Optimizing dose selection in oncology: the rationale for the clinical dose selection of giredestrant, an oral...

'Maximum tolerated dose' (MTD) was historically used to maximize clinical efficacy. However, there is a drive to optimize dose selection to improve safety/tolerability, while maintaining efficacy. This paradigm is increasingly important in oncology clinical development, leading to a focus on careful early-phase trial design to ensure that appropriate dose - or exposure-response data are obtained to guide dose selection.

We describe the development pathway and risk-benefit considerations for clinical dose selection for giredestrant, a next-generation, highly potent, non-steroidal oral selective estrogen receptor antagonist and degrader, under development for estrogen receptor-positive breast cancer. This included evaluating low-grade adverse events to potentially improve tolerability, long-term compliance, and giredestrant combination therapy use; using pharmacodynamic markers for early drug activity assessment; and testing multiple dose levels during dose-escalation and -expansion phases. Data were leveraged from preclinical and phase I/II studies in metastatic and early breast cancer, as a single agent with palbociclib, to inform giredestrant dose selection.

Our learnings challenge the MTD paradigm in drug development, particularly in targeted therapies, and demonstrate the importance of basing dose selection on the totality of evidence, including preclinical data, and may help inform the clinical development of future targeted therapies.