Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations Journal Article
| Authors: | Janjigian, Y. Y.; Smit, E. F.; Groen, H. J. M.; Horn, L.; Gettinger, S.; Camidge, D. R.; Riely, G. J.; Wang, B.; Fu, Y.; Chand, V. K.; Miller, V. A.; Pao, W. |
| Article 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. 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. © 2014 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 4 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-09-01 |
| Start Page: | 1036 |
| End Page: | 1045 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0326 |
| PROVIDER: | scopus |
| PMCID: | PMC4155006 |
| PUBMED: | 25074459 |
| DOI/URL: | |
| Notes: | Export Date: 1 October 2014 -- Source: Scopus |
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