Evaluation of MPR and pCR as surrogate endpoints for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in non-small cell lung cancer.

Introduction Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate endpoints for event free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable non-small cell lung cancer (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 Odds Ratios (OR)s for pCR and MPR and log Hazard Ratios (HR) for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% CI were calculated by 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. OR of 2-year EFS rates by response status were 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For 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 trial level, R2 for 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 demonstrate 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.