Treatment of Non–Small-Cell Lung Cancer with Erlotinib and Gefitinib

Non–small-cell lung cancer (NSCLC) is a common and often a challenging form of cancer to treat, but erlotinib and gefitinib could be effective treatment options—especially for patients who have tumors with gene mutations that activate the epidermal growth factor receptor (EGFR). A recent article in the New England Journal of Medicine [2011;364(10):947-955] explores the clinical evidence, use, and possible adverse effects of these 2 treatment options for patients with NSCLC. NSCLC accounts for approximately 85% to 90% of all lung cancer cases and is considered an incurable disease in its advanced stages. In addition, traditional chemotherapy only provides a small improvement in the overall survival of NSCLC patients in advanced stages and, according to the authors of this report, even if newer agents such as bevacizumab are added to chemotherapy, the median overall survival of patients who have metastatic NSCLC is only about 1 year. Previous research has found that more than half of patients with NSCLC also have an activated EGFR, a cell-surface receptor. This activation can cause protein overexpression, an increased gene copy number, or genetic mutations. Erlotinib and gefitinib have both been found to be effective in treating patients who have tumors with gene mutations that activate the EGFR. According to the report, these 2 drugs are small-molecule tyrosine kinase inhibitors that work by blocking the binding of adenosine triphosphate to its site in the tyrosine kinase domain within the EGFR. The effectiveness of both medications has been studied in various clinical trials. In a study by the National Cancer Institute of Canada Clinical Trials Group, researchers compared 150 mg of erlotinib daily to a placebo in 731 patients with advanced NSCLC who had failed standard chemotherapy. They found that those taking erlotinib had a longer overall survival of 6.7 months when compared with those taking the placebo (overall survival, 4.7 months; P=.001). The erlotinib group also had superior progression-free survival and quality of life. Gefitinib has also had positive results and, according to the Iressa Survival Evaluation in Lung Cancer Trial, 250 mg daily of gefitinib improved the time to treatment failure in NSCLC patients who had previously undergone standard chemotherapy when compared with patients taking a placebo; however, overall survival rate was not significantly different between the 2 groups. When used as a first-line therapy, 2 randomized trials in Japan found that gefitinib significantly improved the median progression-free survival of patients with advanced NSCLC who carried activating EGFR mutations when compared to 2 combinations of platinum and taxane agents. In terms of its current clinical use, erlotinib has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency as second-or third-line therapy for those patients who have locally advanced or metastatic NSCLC. Gefitinib is also approved by the FDA; however, its labeling was modified for use in patients who are currently benefiting or previously benefited from gefitinib therapy. The European Medicines Agency has approved gefitinib for use in any line of therapy for NSCLC patients with activating EFGR mutations. According to the report, in general, erlotinib and gefitinib seem to be similar in efficacy to standard chemotherapy in second- or third-line treatment of advanced NSCLC patients. In terms of first-line therapy results, tyrosine kinase inhibitors appear to be inferior to standard chemotherapy; however, they have been shown to be superior for some patient groups including those with activating EGFR mutations. Both drugs are associated with several adverse effects and have similar toxic-effect profiles. Diarrhea and a rash usually affecting the face, scalp, chest, and back are both common adverse effects of both medications. Interstitial lung disease can also be a life-threatening complication of both agents; however, it is less common. The authors of the report also outlined several areas of uncertainty that remain with both treatment methods. It is still unclear whether those patients who are identified as having EGFR mutations and are then treated accordingly with EGFR tyrosine kinase inhibitors would have a better overall survival. Further research is also needed to determine the subgroup of patients who would most benefit from erlotinib or gefitinib, as well as research to determine the role of the agents when they are used in combination with other treatment options. Currently, erlotinib is recognized by the National Comprehensive Cancer Network (NCCN) as a treatment option for second- and third-line therapy for advanced NSCLC patients who have an Eastern Cooperative Oncology Group score between 0 and 3. The NCCN has also suggested the use of erlotinib monotherapy as a first-line therapy for those patients who are known to carry an EGFR mutation. The drug is also recognized as a maintenance agent for patients who have already undergone platinum-based chemotherapy and have either stable or responsive disease.