There is no question that the recognition of an activating mutation in the gene for the epidermal growth factor receptor (EGFR) has revolutionized our understanding of why some patients with advanced/metastatic NSCLC develop a profound benefit from the class of oral EGFR tyrosine kinase inhibitors (TKIs). We know that the response rate to EGFR TKIs among patients with an EGFR mutation is in the 60-75% range in many trials, but does this mean that the entire benefit of these drugs is explained by the minority of patients with an EGFR mutation (about 10% of patients in North America and Europe, vs. 20-30% range in Asian populations)?
Put simply, the answer is definitely no, that the larger population of patients who don't have an EGFR mutation (also known as EGFR wild type in genetics terminology) experience an improvement in overall survival despite a much lower response rate. The evidence in many studies of EGFR TKIs demonstrates consistently that those patients who don't have an EGFR mutation demonstrate significant tumor shrinkage defined as a partial or complete response in our strict criteria only about 1-5% of the time, a much more sizable fraction of patients without an EGFR mutation have a prolongation in the duration of their cancer demonstrating stable disease that translates to a modest improvement in survival. The benefit is clearly of a lesser magnitude than the benefit seen from EGFR TKIs in patients who have an activating EGFR mutation, but this modest benefit clearly exceeds the benefit seen with placebo, making Tarceva (erlotinib) and possibly Iressa (gefitinib) an appropriate consideration for previously treated patients with advanced NSCLC, even if they are known to not have an EGFR mutation.
More recent studies have directly compared standard chemotherapy with a platinum-based doublet combination to EGFR inhibitor therapy in the first line setting. These studies have very convincingly demonstrated that for patients with an EGFR mutation, first line EGFR TKI therapy is superior to standard chemotherapy as measured by multiple endpoints, while standard chemotherapy is clearly superior to EGFR TKI therapy as first line therapy for patients with advanced NSCLC who do not have an EGFR mutation. Despite the fact that the data very convincingly demonstrate that first line chemotherapy is a better choice for advanced NSCLC patients without an EGFR mutation, EGFR TKI therapy remains a very appropriate and active treatment choice for previously treated patients with advanced NSCLC, regardless of EGFR mutation, with an established modest benefit in overall survival.
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