FDA initiatives to support dose optimization in oncology drug development: the less may be the better.

When anticancer drugs are developed, the first-time-in-human study is initiated with dose escalation to find the best dose for the subsequent development. In this stage, the assumption of the optimal dose is the maximum tolerated dose (MTD) which was well applied to cytotoxic agents since those drugs show a steep dose-response relationship. The more drug administered, the greater the tumor cell die as far as the human body is tolerated. These days, most new anticancer drugs are targeted agents that inhibit molecular pathways of proliferation in cancer cells or inhibit their death. For these agents, dosing at the MTD is often inappropriate. Higher doses lead to off-target effects: toxicity, dose interruptions, and reduced compliance, while much lower doses result in good tumor response with much lower toxicity and better drug compliance. Nevertheless, most new targeted anticancer agents are still tested in early phase clinical trials to determine the MTD without incremental benefit and that dose is carried forward into late-stage studies. Therefore, some groups of oncologists have suggested the optimal dose of a new anticancer drug would be determined best through a randomized dose-ranging phase II trial [1]. Recently FDA and many stakeholders including Friends of Cancer Research have started to advocate the concept and implementation in the early drug development process [2,3]. In this commentary, issues from conventional dose findings in early phase oncology trials and suggestions and recommendations by Friends of Cancer Research and FDA initiatives with a case of sotorasib are addressed.