Immune checkpoint inhibitor; Surrogate endpoint; Overall survival; Gastro-esophageal carcinoma

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