Adding the EGFR inhibitor cetuximab (Erbitux) to standard-of-care chemotherapy for advanced biliary cancer failed to improve patient survival, according to a study published online May 20 in the Lancet Oncology.
This is the third study in a row to show no benefit of EGFR inhibitors in the treatment of biliary cancer.
Cetuximab is a chimeric monoclonal antibody that targets EGFR, blocking growth signals and inducing apoptosis. EGFR is overexpressed in 67% to 100% of biliary cancers.
"Our data suggest that any potential antitumor activity of cetuximab does not translate into a survival advantage when combined with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer compared with chemotherapy alone," write David Malka, MD, PhD, from the gastrointestinal oncology unit at Institut Gustave Roussy in Villejuif, France, and colleagues.
In addition, "neither tumor KRAS or BRAF mutations, nor EGFR overexpression (identified in nearly a quarter of patients), seemed to help to select patients able to respond to therapy," they report.
The results are counter to what has been seen in the treatment of colorectal cancer, where EGFR-targeting antibodies have led to improved outcomes. In colorectal cancer, the presence of KRAS and BRAF mutations predict a lack of response to monoclonal antibodies targeting EGFR.
BINGO Study
Patients in the phase 2 noncomparative open-label BINGO trial had nonresectable cholangiocarcinoma, metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma. Each had a World Health Organization performance status of 0 or 1 and a life expectancy of at least 3 months. The primary end point was progression-free survival at 4 months, analyzed by intention to treat.
All 150 patients received chemotherapy with gemcitabine 1000 mg/m² and oxaliplatin 100 mg/m². Of these, 76 patients were randomly assigned to also receive cetuximab 500 mg/m². Treatment was administered every 2 weeks until there was evidence of disease progression or unacceptable toxicity.
More patients in the cetuximab group than in the chemotherapy-alone group achieved progression-free survival at 4 months (63% vs 54%). Median progression-free survival was also longer in the cetuximab group (6.1 vs 5.5 months).
However, median overall survival was shorter in the cetuximab group than in the chemotherapy alone group (11.0 vs 12.4 months).
This is the third study of EGFR inhibitors in biliary cancer that failed to repeat promising results from an earlier trial. In a phase 2 trial conducted in Austria, 19 of 30 patients (63%) treated with cetuximab plus chemotherapy achieved an objective response, and 3 of those achieved a complete response (Lancet Oncol. 2010;11:1142-1148).
The Austrian study might have been more a triumph of patient selection than a demonstration of the efficacy of cetuximab, writes Juan W. Valle, MB, ChB, MSc, FRCP, from the Department of Medical Oncology at the University of Manchester in the United Kingdom, in an accompanying comment.
"Results of BINGO suggest that the benefit achieved in the earlier study was probably largely due to chemotherapy combined with a proactive surgical approach and careful patient selection, rather than the addition of cetuximab," he explains.
One of the other studies that failed to show a benefit was a phase 3 trial of 268 patients with metastatic biliary tract cancer (Lancet Oncol. 2012;13:181-188). There was no significant difference in progression-free survival between patients who received chemotherapy alone and those who received chemotherapy plus the EGFR inhibitor erlotinib. The difference in median progression-free survival between the erlotinib and chemotherapy-alone groups was not significant (5.8 vs 4.2 months; P = .087). Although more patients in the erlotinib group had an objective response (40 vs 21; P = .005), median overall survival was the same in the 2 groups, at 9.5 months.
The other study that failed to show a benefit randomized 122 biliary cancer patients to either chemotherapy alone or cetuximab plus chemotherapy. The results were presented at the 2013 Annual Meeting of the American Society of Clinical Oncology. Although progression-free survival was better in the cetuximab group (7.1 vs 4 months; P = .0069), the difference in median overall survival was not significant (10.3 vs 8.8 months; P = .4057).
"Despite national or international collaboration, 3 randomized trials, including this study, did not confirm the promising results of previous phase 2 trials regarding the therapeutic potential of EGFR inhibition in patients with advanced biliary tract cancer," Dr. Malka and colleagues write. "More preclinical and early clinical studies are needed to suggest which targeted agent to use."
Several BINGO authors report financial relationships with a number of companies, including Roche, Amgen, ImClone, Bayer, Teva, sanofi-aventis, Ipsen, Celgene, and Novartis. Dr. Valle reports relationships with AstraZeneca, Sirtex, Celgene, and Merck, all unrelated to this research.
Lancet Oncol. Published online May 20, 2014. Abstract
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Cite this: Jenni Laidman. EGFR Inhibitor Fails to Improve Biliary Cancer Survival - Medscape - May 29, 2014.
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