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Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?

Desamparados Roda1, Begoña Jimenez1, Udai Banerji2

  • 1The Institute of Cancer Research, London, United Kingdom. The Royal Marsden NHS Foundation Trust, London, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 20, 2015
PubMed

Insights

Phase I trials often underestimate toxicity for small molecule molecularly targeted agents (SM-MTA) in cancer. Subsequent phase III trials reveal higher adverse events, necessitating dose adjustments and highlighting the need for careful tolerability assessment.

Area of Science:

  • Oncology
  • Clinical Pharmacology
  • Drug Development

Background:

  • Tolerability of molecularly targeted agents (MTA) is crucial for cancer therapeutics.
  • Phase I trials determine initial safety and dosing, but real-world efficacy in larger populations requires further evaluation.
  • Small molecule MTAs (SM-MTA) and monoclonal antibody MTAs (MA-MTA) represent key classes of targeted cancer drugs.

Purpose of the Study:

  • To evaluate the realism of phase I trial dose and schedule recommendations for MTAs in larger patient cohorts.
  • To systematically review the safety profile of SM-MTA and MA-MTA approved by the FDA over the past 12 years.
  • To compare the incidence of toxicity between SM-MTA and MA-MTA in phase III trials.

Main Methods:

  • Systematic review of safety data from phase III clinical trials for FDA-approved SM-MTA and MA-MTA.
  • Analysis of reported grade 3 or 4 adverse events and dose modifications.
  • Comparison of toxicity data for single-agent MTAs versus combination therapies.

Main Results:

  • SM-MTA showed a significantly higher percentage of grade 3 or 4 adverse events compared to MA-MTA in phase III trials (40% vs. 27%).
  • Forty-five percent of patients on SM-MTA required dose modifications due to toxicity in phase III trials, with only 9% discontinuing the drug.
  • Combinations of SM-MTA with other agents resulted in higher grade 3-4 toxicity (64%) compared to single-agent SM-MTA (37%).

Conclusions:

  • Phase I studies tend to underestimate the toxicity of SM-MTA when recommending doses for phase II and III trials.
  • The observed toxicity in phase III trials suggests that current dose recommendations may not be fully realistic for broader patient populations.
  • Increased focus on tolerability is needed, especially with the growing use of SM-MTA combinations in cancer treatment.

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