PD-1/PD-L1 immune checkpoint blockade (ICB) has improved overall survival (OS) in solid tumor trials; however, parallel improvements in RECIST-based surrogate endpoints, progression-free survival (PFS) and objective response rate (ORR), are not always observed. Here, we assess the surrogacy of PFS/ORR for OS with ICB therapy across advanced/metastatic tumors. In a trial-level analysis (N = 40 randomized trials), PFS, ORR, and OS treatment effects were correlated (Spearman's rho). In a patient-level analysis, data were extracted from available trials of durvalumab; the correlation of PFS and OS was evaluated (Bayesian normal-induced-copula-estimation model) and the ordinal association between objective response and OS hazard ratio (HR) were assessed with concordance index measures. High correlation was observed between PFS HR and OS HR in intention-to-treat (ITT) (rho=0.76) and PD-L1-enriched populations (0.74); modest (or limited) benefit in PFS was associated with meaningful improvement in OS. Moderate correlations were observed between ΔORR and OS HR: ITT, -0.63; PD-L1-enriched, -0.53. At the patient level, a positive association was observed between PFS and OS in non-small-cell lung cancer (Kendall's Tau=0.793; 95% confidence interval, 0.789-0.797), head-and-neck squamous-cell carcinoma (0.794; 0.789-0.798), and bladder cancer (0.872; 0.869-0.875). Objective responders had significantly better OS (concordance index >0.9) than non-responders across these tumor types. Modest (or limited) improvement in RECIST-based endpoints did not rule out meaningful OS benefit, indicating they are imperfect surrogates and do not fully capture ICB clinical benefit. Therefore, caution is advised when basing early discontinuation of novel ICB agents on these surrogate endpoints.
Clinical pharmacology and therapeutics. 2020 Jun 21 [Epub ahead of print]
Jiabu Ye, Xiang Ji, Phillip A Dennis, Hesham Abdullah, Pralay Mukhopadhyay
Pfizer Inc, Collegeville, PA, USA., AstraZeneca, Gaithersburg, MD, USA., GlaxoSmithKline, Collegeville, PA, USA.