Proportional Hazards Violations in Phase 3 Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

Autor:	Lin TA; Johns Hopkins Medicine, Baltimore, MD, United States., McCaw ZR; Insitro, South San Francisco, United States., Koong A; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Lin C; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Abi Jaoude J; Stanford Health Care, Stanford, CA, United States., Patel R; Memorial Sloan Kettering Cancer Center, New York, New York, United States., Kouzy R; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., El Alam MB; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Sherry AD; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Noticewala SS; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Fuller CD; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Thomas CR; Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States., Sun R; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Lee JJ; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Lin R; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Yuan Y; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Shyr Y; Vanderbilt University Medical Center, Nashville, TN, United States., Meirson T; Rabin Medical Center, Petah Tikva, Israel., Ludmir EB; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 12. Date of Electronic Publication: 2024 Aug 12.
DOI:	10.1158/1078-0432.CCR-24-0566
Abstrakt:	Background: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHVs) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase 3 oncology trials and assess the utility of restricted mean survival time (RMST) and MaxCombo as additional analyses. Methods: Clinicaltrials.gov and PubMed were searched to identify 2-arm, randomized, phase 3 superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 (23.8%; 95%CI 19.7%, 28.5%) comparisons. In multivariable analysis, non-OS endpoints (odds ratio [OR] 2.16 [95%CI 1.21, 3.87]; P=.009) were associated with higher odds of PHVs, and immunotherapy comparisons (OR 1.94 [95%CI 0.98, 3.86]; P=.058) were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) pre-specified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with RMST or MaxCombo, of which ten (71%) reported negative results. Conclusion: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting non-proportional hazards to be misinterpreted.
Databáze:	MEDLINE
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