Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R² with 95% confidence interval were calculated by the bootstrapping approach. Results: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R² of pCR and MPR with 2-year EFS were 0.82 (0.66–0.94) and 0.81 (0.63–0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07–0.19) and 0.11 (0.05–0.22), respectively. For the 2-year OS, the R² of pCR and MPR were 0.55 (0.09–0.98) and 0.52 (0.10–0.96), respectively. At the trial level, the R² for the association of OR for response and HR for EFS was 0.58 (0.00–0.97) and 0.61 (0.00–0.97), respectively. Conclusions: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.