Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

Abstract

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.

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

“…Coamplification of ERBB2 and EGFR was not, however, required for afatinib response, as the combination of afatinib with trastuzumab showed modest clinical activity in ERBB2-amplified tumors lacking EGFR amplification. Furthermore, EGFR-selective inhibitors such as cetuximab and gefitinib have demonstrated activity in EGFR-amplified tumors lacking ERBB2 amplification, suggesting that these agents may have a different efficacy profile than afatinib (30)(31)(32)(33).…”

What is the value of third‐line chemotherapy in advanced gastroesophageal cancer? A 5‐year retrospective analysis at a single center

“…One of the reasons for such failures is the lack of a predictive biomarker. This is illustrated in the COG study of gefitinib in esophageal carcinoma whereby, even though the overall study result was negative, a survival benefit was observed in a subgroup of patients with tumors amplified for EGFR …”

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

“…In fact, in a recent study of 22 pan-RAS/BRAF/HER2/MET wild-type colorectal carcinoma cases progressing on EGFR antibody therapeutic regimens, tissue and ctDNA analyses at cetuximab or panitumumab progression supported KRAS mutations and HER2 or MET amplification as the dominant mediators of clinical resistance (27). Furthermore, EGFR amplification is an emerging target in gastric and esophageal cancers (29–31). However, in the relatively small analysis of paired samples in this study, no HER2 or MET amplifications (and just one EGFR amplification, found in tissue only) were observed in either subset, so concordance analysis was limited for these specific gene amplifications.…”