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.
The initial or “first line” management of advanced NSCLC has evolved quite a bit over the past 10 years, in that time moving from a much more uniform approach of very similar treatment for just about everyone to a revised approach that is far more individualized. First, we assess key issues like the subtype of NSCLC, focusing largely on whether it is squamous cell or non-squamous NSCLC, because treatment tends to diverge very early based on this factor. Second, a patient’s performance status is another important issue, as patients who are frail often need a customized approach, because a more aggressive standard approach may be prohibitively difficult and even harmful. Third, a minority of patients (about 10% in North America and Europe, closer to 1/3 in Asia) will have a particular molecular marker, specifically a mutation in the epidermal growth factor receptor (EGFR), that is associated with a high probability of having a dramatic and long-lasting response to targeted therapy that inhibit the EGFR pathway. This particular activating mutation is most typically seen in never-smokers or people with a minimal, remote prior smoking history who also have an adenocarcinoma subtype of NSCLC.
Recommendations for first line therapy are most typically for a two drug chemotherapy combination, often with the drug Avastin (bevacizumab) — a targeted therapy that blocks the blood supply to the cancer — added for many patients who don’t have squamous NSCLC. However, for patients with an EGFR mutation identified before they have started treatment, several recent studies have demonstrated that the rate of significant tumor shrinkage and the time before the cancer progresses are significantly longer with an oral agent that works as an EGFR inhibitor, such as Iressa (gefitinib) or Tarceva (erlotinib). Consequently, one of these agents is increasingly recognized as a very appealing first line treatment approach.
Elderly patients are often treated the same as younger patients if they have minimal limitations in their activity level. In contrast, frail patients are sometimes recommended to receive single agent chemotherapy rather than a multi-agent combination that may be prohibitively difficult to tolerate. The available evidence suggests that elderly and frail patients who have an EGFR mutation also typically have a very significant response to EGFR inhibitor therapy.
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