Dose Optimization of Targeted Therapies for Oncologic Indications

Area of Science:

• Oncology
• Pharmacology
• Drug Development

Background:

• 21st-century oncology has seen reduced cancer mortality due to therapeutic advances.
• Targeted therapies represent the majority of US Food and Drug Administration (FDA)-approved oncology drugs in the last 25 years, becoming standard care.
• Traditional dose-finding methods for cytotoxic chemotherapy persist despite evolving targeted therapies.

Purpose of the Study:

• To review challenges in dose-finding for targeted cancer therapies.
• To highlight how oncologists, sponsors, and regulators have managed these challenges.
• To contextualize these challenges within the evolving regulatory landscape.

Main Methods:

• Review of case studies for six different targeted cancer therapies.
• Analysis of dose-finding strategies employed.
• Examination of regulatory initiatives and guidance.

Main Results:

• Identified persistent challenges in adapting traditional dose-finding methodologies for targeted therapies.
• Demonstrated various approaches used by stakeholders to manage dose-finding issues.
• Highlighted the FDA's recent efforts, including Project Optimus and draft guidance, to address these concerns.

Conclusions:

• The current dose-finding paradigm for chemotherapy is inadequate for modern targeted cancer therapies.
• Adapting dose selection is crucial for optimizing efficacy and safety of novel oncology drugs.
• Ongoing regulatory initiatives aim to modernize dose optimization in cancer drug development.