First line gefitinib in patients with advanced non small cell lung cancer harboring somatic EGFR mutations.
PURPOSE Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs) The multicenter iTARGET trial prospectively examined first line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. PATIENTS AND METHODS Chemotherapy naive patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. RESULTS Ninety eight patients underwent EGFR screening and mutations were detected in 34 (35% EGFR mutations were primarily exon 19 deletions (53% and L858R (26% though 21% of mutation positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression free survival was 9.2 months (95% CI, 6.2 to 11.8) Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. CONCLUSION First line therapy with gefitinib administered in a genotype directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.
Journal of clinical oncology official journal of the American Society of Clinical Oncology