Abstract 3638: Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer

Abstract Background: The use of neoadjuvant immunotherapy alone or in combination has rapidly evolved in the last 5 years. There is significant debate as to whether pathologic complete response (pCR) or major pathologic response (MPR) can be considered a surrogate endpoint for survival. We therefore performed a systematic review and meta-analysis to evaluate the surrogacy of pCR and MPR for event free survival (EFS) in neoadjuvant clinical trials for early-stage NSCLC. Methods: We performed a systematic literature search on PubMed and reviewed abstracts of the most relevant international conferences until June 2023. Relevant information relative to response rates, Odds Ratios (ORs) of response, 2-years EFS rates and Hazard ratios (HRs) were retrieved from all eligible clinical trials and the association were analyzed. To evaluate patients level surrogacy the association between response rate and 2-year EFS was evaluated. In trials presenting EFS rates by achievement of pCR and MPR a forest plot with random effect model was also produced. For trial level surrogacy, ORs for pCR and MPR and HRs for EFS were retrieved and analyzed using a linear regression model weighted by sample size. R2 and linear regression slope were used respectively to estimate the proportion of variation in EFS effect explained by pCR effect and the magnitude of change in EFS effect as a function of the magnitude of change in pCR effect. The R2 with 95% CI were calculated by bootstrapping approach. Results: Seven RCTs were identified for a total of 2940 patients. At patient level, the R2 of pCR and MPR with 2-years EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively, with slopes of 0.96 (0.68-1.19) and 0.64 (0.45-0.85), 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) for pCR and MPR, respectively. Conclusions: While we were able to show a strong correlation between pCR and EFS, trial level surrogacy was not proven. The lack of surrogacy can be related to the high heterogeneity among clinical trials and the still scarce number of data available. More research to reduce the heterogeneity (e.g., pathological evaluation, surgery, and staging harmonization) must be done to introduce pCR as a primary measure to predict EFS. Citation Format: Robert B. Cameron, Jacobi B. Hines, Alessandra Esposito, Christine Bestvina, Marina C. Garassino, Valter Torri, Rajat Thawani. Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3638.