137: Landscape Analysis of Adverse Events & Dose Intensity for FDA Approved Oncology Small Molecules

Statement of Purpose: Oncology treatments continue to move from toxic chemotherapies towards targeted therapies, and the dose selection paradigm has shifted away from “more is better” with the goal of determining an optimal dose that reduces the incidence of adverse events while maintaining efficacy. To assess if the approved dose is in fact optimal, we surveyed 48 recently approved FDA oncology small molecules with respect to safety-related events and dose intensity.

Description of Methods & Materials: Adverse event and dose intensity data were extracted from FDA multidisciplinary review documents at the initial approved dose for oncology small molecules approved from 2017-2022 (n = 48). Gathered data included the maximum tolerated dose (MTD), maximum studied dose in the absence of MTD, label dose (LD), overall % of adverse events, individual grade 3+ adverse events with high incidence ( >10%), dose modifications due to adverse events, and relative dose intensity (RDI) for each molecule.

Data & Results: Of the 48 FDA approved small molecules surveyed, 90% reported RDI of >80% at the LD with none less than 70%. There was a trend of higher RDI for molecules where LD < MTD, although the median RDI, without regard to MTD, was roughly 91%. Dose modifications occurred in a higher percentage of patients for molecules where LD = MTD vs LD < MTD (median 58 & 42% interruptions vs 30 & 20% reductions, respectively). Drug discontinuations due to adverse events were similar between compounds where LD < MTD vs LD = MTD (median 11% vs 14%). LD = MTD molecules were associated with a higher percentage of patients experiencing Grade 3+ adverse events vs. molecules where LD < MTD (median 65% vs 53% of patients), with all LD = MTD molecules having >25% patients experiencing Gr3+ adverse events. High incident Gr3+ adverse events (occurring in >10% of patients) that manifested in multiple programs were mostly hematological, but several high incident non-hematological adverse events occurring in multiple programs included diarrhea, fatigue and pneumonia.

Interpretation, Conclusion or Significance: In recently approved oncology small molecules by FDA, the approved dose was associated with an overall high RDI ( >90%), suggesting that the LD is generally tolerable during treatment. Compounds dosed at the MTD are associated with a higher incidence of dose interruptions and reductions, as well as grade 3+ adverse events than compounds with LD lower than the MTD. This analysis suggests that while recently approved oncology small molecules have RDI that could be considered tolerable, the high incidence of Gr3+ adverse events, as well as the generally increased toxicities for molecules where LD = MTD highlight the need for dose optimization in developing oncology therapeutics.

Disclosures: KC, DY, YP and RM are employees of Pfizer and hold Pfizer stock or stock options.