Tumor Burden Modeling versus Progression-Free Survival for Phase II Decision Making
Cette étude compare l'intérêt de deux critères de jugement d'un essai de phase II, la survie sans progression et l'évolution de la tumeur à partir de la somme de ses plus grands diamètres, pour décider de l'opportunité d'entreprendre un essai de phase III
Randomized Phase II oncology trial endpoints for decision making include both progression-free survival (PFS) and change in tumor burden as measured by the sum of longest diameters (SLD) of the target lesions. In addition to observed SLD changes, tumor shrinkage and growth parameters can be estimated from the patient-specific SLD profile over time. The ability of these SLD analyses to identify an active drug is contrasted with that of a PFS analysis through the simulation of Phase II trials via re-sampling from each of six large, Phase II and III trials, five of which were positive and one negative. From each simulated Phase II trial, a p-value was obtained from four analyses-a log-rank test on PFS, a Wilcoxon rank-sum test on the minimum observed percentage change from baseline in SLD, and two non-linear, mixed-effects model analyses of the SLD profiles. All four analyses led to approximately uniformly distributed p-values in the negative trial. The PFS analysis was the best or nearly the best analysis in the other five trials. In only one of the positive studies did the modeling analysis outperform the analysis of the minimum SLD. In conclusion, for the decision to start a Phase III trial based on the results of a randomized Phase II trial of an oncology drug, PFS appears to be a better endpoint than does SLD, whether analyzed through simple SLD endpoints, such as the minimum percentage change from baseline, or through the modeling of the SLD time course to estimate tumor dynamics.
Clinical Cancer Research , résumé, 2012