• Ther Adv Med Oncol · Jan 2020

    Surrogate endpoints for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials of advanced melanoma.

    • Run-Cong Nie, Shu-Qiang Yuan, Yun Wang, Xue-Bin Zou, Shi Chen, Shu-Man Li, Jin-Ling Duan, Jie Zhou, Guo-Ming Chen, Tian-Qi Luo, Zhi-Wei Zhou, and Yuan-Fang Li.
    • Department of Gastric Surgery & Melanoma Surgical Section, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
    • Ther Adv Med Oncol. 2020 Jan 1; 12: 1758835920929583.

    BackgroundWe assessed the surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs).MethodsPubMed and EMBASE were searched for phase II/III RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings.ResultsWe included 8 RCTs (4110 patients; 11 comparisons). We did not identify strong correlations between ORR [coefficient of determination (R2): 0.09-0.25], DCR (0.41-0.57) and OS. However, we noted a strong correlation between PFS and OS, with R2 of 0.82 in sample size, 0.75 in fixed effect and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover, phase III trials, large trials and first-line trials strengthened the correlation (0.78-0.94). The STE for PFS was 0.78.ConclusionsPFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.© The Author(s), 2020.

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