Hirsch FR et al. (2006) Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24: 5034–5042

Response to the EGFR inhibitor gefitinib is correlated with mutations in EGFR and with phosphorylated Akt in some patients, although the association of KRAS and BRAF mutations with gefitinib resistance is unclear. Hirsch et al. recently assessed the relationship between such biomarkers and clinical outcome in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib.

The phase III trial included 1,629 patients randomly assigned to receive either 250 mg of gefitinib, or placebo. Patients who had a high EGFR copy number had a significantly improved survival following gefitinib treatment compared with patients with low EGFR copy numbers (P = 0.045), and a 39% lower risk of death than patients who received placebo (P = 0.067). Gefitinib also prolonged median survival in individuals with a high EGFR copy number when compared with placebo (8.3 vs 4.5 months), but this difference was not observed for those with a low EGFR copy number (P = 0.417). Gefitinib-treated patients with EGFR-positive tumors had significantly better survival (P = 0.049) and improved response rates (8.2% vs 1.5%) compared with patients with EGFR-negative tumors. Objective tumor response rates were also higher in gefitinib-treated patients with mutated EGFR than in those without such mutations (37.5% vs 2.6%). In contrast to previous studies, there was no correlation between phosphorylated Akt protein expression and survival outcome; the role of KRAS and BRAF mutations in relation to clinical outcome could not be assessed.

The authors conclude that EGFR copy number is a potential biomarker that could identify the patients with NSCLC who are most likely to benefit from gefitinib treatment.