The American Society of Clinical Oncology (ASCO) today issued a provisional clinical opinion (PCO) on the clinical use of epidermal growth factor receptor (EGFR) mutation testing to identify patients with advanced lung cancer who may benefit from targeted agents known as EGFR tyrosine kinase inhibitors. These treatments include gefitinib (Iressa?, AstraZeneca) and erlotinib (Tarceva?, Genentech/OSI Oncology).

The provisional clinical opinion (PCO), which is based on the results of five recent randomized clinical trials, recommends that patients with advanced non-small cell lung cancer who are being considered for first-line therapy with an EGFR tyrosine kinase inhibitor (meaning the patient has not previously been treated with chemotherapy or other anti-cancer drugs) should first have their tumor tested for EGFR mutations. Such testing is currently available, both at academic medical centers and at some community medical centers.

A PCO panel, convened by ASCO, examined evidence compiled through a review of the medical research literature – in addition to suggestions by panel members – to develop its recommendation. The PCO will be published online today in the Journal of Clinical Oncology (JCO).

“EGFR testing helps us move toward the goal of tailoring cancer treatments for each patient,” said panel co-chair Vicki Keedy, MD, assistant professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, TN. “We’ve learned over the years that non-small cell lung cancer is really a collection of genetically distinct diseases. We want to treat patients with drugs that target the molecular drivers of their specific tumors, rather than using a one-size-fits-all approach. But how this approach affects the patients’ overall outcome remains uncertain.”

Approximately 220,500 new cases of lung cancer occurred in the United States in 2010, with non-small-cell lung cancer making up about 80 percent of cases. Approximately 15 percent of U.S. patients with adenocarcinoma of the lung – a type of non-small-cell lung cancer – carry mutations in the EGFR gene. EGFR affects cell growth and division, and mutations in the gene can lead to uncontrolled cell division and cancer. Clinical trials have shown that patients with EGFR mutations who are treated with first-line gefitinib and erlotinib benefit from the drugs in terms of tumor response and progression-free survival (PFS), but not overall survival. Neither drug has yet been approved as first-line therapy for lung cancer by the U.S. Food and Drug Administration.

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The PCO panel examined the use of EGFR mutation testing in first-line therapy for non-small cell lung cancer in trials comparing an EGFR tyrosine kinase inhibitor to the standard chemotherapy combination of carboplatin and paclitaxel. The major impetus for the PCO was the Iressa Pan-Asian Study (IPASS), a Phase III multicenter trial comparing gefitinib with standard carboplatin and paclitaxel chemotherapy as first-line treatment in patients in East Asia who had advanced non-small cell lung cancer and were either non-smokers or light smokers. ASCO asked the National Cancer Institute’s (NCI) Physician Data Query (PDQ) Adult Cancer Editorial Board to assess the trial, and it reported that the study showed that patients given gefitinib as initial therapy had better PFS overall than those receiving chemotherapy.

The IPASS trial found that among patients with negative tests for EGFR mutation, PFS and response rates were greater in patients treated with chemotherapy, while patients with mutated EGFR had better PFS and higher response rates when treated with gefitinib. Although this trial was conducted among Asian patients, outcomes of treatment in patients with mutated EGFR appear to be similar across populations. Four smaller studies examining the use of gefitinib (and in some cases, erlotinib) as first-line treatment reported similar results. None of the studies showed differences in overall survival between those who tested negative for EGFR mutations and those with mutations.

The panel, in its review, acknowledged that erlotinib, which is approved in the United States as second-line therapy, is very similar to gefitinib, which has limited U.S. approval for second-line therapy and is not readily available. For patients with EGFR mutations, drugs such as gefitinib and erlotinib target the mutations that fuel their cancer more specifically than chemotherapy.

“Only a minority of patients with EGFR mutations responds to standard chemotherapy, and while there is some survival benefit, it’s not as much as we’d like. We’re finding that newer, molecularly targeted drugs like gefitinib and erlotinib are superior options for patients with EGFR mutations,” said panel co-chair Giuseppe Giaccone, MD, PhD, chief of the medical oncology branch at the NCI. “On the other hand, for patients who do not have the mutation, giving erlotinib up front is not the right thing to do. It’s not as efficacious for those patients, and we may be losing the opportunity to give chemotherapy, which clinical trials have demonstrated to be more effective.”

Keedy stressed the importance of designing trials to determine whether first treating a patient who tested negative for an EGFR mutation with a tyrosine kinase inhibitor – which is very likely to be ineffective – delays chemotherapy and affects outcome. Researchers would also like to know if outcome is affected for those patients with an EGFR mutation who are given potentially ineffective chemotherapy, and don’t immediately receive treatment with an EGFR tyrosine kinase inhibitor. The PCO pointed to several other research priorities, such as whether there are clinically significant differences between erlotinib and gefitinib among patients with EGFR mutations, since gefitinib is not FDA-approved in the United States.

For more Information:
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non?Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011 Apr 11. [Epub ahead of print] doi: 10.1200/JCO.2010.33.1280 and editorial 10.1200/JCO.2010.34.1974. Full Article

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