© 2008 American Thoracic Society doi: 10.1164/rccm.200806-910ED
Gefitinib First or Gefitinib SecondIs Timing Everything in the Treatment of EGFR Mutant Non–Small Cell Lung Cancer?
Lowe Center for Thoracic Oncology Somatic mutations in the epidermal growth factor receptor (EGFR) have emerged as important biomarkers in predicting the likelihood of tumor response to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non–small cell lung cancer (NSCLC). EGFR mutations were originally described in 2004 in several retrospective studies and subsequently led to a number of prospective phase II clinical trials where NSCLC patients with EGFR mutations were treated with either gefitinib or erlotinib (1–6). In these prospective studies, tumor responses have been observed in 60–80% of patients and the median times to progression range from 8 to 12 months (4–6). These findings are substantially different from those typically observed with systemic chemotherapy in patients with advanced NSCLC (7). This has prompted the initiation of phase III clinical trials comparing gefitinib or erlotinib with chemotherapy in NSCLC patients with EGFR mutations or in NSCLC patient populations, such as those with Asian ethnicity or never or former light smokers with adenocarcinoma, that are heavily enriched for EGFR mutations. There are several practical issues in examining EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC. Gefitinib and erlotinib are approved by the U.S. Food and Drug Administration only for the treatment of patients with NSCLC who have failed systemic chemotherapy. The impact of systemic chemotherapy on the subsequent efficacy of an EGFR TKI in an EGFR-mutant patient with NSCLC is currently not known. Are EGFR TKIs more effective in EGFR-mutant patients with NSCLC as initial therapy or are they just as effective when administered after systemic chemotherapy? The study by Wu and colleagues in this issue of the Journal (pp. 847–853) begins to provide answers to this question (8). The investigators retrospectively identified patients with NSCLC treated with gefitinib from a single center in Taiwan. Of the 328 treated patients, 192 had EGFR mutations and, of those, 152 (79%) had either the EGFR exon 19 deletion or L858R mutation. These two mutations account for about 80% of all known EGFR mutations and are the ones most closely associated with tumor regressions with gefitinib or erlotinib treatment in both retrospective and in prospective clinical trials (9). Of the 152 EGFR-mutant patients with NSCLC, 91 received gefitinib as first-line therapy, whereas 61 received gefitinib after between one and five different chemotherapy regimens. Both the tumor response rate (76 vs. 54%; P = 0.005) and disease control rate (defined as those patients with either a response or stable disease to treatment) (93 vs. 80%; P = 0.014) were significantly higher in the EGFR-mutant patients with NSCLC who received gefitinib as their initial systemic therapy compared with those who were treated with gefitinib after systemic chemotherapy. Neither the median time to progression (TTP) (8.2 vs. 7.0 mo; P = 0.804) nor the overall survival (OS) (16.9 vs. 14.7 mo; P = 0.207) was significantly longer in the chemotherapy-naive patients compared with those who had received prior chemotherapy. What does the study by Wu and colleagues teach about the biology of EGFR-mutant NSCLC? A question that is sometimes raised is whether systemic chemotherapy can cause resistance and/or affect the likelihood of response to subsequent therapy using an EGFR inhibitor? The current study would suggest for patients with NSCLC with EGFR mutations that, if such an effect exists, it is likely relatively minor given no statistical differences in TTP in chemotherapy-naive compared with chemotherapy-treated patients. Furthermore, the biologic mechanisms that govern chemotherapy resistance are not likely to share a significant degree of overlap between those that lead to gefitinib or erlotinib resistance. What is not entirely clear is why the response and disease control rates are significantly better in the chemotherapy-naive patients. Response to gefitinib was the only variable associated with overall survival in the study by Wu and colleagues and yet there is no difference in the overall survival between the two treatment arms. Although the numbers of patients are limited, it would be of interest to see if the response rates to gefitinib in EGFR-mutant patients with NSCLC treated with one prior regimen, two prior regimens, or three or more regimens decreased with increasing number of prior chemotherapy treatments. As we move toward an era of personalized medicine, tumor-specific genomic information will need to be incorporated into our treatment decisions. In a patient with a known EGFR mutation, the study by Wu and colleagues supports the use of gefitinib as initial therapy in this patient population and the findings are consistent with prospective clinical trials (4–6). However, the findings also suggest that, for patients with NSCLC with EGFR mutations previously treated with chemotherapy, the benefits are substantial and almost as good as for the chemotherapy-naive patients. Thus, even for patients previously treated with chemotherapy, it is worth pursuing EGFR genotyping as this will help identify a subset of patients (i.e., those with EGFR mutations) who can derive a significant benefit from EGFR TKI treatment. What this study does not address is quality of life during treatment. When compared with systemic chemotherapy, the side-effect profile of gefitinib or erlotinib is better compared with systemic chemotherapy and such therapy is more convenient for patients. This added quality of life should not be underestimated and provides additional enthusiasm for treating EGFR-mutant patients with NSCLC with gefitinib or erlotinib. The gold standard for approving a new therapy into clinical practice is the ability to demonstrate a survival benefit in a phase III clinical trial. Given the findings by Wu and colleagues, this may be difficult in patients with EGFR mutations for whom the treatment is an EGFR inhibitor. In such studies, progression-free survival (PFS) or TTP may be a better endpoint as these would not be influenced by subsequent treatments, which are likely to include an EGFR inhibitor. This is also illustrated in the recently completed and presented phase III clinical trial comparing gefitinib to docetaxel (10). Although there was no difference in overall survival between gefitinib or docetaxel treatment in the subset of patients with EGFR mutations, there was a significant difference in PFS (hazard ratio, 0.16; 95% confidence interval, 0.05–0.49; P = 0.0012) favoring gefitinib treatment in patients with NSCLC with EGFR mutations. The current phase III clinical trials comparing geftinib or erlotinib to chemotherapy both have PFS as the primary statistical endpoint. We have learned a great deal about the use of gefitinib and erlotinib in the treatment of EGFR-mutant NSCLC over the last 4 years. We eagerly await the results of the ongoing phase III clinical trials to determine whether this therapeutic approach will become the standard of care for EGFR-mutant NSCLC. FOOTNOTES Conflict of Interest Statement: P.A.J. received honoraria for acting as a consultant to Roche, AstraZeneca, Boehringer Ingelheim, and AVEO Pharmaceuticals, with all totals less than $10,000 annually per company; he has received grant support from Pfizer; he has received royalties from technology (patent application on EGFR mutations) that is owned by DFCI and licensed to Genzyme (less than $10,000 annually). REFERENCES
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