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Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer
Petty RD, Dahle-Smith A, Stevenson DAJ, Osborne A, Massie D, Clark C, et al.
J Clin Oncol. 2017 May 24:JCO2016703934. [Epub ahead of print]
Commentary by Prof Lordick and Dr Elizabeth Smyth:
Several randomized controlled trials investigating EGFR-directed drugs - monoclonal antibodies and TKI’s - in upper gastrointestinal cancers, including EXPAND, REAL-3 and COG, were published over the last years. All of these were negative for efficacy endpoints and there was only little hope that subgroups of tumours maybe identified which can be treated with EGFR-inhibitors. The preplanned analysis of EGFR-FISH from the COG (Cancer Esophagus Gefitinib) Study indicates such a subgroup of patients who may derive benefit from Gefitinib after failure of previous chemotherapy. Patients with cancers that display EGFR high polysomy or amplification, which is the case in approximately every 5th patient, have a longer overall survival with Gefitinib compared to placebo.
The working group should be congratulated on this important analysis which was based on sound methodological work-up as published previously by the same working group (Dahle-Smith et al. 2015).
We believe that these results should re-stimulate the way how to investigate new treatments for upper GI cancers. Proper definition of molecular pathways and assessment of targeted drugs in promising subgroups is the way to move this difficult field forward. We hope that confirmation of the results from the COG trial will become available from independent studies in order to translate this promising finding into clinical practice.
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.
© 2017 by American Society of Clinical Oncology