Tumor Response, Disease Control, and Progression-Free Survival as Surrogate Endpoints in Trials Evaluating Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Study- and Patient-Level Analyses

SIMPLE SUMMARY: How tumor response and progression-free survival (PFS) reflect the overall survival (OS) in advanced non-small cell lung cancer (NSCLC) clinical trials with immune checkpoint inhibitors (ICI) have not been clarified. This study validated the uses of objective response rate and PFS for NSCLC trials with ICI through an individual-patient level and a trial level. ABSTRACT: Background: To assess the usefulness of tumor response and progression-free survival (PFS) as surrogates for overall survival (OS) in non-small cell lung cancer (NSCLC) trials with immune checkpoint inhibitors (ICI), which have not been confirmed. Methods: Patient- and trial-level analyses were performed. The Response Evaluation Criteria in Solid Tumors was preferred for image assessment. For trial-level analysis, surrogacy was assessed using the weighted rank correlation coefficient (r) following “reciprocal duplication.” This method duplicates all plots as if the experimental and the reference arms were switched. Monte Carlo simulations were performed for evaluating this method. Results: A total of 3312 cases were included in the patient-level analysis. Patients without response (first line (1L): hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.71–2.23; second or later line (2L-): HR 4.22, 95% CI 3.22–5.53), without disease control (1L: HR 4.34, 95% CI 3.82–4.94; 2L-: HR 3.36, 95% CI 2.96–3.81), or with progression during the first year (1L: HR 3.42, 95% CI 2.60–4.50; 2L-: HR 3.33, 95% CI 2.64–4.20), had a higher risk of death. Systematic searches identified 38 RCTs including 17,515 patients for the study-level analysis. Odds ratio in the objective response rate (N = 38 × 2, r = −0.87) and HR in PFS (N = 38 × 2, r = 0.85) showed an excellent association with HR in overall survival, while this effect was not observed in the disease control rate (N = 26 × 2, r = −0.03). Conclusions: Objective response rate and PFS are reasonable surrogates for OS in NSCLC trials with ICI.