Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules.

As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD). Compared to compounds where the label dose was less than the MTD, compounds where the Label Dose = MTD reported overall lower dose intensity and higher dose modifications due to adverse events, though treatment discontinuations due to adverse events were similar. A post-marketing requirement (PMR) for dose optimization was issued for 7 compounds in the dataset, of which 3 were at the Label Dose = MTD. None of these 7 compounds reported a positive exposure-response relationship in efficacy and only 4 reported an exposure-response in safety events. Overall, dose intensity was lower, and incidence of dose modifications, discontinuations, and Grade ≥ 3 TEAEs were higher in compounds issued a PMR vs. the latter. This analysis suggests that while recently approved oncology small molecules have a reasonable relative dose intensity (RDI), the higher incidence of Grade ≥ 3 TEAEs and dose modifications where Label Dose = MTD highlight the continuing need for dose optimization while developing oncology therapeutics.