Oncology Dose Selection in Subsequent Indications: What Can We Learn From FDA-approved Oncology Drugs?

Purpose: The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed. This review examines how approved dosing regimens were selected in subsequent indications for FDA-approved oncology drugs. Methods: The Drugs@FDA database was used to identify FDA-approved new molecular entities (NMEs) between 2010 and 2023. NMEs with more than 1 approved indication were included in the analysis. In total, the dosing regimens for 67 novel oncology drugs that obtained FDA approvals for multiple indications were evaluated. Findings: Overall, in subsequent indications, 72% of NMEs used the same or clinically equivalent alternative dosing regimens to those approved in the initial indications. Amongst the 28% of NMEs that used different dosing regimens, safety/tolerability was the leading cause of a dosing regimen changes in both monotherapy and combination therapy settings. Other factors leading to changes in dosing regimens include differences in tumor biology, disease burden, pharmacokinetics, and overall benefit-risk profiles obtained from dose-finding studies. Implications: Our analysis highlighted the importance of selecting a safe, tolerable, and yet efficacious dosing regimen for the initial indication as a suboptimal initially approved regimen could lead to dosing regimen changes in later indications. Preclinical and clinical data could be leveraged to understand the pharmacology, pharmacokinetic, and pharmacodynamic differences between indications and thus support dose selection in subsequent indications.