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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 922 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.102
In Reply:Fourth Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan We appreciate the interest of Dr Noberasco et al in both our article1 and the related Editorial.2 In our study and a similar study reported by Kris et al,3 approximately 50% of previously treated patients with non-small-cell lung cancer (NSCLC) benefited from treatment with 250 mg/d gefitinib (IRESSA; AstraZeneca, Wilmington, DE) in terms of objective response or stable disease, often accompanied by symptom improvement.4 To optimize use of this new targeted therapy, it is of interest to seek predictive markers that identify those patients who will benefit most from gefitinib treatment. As gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, Noberasco et al studied the relationship between expression of EGFR and HER2 (a frequent dimerization partner of EGFR) and response to gefitinib 250 mg/d in patients with NSCLC. No significant correlation was found between EGFR expression and sensitivity to gefitinib, and increased HER2 expression was too rare to predict response. These findings are in keeping with analysis of tumor tissue from patients involved in our study, which showed no correlation between baseline EGFR membrane staining intensity and objective tumor response.5 A major advance in identifying patients who benefit from treatment with gefitinib has been made with the recent reports of somatic mutations in the adenosine triphosphate-binding pocket of tumor EGFR that are associated with dramatic responses to gefitinib.6–8 Interestingly, the EGFR mutations were in agreement with patient characteristics reported in our study to correlate with clinical benefit following treatment with gefitinib. These exciting findings may facilitate development of diagnostic tests, potentially allowing targeted treatment of patients with early-stage NSCLC, provided that tissue samples can be obtained. However, EGFR mutations were not observed in all patients with partial responses,7 and it is still unknown whether the mutation occurs in the many patients (approximately 35%) who experience clinical benefit through disease stabilization and rapid symptom improvement with gefitinib. There is, therefore, a need for identification of predictors of clinical benefit in these patients. Currently, as symptom improvement is associated with objective response and occurs with a median time to onset of 8 to 10 days, this is probably the most reliable rapid predictor of clinical benefit with gefitinib until further predictive markers are identified. As Noberasco et al propose, extensive studies are underway to evaluate gene expression profiles, and to study biomarkers such as the EGFR/MAP-kinase pathways, and other signaling pathway members that cross-talk with the EGFR pathway. The recent reports on EGFR mutations emphasize the importance of obtaining tumor biopsy samples, where possible, in order to conduct these important analyses. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have 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. Honoraria: Masahiro Fukuoka, AstraZeneca. For a detailed description of these 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 of Information for Contributors found in the front of every issue. REFERENCES
1. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003
2. Johnson DH, Arteaga CL: Gefitinib in recurrent non-small-cell lung cancer: An IDEAL trial? J Clin Oncol 21:2227-2229, 2003
3. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003 4. Fukuoka M, Kris M, Giaccone G, et al: Phase II trials of gefitinib ('Iressa', ZD1839): rapid and durable objective responses in patients with advanced non-small-cell lung cancer (IDEAL 1 and IDEAL 2). Lung Cancer 41:S247, 2003 (suppl 2, abstr P-615) 5. Bailey LR, Kris M, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib ('Iressa', ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 44:1362, 2003 (abstr LB-170)
6. Green MR: Targeting targeted therapy. N Engl J Med 350:2191-2193, 2004
7. 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
8. 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
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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