title: Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Thoracic Oncology and Gastrointestinal Oncology Services, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. janjigiy@mskcc.org.
authors: Yelena Y
authors: YY
authors: Janjigian
authors: Department of Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, the Netherlands.
authors: Egbert F
authors: EF
authors: Smit
authors: Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
authors: Harry J M
authors: HJ
authors: Groen
authors: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors: Leora
authors: L
authors: Horn
authors: Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
authors: Scott
authors: S
authors: Gettinger
authors: University of Colorado Cancer Center, Aurora, Colorado.
authors: D Ross
authors: DR
authors: Camidge
authors: Thoracic Oncology and Gastrointestinal Oncology Services, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors: Gregory J
authors: GJ
authors: Riely
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors: Bushi
authors: B
authors: Wang
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors: Yali
authors: Y
authors: Fu
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors: Vikram K
authors: VK
authors: Chand
authors: Thoracic Oncology and Gastrointestinal Oncology Services, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors: Vincent A
authors: VA
authors: Miller
authors: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors: William
authors: W
authors: Pao
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors; D000068818:Cetuximab