Inappropriate dose of multitargeted tyrosine kinase inhibitors: the original sin

Area of Science:

• Oncology
• Pharmacology
• Clinical Trial Design

Background:

• Antiangiogenic tyrosine kinase inhibitors (TKIs) present challenges in clinical use, frequently necessitating dose adjustments or treatment cessation.
• The efficacy and safety of TKIs are often compromised by suboptimal dosing strategies established during early drug development.

Purpose of the Study:

• To highlight the impact of flawed early study designs on the recommended dosing of antiangiogenic TKIs.
• To propose innovative methodologies for optimizing TKI dose selection and toxicity management.

Main Methods:

• Review of pitfalls in the development of TKIs such as sunitinib, sorafenib, regorafenib, and pazopanib.
• Analysis of current approaches to dose-limiting toxicity assessment and TKI mechanism of action.

Main Results:

• Identified critical issues in the early development phases of several antiangiogenic TKIs.
• Demonstrated the need for revised strategies in determining the recommended phase II dose (RP2D).

Conclusions:

• Early drug development studies for TKIs require more rigorous designs to establish optimal dosing.
• Implementing innovative approaches, including extended toxicity assessments and intermediate randomized trials, can improve TKI therapy.
• Better definition of TKI-induced toxicity is crucial for effective dose management and patient outcomes.