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Originally published as JCO Early Release 10.1200/JCO.2006.06.6555 on June 19 2006 © 2006 American Society of Clinical Oncology.
Gefitinib for Epidermal Growth Factor Receptor Mutant Lung Cancers: Searching for a Weapon of Mass DestructionLowe Center of Thoracic Oncology, Dana-Farber Cancer Institute; and Brigham and Women's Hospital and Harvard Medical School, Boston, MA In the spring of 2004, the association between somatic mutations in the epidermal growth factor receptor (EGFR) in non–small-cell lung cancer (NSCLC) and sensitivity to the EGFR tyrosine kinase inhibitor gefitinib was first described.1,2 Since that time, numerous retrospective studies have confirmed these original observations.3-7 Patients with EGFR mutations treated with gefitinib have a 60% to 90% chance of achieving a radiographic partial response and a median time to progression of approximately 12 months (Table 1). However, these were all retrospective observations that were limited by multiple potential biases including patient selection based on the availability of tumor material, differences in prior treatments, and the methods of EGFR mutation detection. In addition, other biomarkers associated with gefitinib's clinical benefit, including increased EGFR copy number and EGFR expression as detected by immunohistochemistry, have also emerged over the last 2 years.9,10 The contribution and role of EGFR mutations remain to be definitively determined from ongoing prospective studies.
In this issue, Inoue et al8 report the first prospective clinical trial in which chemotherapy-naïve advanced NSCLC patients with somatic EGFR mutations were treated with gefitinib as their first systemic therapy. They started the study in June 2004, performed mutational analyses in 99 patients (75 patients were assessable), and found EGFR mutations in 25 of the patients (33%). The mutation frequency in this study is consistent with the previously published somatic EGFR mutation frequency in Japanese lung cancer patients.1 The 16 patients with EGFR mutations had a response rate of 75% and a median progression-free survival time of 9.7 months, which is consistent with the retrospective observations (Table 1). Inoue et al8 also found the same types of EGFR mutations as previously identified, with in-frame deletion of exon 19 being the most common type of mutation (Table 1). Despite the small sample size, the study met its primary protocol-defined end point of a 70% response rate, and this observation in a prospective trial confirms the previous retrospective observations associating EGFR mutations and the efficacy of gefitinib. What are the implications of this study? The findings of Inoue et al8 leave little doubt about the predictive value of EGFR somatic mutations (exon 19 deletions and L858R) for radiographic response after treatment with gefitinib. However, their study does not address whether these patients will survive longer when treated with gefitinib compared with chemotherapy. This will require a phase III trial comparing the outcome of patients with EGFR somatic mutations treated with chemotherapy with the outcome of patients treated with gefitinib. In addition, the role of adding systemic chemotherapy to EGFR tyrosine kinase inhibitors for this patient population remains to be determined and is being evaluated in ongoing studies. Inoue et al8 also demonstrate the feasibility of EGFR mutation detection in the routine clinical care of chemotherapy-naïve patients with advanced NSCLC. The Japanese population is more likely to have a somatic EGFR mutation than the white population (30% in Japanese patients compared with 10% to 15% in white patients). This increased mutation frequency, combined with the rapid turn around time (median, 7 days) for EGFR sequencing, clearly helped this study. In the United States or Western Europe, approximately 300 patients would need to be screened (rather than the 99 patients screened in the study by Inoue et al8) to find patients with sufficient tumor material for EGFR sequencing and, ultimately, patients with EGFR mutations to obtain a similar number of assessable patients. Nevertheless, these findings suggest that this may be a worthwhile effort in Western populations as well. Inoue et al8 found the most common types of EGFR mutations (exon 19 deletions and L858R) in their patient population. To date, more than 20 different EGFR mutations have been described.11-15 The predictive value for radiographic response to gefitinib treatment of EGFR mutations, other than exon 19 deletions or L858R, still needs to be determined from ongoing clinical studies. In the study by Inoue et al,8 there were four patients with NSCLC and EGFR mutations who either had stable (n = 2) or progressive disease (n = 2) after treatment with gefitinib. What is different about these patients compared with the patients with EGFR mutations who respond to treatment with gefitinib? There are no obvious differences in the types of EGFR mutations among these patients compared with the other 12 patients who achieved a partial response. In addition, the DNA from the tumors of the patients with stable or progressive disease did not contain the previously described EGFR T790M mutation associated with gefitinib resistance.16,17 Several recent studies have demonstrated that, both in EGFR mutant NSCLC cell lines and in patients with EGFR mutations, the EGFR locus is also often concurrently amplified.5,9,18,19 In addition, at least one retrospective study has suggested that, in the absence of an EGFR amplification, the likelihood of tumor regression of an EGFR mutant tumor is low.9 Is it possible that these four patients only had EGFR mutations but lacked concurrent EGFR DNA amplification? The presence of other ErbB family members, ErbB-2 and ErbB-3, may also contribute to the efficacy of gefitinib as demonstrated by both recent in vitro and clinical studies.20-22 The determination of these factors may help further refine the selection of patients with EGFR mutations for gefitinib treatment in future studies. The concept of patient selection is not novel in molecular oncology. However, most patients with solid tumors are still treated based on the anatomic origin of their tumor rather than on the specific molecular characteristics of the tumor. Compelling examples, such as the present study by Inoue et al,8 the treatment of ErbB-2–amplified breast cancer with trastuzumab, and the use of imatinib in patients with KIT or PDGFRA mutations, suggest that continued identification and understanding of molecular targets will lead to improved outcomes of subsets of patients with solid tumors. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 3. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non–small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005 4. Mitsudomi T, Kosaka T, Endoh H, et al: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non–small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513-2520, 2005 5. Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:6829-6837, 2005 6. Cortes-Funes H, Gomez C, Rosell R, et al: Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 16:1081-1086, 2005 7. Taron M, Ichinose Y, Rosell R, et al: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 11:5878-5885, 2005 8. Inoue A, Suzuki T, Fukuhara T, et al: Prospective phase II study of gefitinib for chemotherapy-naïve patients with advanced non–small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340-3346, 2006 9. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 10. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group study. J Clin Oncol 23:6838-6845, 2005 11. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005 12. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 13. Huang SF, Liu HP, Li LH, et al: High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10:8195-8203, 2004 14. Yang SH, Mechanic LE, Yang P, et al: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 11:2106-2110, 2005 15. Chou TY, Chiu CH, Li LH, et al: Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 11:3750-3757, 2005 16. Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005 17. Pao W, Miller VA, Politi KA, et al: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73, 2005 18. Tracy S, Mukohara T, Hansen M, et al: Gefitinib induces apoptosis in the EGFR L858R non-small-cell lung cancer cell line H3255. Cancer Res 64:7241-7244, 2004 19. Amann J, Kalyankrishna S, Massion PP, et al: Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65:226-235, 2005 20. Cappuzzo F, Varella-Garcia M, Shigematsu H, et al: Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor–positive non–small-cell lung cancer patients. J Clin Oncol 23:5007-5018, 2005 21. Engelman JA, Janne PA, Mermel C, et al: ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci U S A 102:3788-3793, 2005 22. Fujimoto N, Wislez M, Zhang J, et al: High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 65:11478-11485, 2005 Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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