The impact of high PD-L1 expression on the surrogate endpoints and clinical outcomes of anti-PD-1/PD-L1 antibodies in non-small cell lung cancer

Background: Recent reports have indicated that the objective response rate (ORR) and progression-free survival (PFS) cannot serve as surrogates for predicting overall survival (OS) in immune checkpoint inhibitor (ICI) trials. We performed a trial-based correlative analysis to evaluate conventional endpoints as surrogates for predicting OS in ICI-treated non-small cell lung cancer (NSCLC) patients. Methods: A systematic electronic literature search for randomized clinical trials using ICI monotherapies for NSCLC revealed 7 trials. The correlative analysis to clarify the correlations among clinical outcomes used a weighted Spearman rank correlation coefficient (wS), weighted Pearson correlation coefficient (wP), and weighted linear regression model (wL) in all patients and patients with high PD-L1 expression. Results: The correlative analysis of the total population revealed that the odds ratio of the ORR (OR-ORR) and the hazard ratio of OS (HR-OS) were strongly correlated with the hazard ratio of PFS (HR-PFS) (R for wP and wS, R-2 for wL; 0.869, 0.968, 0.756 between OR-ORR and HR-PFS; 0.923, 0.959, 0.851 between HR-PFS and HR-OS). The strongest correlation was observed between one-year overall survival (1y-OS) and the HR-OS (R for wP and wS, R-2 for wL; 0.985, 1.000, R-2: 0.968). In those with high PD-L1 expression, the ORR and PFS were strongly associated with OS (R-2: 0.842 between ORR and OS; 0.771 between PFS and OS). Conclusions: The OR-ORR and HR-PFS could serve as surrogate endpoints for predicting the HR-OS in randomized trials using ICIs for NSCLC, while the ORR and PFS could be useful endpoints for predicting OS in trials with patient selection based on high PD-Ll expression.