Overall survival in oncology phase III trials: an individual patient level meta-analysis (OPTIMA)

Designing phase III oncology trials to demonstrate overall survival (OS) superiority may be challenging due to sample size, follow-up time, resources, and costs as compared to trials evaluating intermediate endpoints, which may or may not be reliable surrogates of OS. In this study, we investigate at scale the relative gains in OS achieved in modern phase III oncology trials using OS primary endpoints in OPTIMA, a prospectively registered, pre-specified meta-analysis leveraging a large assembly of reconstructed individual patient-level data (PROSPERO: CRD420251162778). After screening 1184 trials and excluding 937 without an OS primary endpoint, 159 trials enrolling 104 740 patients met the inclusion criteria. In the two-stage Cox model, randomization to the experimental arm was associated with improvement in OS (random effects HR, 0.87; 95% CI, 0.85-0.89; P < .0001). In the one-stage Cox model stratified by trial identity, OS was also longer with the experimental arm (HR, 0.88; 95% CI, 0.85-0.90; P < .0001). Taken together, the data from OPTIMA should encourage renewed enthusiasm among trialists, funders, regulatory agencies, and policymakers for prioritizing phase III oncology trials evaluating OS primary endpoints.