Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR -Mutant Lung Cancer with and without T790M Mutations

作者：Yelena Yuriy Janjigian, Egbert Frederik Smit, Harry J.M. Groen, Leora Horn, Scott N. Gettinger, D. Ross Camidge, Gregory J. Riely, Bushi Wang, Yali Fu, Vikram K. Chand, Vincent A. Miller, William J. Pao · 发表于：Cancer Discovery · 年份：2014 · DOI：10.1158/2159-8290.cd-14-0326 · 被引用次数：363 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Immunotherapy and Biomarkers、Lung Cancer Diagnosis and Treatment

UNLABELLED: 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. SIGNIFICANCE: 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 acquire...