Assessing the relationship between event-free and overall survival in the era of perioperative chemoimmunotherapy in gastroesophageal cancers.

Abstract

e16135 Background: Perioperative chemoimmunotherapy is emerging as a global standard for non-metastatic gastroesophageal cancers, but data in phase III trials are mixed. Event-free survival (EFS) is a common endpoint in perioperative trials but whether EFS is a surrogate for overall survival in the era of chemoimmunotherapy is not well studied. Understanding EFS performance as a surrogate for overall survival is important to inform regulatory approval and early access to promising agents in this tumor type. Methods: We performed a systematic literature review to identify all randomized controlled trials (RCTs) evaluating neoadjuvant or perioperative systemic therapy for gastroesophageal adenocarcinomas. Using weighted linear regression of the hazard ratios extracted from the published literature, a meta-analysis was performed to evaluate the strength of correlation between EFS and overall survival (OS) across trials. Consistent with criteria from the Institute for Quality and Efficiency in Health Care, strong correlation was defined as a correlation coefficient (R) ≥0.85. Sensitivity analyses examining trials with heterogeneous tumor locations, perioperative systemic therapy only, and those with a clear definition of EFS, were performed to evaluate the consistency of the findings. Results: A total of 30 RCTs were included in the main analysis. Trial-level comparison identified a positive relationship between EFS and OS (estimated coefficient 0.68, 95% CI, 0.50–0.85; p < 0.001) corresponding to a correlation coefficient (R) of 0.83. Surrogate threshold effect (STE) analysis identified an HR for EFS of 1.18 or lower as a threshold at which the lower bound of the 95% confidence interval for HR_OS excluded 1.0.This correlation was preserved in sensitivity analyses, including 20 studies that defined EFS as beginning from cycle 1, day 1 of neoadjuvant therapy (slope relating log(HR_EFS) to log(HR_OS) was 0.6536 (95% CI, 0.4551–0.8521; p < 0.0001). Conclusions: EFS remains a good surrogate for OS in modern phase III perioperative chemoimmunotherapy trials including MATTERHORN, supporting the validity of intermediate endpoints for use in treatment regulatory decisions and drug development in operable gastroesophageal adenocarcinomas.