The evaluation of epidermal growth factor receptor copy number gain identified a subgroup of patients with esophageal cancer who benefitted from second-line gefitinib, according to a prespecified, blinded molecular analysis of the Cancer Esophagus Gefitinib trial.
In that trial, researchers randomly assigned patients with chemotherapy-resistant esophageal cancer to receive gefitinib (Iressa, AstraZeneca; n = 450) — an EGFR tyrosine kinase inhibitor — or placebo as second-line therapy. A minority subset of patients who received gefitinib demonstrated rapid and durable responses.
Russell D. Petty, MBChB, PhD, professor of medical oncology at the University of Dundee School of Medicine in Scotland, and colleagues hypothesized that genetic alteration of the EGFR pathway would identify patients who would benefit from gefitinib.
“A variety of different EGFR signaling abnormalities have been described in esophageal cancer, including copy number gain of EGFR,” Petty and colleagues wrote. “Study results suggest that chromosomal instability is an early and frequent feature of esophageal cancer pathogenesis, and somatic copy number alterations occur frequently in esophageal adenocarcinoma and squamous cell carcinoma.”
The researchers analyzed biomarker data from patients’ tumors to evaluate EGFR copy number gain by fluorescent in situ hybridization (FISH; n = 292) and EGFR, KRAS, BRAF and PIK3CA mutation status (n = 326).
“Identification of a predictive biomarker for patients who receive benefit from gefitinib would enable a more accurate selection of patients for treatments and prevent futile treatment in those patients who are unlikely to benefit,” Petty and colleagues wrote.
Fifty-nine patients with EGFR FISH–positive tumors (high polysomy, 13%; amplification, 7.2%) who received gefitinib demonstrated superior disease control rate (37% vs. 14%), PFS (HR = 0.55; 95% CI, 0.32-0.95) and OS (HR = 0.59; 95% CI, 0.35-1) compared with the placebo arm.
Performance status, prior treatment, BMI, histology, disease site, age and sex did not appear associated with PFS or OS in EGFR FISH–positive tumors, according to a multivariate Cox proportional hazards analysis.
A post hoc analysis suggested that the patients with EGFR amplification had greater benefit with gefitinib than those with high polysomy (HR for death = 0.21; 95% CI, 0.07-0.64).
Patients with EGFR FISH–negative tumors who received gefitinib also demonstrated superior disease control rates (25% vs. 14%) compared with the placebo arm. However, PFS (HR = 0.87; 95% CI, 0.66-1.12) and OS (HR = 0.9; 95% CI, 0.69-1.18) did not differ among those treated with gefitinib or placebo.
Patients did not demonstrate a difference in disease control rate and survival regarding EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation vs. none.
“EGFR FISH appears to predict a benefit from gefitinib in patients with esophageal cancer whose disease has progressed after previous chemotherapy,” Petty and colleagues wrote. “The role of gefitinib and other anti-EGFR therapies should be explored in prospective clinical trials in different settings in EGFR FISH–positive esophageal cancer, particularly in EGFR–amplified tumors, in which the impact of these agents is likely to be greatest.” – by Kristie L. Kahl
Disclosure: Petty reports honoraria from Eli Lilly and Pfizer; consultant and advisory fees from Bristol-Myers Squibb UK and Eli Lilly; research funding from AstraZeneca, Boston Biomedical, Eli Lilly, Janssen and Merck KGaA; travel accommodations from Bristol-Myers Squibb UK, Eli Lilly and Merck KGaA; and a speaker role with Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.