Revisiting the ethics of phase 1 oncology trials in the era of precision medicine: A systematic review.

Abstract

e14060 Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.