141 - Overall Survival in Oncology Phase III Trials: An Individual Patient Level Meta-Analysis (OPTIMA)
Presenter(s)
A. D. Sherry1, N. Meimoun2, A. M. Miller2, J. Liu2, K. Chauhan3, R. Kouzy2, T. Lin4, P. Msaouel2, and E. B. Ludmir2; 1Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 2The University of Texas MD Anderson Cancer Center, Houston, TX, 3Mayo Clinic, Rochester, MN, 4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): The primary endpoints of phase III oncology trials have shifted over time from overall survival (OS) to alternative endpoints such as progression-free survival. In previous work, we reviewed the outcomes of 791 modern phase III oncology trials and found that only 28% (n=221) demonstrated OS superiority, despite 55% (n=434) claiming superior treatment effects via alternative endpoints (Sherry et al, JAMA Oncol 2025). Importantly, OS was a primary or co-primary endpoint in 35% of trials (n=420), a foundational design feature which may partly explain why OS superiority was only infrequently observed. Here, using the largest assembly of individual patient level data to our knowledge from phase III trials, we evaluate the relative gains in OS at the individual patient level across the body of modern phase III oncology trials with OS primary endpoints.
Materials/Methods: OPTIMA was a prospectively registered, pre-specified meta-analysis of phase III oncology trials. Eligible trials screened from ClinicalTrials.gov were two-arm superiority-design phase III interventional oncology studies with a matured reported primary endpoint of OS and published reconstructable Kaplan-Meier plot. Reconstructed individual patient-level data were obtained from eligible trials manually using established methods (Guyot et al, BMC Med Res Methodol 2012). Both a two-stage random effects model and a one-stage meta-analytical approach leveraging the individual patient-level data were used. In the one-stage model, the Cox regression for OS was stratified and clustered by trial identity to account for varying baseline hazards.
Results: After screening 1184 trials and notably excluding 937 without an OS primary endpoint, 159 trials enrolling 104,740 patients met inclusion criteria. The OS primary endpoint was met in 42% of studies. In the two-stage model, randomization to the experimental arm was associated with improvement in OS (random effects HR, 0.87; 95% CI: 0.85 to 0.89; p < 0.0001). As anticipated, there was between-study heterogeneity (I² = 64%; t² = 0.02; Cochran’s Q = 437, p < 0.0001) consistent with the a priori choice of random effects modeling. In the one-stage meta-analysis, OS was also longer (HR, 0.88; 95% CI: 0.85 to 0.90; p < 0.0001). OS superiority was also seen among multiple subgroups, including according to disease site, stage, and sponsor.
Conclusion: While the prevalence of OS primary endpoints and OS superiority is infrequent among all phase III oncology trials, among the subset with an OS primary endpoint, the present OPTIMA meta-analysis demonstrates a statistically significant OS benefit associated with randomization to the experimental arm. The data from OPTIMA should encourage renewed enthusiasm for developing and accruing to phase III oncology trials prioritizing OS evaluations. (PROSPERO: CRD420251162778)