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Originally published as JCO Early Release 10.1200/JCO.2005.07.799 on March 14 2005

Journal of Clinical Oncology, Vol 23, No 11 (April 10), 2005: pp. 2556-2568
© 2005 American Society of Clinical Oncology.
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REVIEW ARTICLE

Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non–Small-Cell Lung Cancer: Current Knowledge and Future Directions

William Pao, Vincent A. Miller

From the Program in Cancer Biology and Genetics and the Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; and Weill Medical College of Cornell University, New York, NY

Address reprint requests to William Pao, MD, PhD, Varmus Lab—Box 62, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: paow{at}mskcc.org.

PURPOSE: Gefitinib and erlotinib are small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. When these drugs were introduced into the clinic, the specific targets affected in human tumors were unknown. In April 2004, two groups reported that mutations in the tyrosine kinase domain of EGFR are strongly associated with gefitinib sensitivity in patients with non–small-cell lung cancer (NSCLC). We subsequently extended these findings and showed that such mutations are also associated with sensitivity to erlotinib. Here, we present current knowledge about EGFR mutations in the context of clinical trials involving gefitinib and erlotinib in NSCLC.

DESIGN: This article reviews the rationale for targeting EGFR, the development of gefitinib and erlotinib, the discovery of EGFR mutations, and subsequent studies to define the incidence, spectrum, and functions of EGFR mutations.

RESULTS: The discovery of EGFR mutations promises to alter the ways in which we consider and treat NSCLC.

CONCLUSION: This information can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC.

W.P. is supported by the CHEST and LUNGevity Foundation Clinical Research Award in Lung Cancer 2004.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.




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