Gene mutation patients respond to gefitinib

Screening may identify those who would benefit

New research shows that mutations in the epidermal growth factor receptor (EGFR) gene correlate with clinical responsiveness in patients with non-small-cell lung cancer to the tyrosine kinase inhibitor gefitinib (Iressa). The study was published in the May 20 issue of The New England Journal of Medicine (NEJM), but was posted in early release on the NEJM web site on April 29.

The work of Lynch, et al, if borne out by additional studies, will fundamentally change targeted therapy for solid tumors, says Mark R. Green, MD, professor of medicine and Gilbreth Professor of Clinical Oncology at the Medical University of South Carolina in Charleston. He commented on the research in the NEJM.

"For patients with lung cancer, mutational analysis of EGFR by experienced laboratories should provide guidance about treatment. More generally, this work suggests the relevance of a two-step evaluation of targeted therapy."

The researchers wanted to look closer at gefitinib, which targets EGFR, to see why some patients show a "remarkably rapid and often profound response" to the drug, while others showed no clinically significant response. The researchers searched for mutations in the EGFR gene in primary tumors in patients who had a response to gefitinib, those who did not have a response, and those who had not been exposed to the drug.

They found somatic mutations within the tyrosine kinase domain of EGFR in eight of nine patients who had exhibited a response to gefitinib. The researchers believe that the ninth patient may have had an undetected mutation or a mutation in a heterodimerization partner of EGFR. "These results, together with the finding of EGFR mutations in tumors from two of 25 patients with non-small-cell lung cancer who had not received gefitinib (8%), suggest that such mutations account for the majority of responses to gefitinib reported in clinical studies," the researchers say.

Understanding the molecular basis of responsiveness to gefitinib has immediate clinical implications for patients with this disease, they continue. Diagnostic testing can help guide the clinical use of gefitinib, and patients may benefit if they receive an earlier course of treatment.

"Prospective validation of EGFR tyrosine kinase mutations as predictors of the responsiveness to gefitinib is warranted, and genotype-directed clinical trials of this tyrosine kinase inhibitor in the initial treatment of advanced non-small-cell lung cancer — and even in the adjuvant setting after surgical resection — should now be considered."