92
Views
14
CrossRef citations to date
0
Altmetric
Review

Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer

&
Pages 285-295 | Published online: 19 Sep 2014
 

Abstract

The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%–30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10–13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.

Acknowledgments

SP and TAY acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre.

Disclosure

TAY is funded by the National Institute for Health Research and the Academy of Medical Sciences. SP is a noncompensated consultant to AstraZeneca, Boehringer Ingelheim, Clovis, Lilly, and Roche.