Purpose The
Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the
epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced
esophageal cancer who had
disease progression after
chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from
gefitinib. Methods A prespecified, blinded molecular analysis of
Cancer Esophagus Gefitinib trial
tumors was conducted to compare efficacy of
gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results
Biomarker data were available for 340 patients. In EGFR FISH-positive
tumors (20.2%), overall survival was improved with
gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative
tumors, there was no difference in overall survival with
gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from
gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for
gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with
esophageal cancer who may benefit from
gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR
therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified
esophageal cancer.