Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations

• Published in: Cancer discovery 2014-09, Vol.4 (9), p.1036-1045
• Main Authors: Janjigian, Yelena Y, Smit, Egbert F, Groen, Harry J M, Horn, Leora, Gettinger, Scott, Camidge, D Ross, Riely, Gregory J, Wang, Bushi, Fu, Yali, Chand, Vikram K, Miller, Vincent A, Pao, William
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cetuximab - administration & dosage; Drug Resistance, Neoplasm - genetics; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Middle Aged; Mutation; Protein Kinase Inhibitors - administration & dosage; Quinazolines - administration & dosage; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Treatment Outcome
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-14-0326

EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3-6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8-24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib-cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation. This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival.