Validating ORR and PFS as surrogate endpoints in phase II and III clinical trials for NSCLC patients: difference exists in the strength of surrogacy in various trial settings

OBJECTIVE: This study aims to systematically validate the performance of surrogate endpoints in phase II and III clinical trials for NSCLC patients under various trial settings. METHODS: A literature search retrieved all registered phase II and III trials of NSCLC patients in which OS, with at least one of ORR and PFS, were reported. Associations between surrogate and true endpoints were assessed on two levels. On the arm level, three pairs of correlations, i.e., ORR vs. median OS, ORR vs. median PFS, and median PFS vs. median OS, were analysed using Spearman’s rho. On the trial level, similarly, three pairs of correlations, i.e., ΔORR vs. HR of OS, ΔORR vs. HR of PFS, and HR of PFS vs. HR of OS, were analysed using Spearman’s rho and weighted linear regression model respectively. Finally, sensitivity analyses were performed to explore surrogacy under various trial settings. RESULTS: At arm level, three pairs of correlations are all high (Spearman’s rho = 0.700, 0.831, 0.755, respectively). At trial level, there is a low correlation between ΔORR and HR of OS, a high correlation between ΔORR and HR of PFS and a moderate correlation between HR of PFS and HR of OS (Spearman’s rho = 0.462, 0.764, 0.584, respectively). In the sensitivity analysis, we find correlations between surrogate and true endpoints vary by different trial settings. It is noteworthy that the strength of surrogacy of these intermediate endpoints in targeted therapy is greater than that in immunotherapy. CONCLUSION: According to the arm-level and trial level-analysis, we suggest that in phase II and III trials of targeted therapy and immunotherapy for NSCLC patients: 1) ORR lacks validity for the surrogacy of OS, excluding in first-line therapy, and 2) ORR may be an appropriate surrogate endpoint for PFS, and 3) PFS may be considered a modest surrogacy for OS, with better performance in first-line therapy trials. Moreover, to provide more convincing evidence of surrogacy of the surrogate endpoints, patient-level analyses are in desperate need. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-10046-z.