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Development of the novel biologically targeted anticancer agent gefitinib: determining the optimum dose for clinical

Michael Wolf1, Helen Swaisland, Steven Averbuch

  • 1Clinical Research, AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 23, 2004
PubMed

Insights

Determining the optimal dose for gefitinib, a targeted anticancer drug, is crucial. Phase I trials revealed 250 mg daily provides sufficient pharmacological activity and antitumor effects without increased toxicity in non-small cell lung cancer patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trial Design

Background:

  • Novel biologically targeted anticancer agents like gefitinib require new dosing strategies compared to traditional cytotoxic drugs.
  • Determining the maximum tolerated dose (MTD) is standard for cytotoxic agents, but biologically targeted drugs may have an optimal biological dose (OBD) separate from MTD.
  • Gefitinib (Iressa) is a targeted therapy whose dose optimization for advanced non-small cell lung cancer (NSCLC) needed investigation.

Purpose of the Study:

  • To establish the optimal dosing regimen for gefitinib in late-stage clinical development and use.
  • To evaluate the pharmacokinetics, safety, efficacy, and targeted biological activity of gefitinib.
  • To determine if higher doses beyond a certain threshold offer additional efficacy benefits or increased toxicity in NSCLC.

Main Methods:

  • A multifaceted Phase I clinical trial program assessed once-daily oral gefitinib doses.
  • Pharmacokinetic, safety, and biological activity data were collected to identify potential OBD.
  • Phase II trials ('Iressa' Dose Evaluation in Advanced Lung Cancer 1 and 2) compared gefitinib doses of 250 mg and 500 mg daily in NSCLC patients.

Main Results:

  • The MTD for gefitinib was determined to be greater than or equal to 700 mg/day.
  • Doses as low as 150 mg/day achieved sufficient plasma concentrations for pharmacological activity, biological effect, and antitumor activity.
  • Phase II trials showed no additional efficacy benefit for doses above 250 mg/day, while adverse effects increased dose-dependently.

Conclusions:

  • The recommended clinical dose for gefitinib in advanced non-small cell lung cancer is 250 mg/day.
  • This dose provides a balance of pharmacological activity, efficacy, and acceptable toxicity.
  • The gefitinib development model can inform the development of other novel, non-cytotoxic anticancer agents.

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