Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead

Abstract

Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a ‘more is better’ approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile. In this review, post-marketing dose optimization efforts were reviewed including those required by a regulatory pathway or voluntarily conducted by the sponsor to improve efficacy, safety, or method of administration. Lessons learned and future implications from this deep dive review are discussed considering the evolving regulatory landscape on dose optimization for oncology compounds. • Dose finding/optimization paradigm in oncology is evolving. • Most dose optimization PMRs requested evaluation of the B/R at a lower dose. • Most PMRs seeking a higher dose are focused on a subgroup of the approved population. • Positive ER-safety and flat ER-efficacy may be an indicator of the need for a lower dose. • Completed post-marketing dose optimization efforts have rarely led to a label change.

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