FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high

This NEJM perspective from the FDA Oncology Center of Excellence set out why oncology dose selection had to change. Phase 1 trials find the maximum tolerated dose over one cycle, a rational approach for cytotoxics but not for targeted agents and immunotherapies whose effects plateau at lower exposures and whose chronic, low-grade toxicity drives discontinuation.

The authors cited sotorasib, approved at 960 mg daily although early data showed similar exposure and activity at 240 mg; the FDA required a randomised post-marketing comparison of the two doses, which did not establish the lower dose as equivalent and left the label at 960 mg. Other examples included post-approval dose reductions of cabozantinib, niraparib, ceritinib and dasatinib.

Project Optimus, launched the same year, now expects sponsors to compare more than one dose before pivotal trials; FDA's 2024 guidance on dose optimisation formalised this.