Potential alternative dosing strategies for FDA-approved oncology biologics based on reanalysis of exposure-response data.

Abstract

e15135 Background: Many modern oncology biologics were developed using historical maximum tolerated dose paradigms that are poorly aligned with targeted/immunotherapy PK/PD features including long half-life, early efficacy plateaus, and target saturation. Therefore, labeled regimens may exceed the exposure needed for maximal benefit and could be candidates for lower doses and/or longer dosing intervals, with potential to reduce avoidable toxicity and financial burden. Regulatory initiatives (e.g., Project Optimus) emphasize selecting optimal rather than maximal doses through prospective robust dose exploration and PK/exposure-response (E-R) integration. Methods: FDA-approved large-molecule oncology drugs were identified using Drugs@FDA reports. Labeling, FDA multidisciplinary and clinical pharmacology reviews, and published literature were systematically reviewed. Pharmacokinetic and population PK parameters, covariates, and E–R evidence were extracted. Alternative dosing regimens (dose reduction and/or interval extension) were proposed when dosing appeared potentially non-optimal, defined as: (1) no credible E–R relationship or likely false-positive E–R, due to confounding, with limited lower-dose exploration; (2) dosing exceeding that required for maximal response or target saturation; or (3) dosing frequency excessive relative to drug PK. Drug cost impact was estimated using average wholesale price (AWP; Micromedex Red Book), assuming no vial sharing or storage. Results: Twenty-nine FDA-approved oncology mAbs/immunotherapies were screened; 21/29 (72%) had candidate alternative dosing with potential maximum dose savings of 25–67%. 19/21 (90%) had estimable annual per-patient impact, with maximum annual per-patient savings ranging from $39,645–$240,583. For drugs with available 2024 annualized global sales, the theoretical upper-bound global annual savings (sales × maximum dose-saving %) totaled ~$31.1B/year, led by pembrolizumab (~$14.7B), trastuzumab including biosimilars (~$3.7B), bevacizumab including biosimilars: (~$3.63B), atezolizumab (~$3.0B), and nivolumab (~$2.7B), followed by durvalumab (~$1.57B) and ipilimumab (~$1.31B). The highest maximum dose-saving percentages were observed for atezolizumab (67%) and toripalimab (66.6%), with several additional agents showing ~50% potential dose savings, including pembrolizumab, nivolumab, trastuzumab, bevacizumab, dostarlimab, penpulimab, and ipilimumab. Conclusions: A substantial proportion of marketed oncology biologics may be administered at doses and/or intervals exceeding those needed to maintain pharmacologically active exposure. PK/E–R–informed dose optimization aligns with Project Optimus principles and may reduce drug use and financial toxicity without compromising efficacy.