Efficacy assessment in phase I clinical trials: endpoints and challenges

The scope of phase I clinical trials in oncology goes beyond the conventional safety evaluation-only objectives of these trials in other specialties. Rather, most first-in-human oncology clinical trials have therapeutic intent, and efficacy signals observed in phase I trials can drive a go/no-go decision of advancing a new molecule to phase II testing. The complexity of efficacy assessment in the context of a small, heterogeneous patient population and a complex study design requires a more liberal perspective compared with later trial phases when looking into efficacy endpoints. Classically, in later-phase clinical trials, these endpoints would include the objective response rate, progression-free survival, and overall survival. However, new, evolving endpoints may be worth investigating when looking into the antitumor activity signals in phase I trials. Integration of all these endpoints into trial designs can improve the assessment of therapeutic efficacy during early drug development and guide decisions related to the further advancement of novel molecules into later phases. In this review, we discuss the advantages and pitfalls of different classic efficacy endpoints when evaluated as part of phase I trials in oncology and describe how challenges in assessing the antitumor activity of new drugs can be overcome through the incorporation of novel endpoints that have thus far proven successful in clinical trials.