Abstract
IMPORTANCE: Phase 2 trials and early efficacy end points play a crucial role in informing decisions about whether to continue to phase 3 trials. Conventional end points, such as objective response rate (ORR) and progression-free survival (PFS), have demonstrated inconsistent associations with overall survival (OS) benefits in immune checkpoint inhibitor (ICI) trials. Restricted mean duration of response (DOR) is a rigorous metric that combines both response status and duration information. However, its utility in clinical development has not been comprehensively explored. OBJECTIVE: To determine whether using restricted mean DOR in phase 2 trials can advance promising regimens to phase 3 trials sooner and eliminate unfavorable regimens earlier and with a higher degree of confidence compared with PFS and ORR. DESIGN, SETTING, AND PARTICIPANTS: This simulated modeling study randomized phase 2 screening trials by resampling 1376 patients from 2 completed randomized phase 3 trials of ICIs. Data were analyzed from August 2019 to July 2020. EXPOSURES: Use of ICIs. MAIN OUTCOMES AND MEASURES: Restricted mean DOR, PFS, ORR, and OS were estimated and compared between groups. Three scenarios were considered: (1) significant differences in OS, PFS, and ORR; (2) significant differences in OS and noticeable differences in ORR but not PFS; and (3) no differences in OS, PFS, or ORR. For each setting, 5000 randomized phase 2 trials with different sample sizes were simulated, with additional censoring applied to mimic staggered accruals and ensure fair comparisons between different analysis methods. Probabilities of concluding positive phase 2 trials using PFS, ORR, and DOR were summarized and compared. RESULTS: The restricted mean DOR difference correctly estimated a positive OS benefit more frequently than did the ORR or PFS tests, across different sample sizes, significance levels, and censoring levels evaluated. When both OS and PFS differed, the ranges of true-positive or power rates were 79.2% to 98.7% for DOR, 56.3% to 93.2% for PFS, and 67.0% to 96.0% for ORR. When OS differed but PFS did not, the ranges of power rates were 24.0% to 76.0% for DOR, 3.0% to 19.0% for PFS, and 10.5% to 38.0% for ORR. When OS was similar, the false-positive rate of restricted mean DOR test was close to the chosen significance level. CONCLUSIONS AND RELEVANCE: These findings suggest that restricted mean DOR in randomized phase 2 trials is potentially more sensitive and useful than PFS and ORR in estimating the subsequent phase 3 conclusions and, thus, may be considered to complementarily facilitate decision-making in future clinical development.