Nonproportional Hazards—An Evaluation of the MaxCombo Test in Cancer Clinical Trials

Abstract

The Cross-PhRMA working group has proposed using the MaxCombo test in place of the log-rank test to evaluate treatment differences based on time-to-event endpoints, particularly if nonproportional hazards are expected. Despite demonstrating improved power and overall Type I error control, concerns about using this test for inferential purposes remain. We evaluated the MaxCombo test by reanalyzing data from six cancer clinical trials submitted to the U.S. Food and Drug Administration. Interpretation of the MaxCombo test results is not clear when the Kaplan–Meier curves crossed or had early separation. In addition, we note difficulty in interpretation of the results from the MaxCombo test when the source cause of deviation from proportionality of the survival distributions is due to underlying factors such as differential treatment effect of subgroups or intercurrent events. We illustrate these concerns based on the case examples.