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Dose Optimization of Targeted Therapies for Oncologic Indications
1Clinical Science, Accutar Biotechnology Inc., Cranbury, NJ 08512, USA.
Abstract:
Therapeutic advances in oncology in the 21st century have contributed to significant declines in cancer mortality. Notably, targeted therapies comprised the largest proportion of oncology drugs approved by the United States (US) Food and Drug Administration (FDA) over the past 25 years and have become the standard of care for the treatment of many cancers. However, despite the metamorphosis of the therapeutic landscape, some aspects of cancer drug development have remained essentially unchanged. In particular, the dose-finding methodology originally developed for cytotoxic chemotherapy drugs continues to be implemented, even though this approach no longer represents the most appropriate strategy for modern cancer therapies. In recognition of the need to reconsider assumptions, adapt the dose selection process for newer drugs, and design alternative strategies, the FDA has undertaken several initiatives in recent years to address these concerns. These actions include the launch of Project Optimus in 2021 and the issuance of draft guidance for industry on dose optimization of oncology drugs in 2023. Amid this evolving regulatory environment, the present manuscript reviews case studies for six different targeted cancer therapies, highlighting how dose-finding challenges have been managed to date by oncologists, sponsors, and regulators.
Insights
Modern cancer drug development requires updated dose-finding methods beyond traditional cytotoxic chemotherapy. The US Food and Drug Administration (FDA) is leading initiatives like Project Optimus to optimize targeted therapy dosing.
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.
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