Single-Arm Phase II Trials of Combination Therapies: A Review of the CTEP Experience 2008-2017
A partir de l'analyse des données de la base du "Cancer Therapy Evaluation Program" portant sur 120 essais cliniques ouverts entre 2008 et 2017, cette étude examine la crédibilité des preuves avancées pour démontrer la supériorité d'une combinaison thérapeutique sur ses composants en monothérapie
Designing and interpreting single-arm phase II trials of combinations of agents is challenging because it can be difficult based on historical data to identify levels of activity for which the combination would be worth pursuing. We identified Cancer Therapy Evaluation Program (CTEP) single-arm combination trials that were activated in 2008-2017 and tabulated their design characteristics and results. Positive trials were evaluated as to whether they provided credible evidence that the combination was better than its constituents. 125 trials were identified, and 120 trials had results available. Twelve had designs where eligible patients were required to be resistant or refractory to all but one element of the combination. Only 17.8% of the 45 positive trials were deemed to provide credible evidence that the combination was better than its constituents. Of the ten positive trials with observed rates ten percentage points higher than their upper (alternative hypothesis) targets, only five were deemed to provide such credible evidence. Many trials were definitively negative, with observed clinical activity at or below their lower (null hypothesis) targets. Ideally, use of single-arm combination trials should be restricted to settings where each agent is known to have minimal monotherapy activity (and a randomized trial is infeasible). In these settings, an observed signal is attributable to synergy and thus could be used to decide whether the combination is worth pursuing. In other settings, credible evidence can still be obtained if the observed activity is much higher than expected, but experience suggests that this is a rare occurrence.
Journal of the National Cancer Institute , article en libre accès, 2018