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Cancer Discov. 2014 Sep;4(9):1036-45. doi: 10.1158/2159-8290.CD-14-0326. Epub 2014 Jul 29.

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

Author information

1
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.
2
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, the Netherlands.
3
Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
4
Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
5
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
6
University of Colorado Cancer Center, Aurora, Colorado.
7
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.
8
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.

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.

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 acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01090011.

PMID:
25074459
PMCID:
PMC4155006
DOI:
10.1158/2159-8290.CD-14-0326
[Indexed for MEDLINE]
Free PMC Article
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