Gefitinib therapy for non-small cell lung cancer

Abstract

Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.