LAUSR

Introduction: Molecularly targeted (MTAs) and immune-oncology (IO) agents are more selective with wider therapeutic window than cytotoxic agents resulting in maximal activity at doses < MTD. However, these agents commonly selected the MTD (or highest tested dose) which is assessed using dose-limiting toxicities in escalating doses in limited number of patients/dose. This led to several post-marketing requirement (PMR) studies to evaluate alternative dosing regimens to optimize the benefit-risk. Methods: Post-marketing dose optimization studies (required by FDA or sponsor initiated) for oncology MTAs/IO agents were reviewed. These studies/analyses were classified in to attempts to improve efficacy, safety, or ‘life cycle management’ (ie, fixed vs body size-based dosing, favorable route of administration, or extending the dosing interval). Approvals 1999-April/2022 were evaluated using FDA review documents and published literature. PMR studies for organ impairment, DDI, or food effect were excluded. Results: Overall, 27 (16 MTAs and 9 IO) out 126 FDA oncology approvals reviewed were identified to have conducted post-approval dose optimization studies (27/126, 21.4%). Dose optimization studies were either efficacy-driven (n = 4), safety-driven (n = 13), or to improve method of administration (ie, IV to SC route; body-weight to fixed dosing; less dosing frequency) (N = 14). Efficacy-driven PMRs evaluated a higher dose either for the overall population (1/4) or for a subgroup with lower exposure (3/4); the latter cases showed no clear benefit in this subgroup vs case-matched subgroup from the control arm. No changes of label dosing recommendations resulted from efficacy-driven PMRs. All safety-driven PMRs which evaluated lower doses were for drugs with a positive exposure-safety relationship and most had a flat exposure-efficacy relationship (9/13, 69%) suggesting that a lower dose might improve safety without compromising efficacy. Completed safety-driven PMR studies resulted in changing the approved dose in 2/7 cases (29%). Lower doses were commonly associated with better safety profiles, however, establishing efficacy non-inferiority vs approved doses was typically not successful except in 1 case where non-inferiority was met for the primary endpoint of overall survival; this did not lead to label change as secondary endpoints, eg, PFS, favored the higher dose.Attempts to improve method of administration tended to be feasible and resulted in a successful change of the label dose for drugs with relatively flat exposure-efficacy and safety profiles and with adequate efficacy/safety data at multiple dose levels. Conclusion: Our results suggest that safety or efficacy-driven post-marketing dose optimization studies were rarely successful in changing the label dose. Dose optimization could be more important for drugs with a steep exposure-safety relationship and a flat exposure-efficacy relationship. Citation Format: Pooneh Soltantabar, Hoi-Kei Lon, Kourosh Parivar, Diane Wang, Mohamed Elmeliegy. Optimizing benefit/risk in oncology: Review of post marketing dose optimization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5063.