Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead

Area of Science:

• Oncology
• Pharmacology
• Drug Development

Background:

• Cancer therapy has evolved from chemotherapy to targeted agents and immunotherapy.
• Molecularly targeted agents offer selectivity and a wider therapeutic window compared to cytotoxic drugs.
• Traditional early-phase trials focus on identifying the maximum tolerated dose (MTD), potentially overlooking optimal dosing strategies.

Purpose of the Study:

• To review post-marketing dose optimization efforts for molecularly targeted oncology agents.
• To analyze regulatory and sponsor-initiated studies aimed at improving efficacy and safety.
• To discuss lessons learned and future implications for oncology drug development.

Main Methods:

• Literature review of post-marketing requirement (PMR) studies and voluntary sponsor-initiated dose optimization efforts.
• Analysis of strategies to improve efficacy, safety, and administration methods.
• Examination of the evolving regulatory landscape for oncology drug dosing.

Main Results:

• First-in-patient studies often identify the MTD using a 'more is better' approach.
• Post-marketing studies frequently explore lower doses or altered frequencies to optimize the benefit-risk profile.
• Dose optimization is crucial for enhancing patient outcomes and drug safety.

Conclusions:

• The 'more is better' approach to MTD in early oncology trials may not be optimal for targeted agents.
• Post-marketing dose optimization is essential for refining the therapeutic use of oncology drugs.
• Future oncology drug development should consider adaptive dosing strategies and regulatory flexibility.