Combination therapy with the epidermal growth factor receptor–-blocker afatinib and cetuximab, a monoclonal antibody with anti-EGFR action, showed "robust and durable" clinical activity against advanced lung cancers that had acquired resistance to erlotinib or gefitinib in an international, uncontrolled industry-sponsored phase Ib clinical trial, according to a report published online July 29 in Cancer Discovery.
Dr. Yelena Janjigian
Until now, there have been no effective therapies for patients who initially showed dramatic tumor regression and prolonged survival with the EGFR inhibitors erlotinib or gefitinib but then, inevitably, developed resistance to those agents and had recurrences. "This study demonstrates that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent upon EGFR signaling for survival, and confirms the preclinical hypothesis that dual EGFR inhibition is particularly meaningful in this patient population," said Dr. Yelena Y. Janjigian of thoracic oncology and gastrointestinal oncology services at Memorial Sloan-Kettering Cancer Center, New York, and her associates.
They assessed the combination therapy in 126 patients at six centers in the Netherlands and the United States who had progressive lung cancer despite receiving multiple previous therapies, including 1-7 years on the EGFR tyrosine kinase inhibitors erlotinib or gefitinib. A total of 37 patients (29%) showed an objective partial response to afatinib plus cetuximab, including 22 (18%) who had tumor shrinkage of 50% or more. The median duration of response to the combination therapy was 5.7 months (range, 1.8-24.4 months). This "is particularly meaningful considering the majority of patients were heavily pretreated; that is, 52% had failed two or more lines of standard cytotoxic chemotherapy in addition to an EGFR tyrosine kinase inhibitor," Dr. Janjigian and her associates said (Cancer Discovery 2014 July 29 [doi:10.1158/2159-8290.CD-14-0326]).
The combination therapy’s safety profile was deemed "manageable," with most patients developing rash, diarrhea, stomatitis, and fatigue, and half of them developing grade 3 adverse events. A total of 14% of patients developed serious adverse events – usually drug hypersensitivity or dehydration – and 13% discontinued therapy due to treatment-related adverse effects.
This study was sponsored by Boehringer Ingelheim. Dr. Janjigian reported receiving grants from Boehringer Ingelheim, Bayer, Genentech, and Eli Lilly; her associates reported ties to Novartis, Roche, Infinity, Pfizer, Millennium, GlaxoSmithKline, Ariad, Mersana, Foundation Medicine, Abbott, and Celgene.