Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.

Abstract

PURPOSE:

Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC.

PATIENTS AND METHODS:

Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect.

CONCLUSION:

Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.

• Authors: Roy S Herbst, Giuseppe Giaccone, Joan H Schiller, Ronald B Natale, Vincent Miller, Christian Manegold, Giorgio Scagliotti, Rafael Rosell, Ira Oliff, James A Reeves, Michael K Wolf, Annetta D Krebs, Steven D Averbuch, Judith S Ochs, John Grous, Abderrahim Fandi, David H Johnson
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 22 Issue 5 Pg. 785-94 (Mar 01 2004) ISSN: 0732-183X [Print] United States
• PMID: 14990633 (Publication Type: Clinical Trial, Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Quinazolines
• Carboplatin
• Paclitaxel
• Gefitinib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality, pathology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Gefitinib
• Humans
• Infusions, Intravenous
• Lung Neoplasms (drug therapy, mortality, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Multivariate Analysis
• Neoplasm Staging
• Paclitaxel (administration & dosage)
• Predictive Value of Tests
• Prognosis
• Quinazolines (administration & dosage)
• Reference Values
• Risk Assessment
• Survival Analysis
• Treatment Outcome