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CORRESPONDENCE |
RESPONSE: Re: Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non–Small-Cell Lung Cancer
Correspondence to: Federico Cappuzzo, MD, Division of Medical Oncology, Bellaria Hospital, Bologna, Italy (e-mail: federico.cappuzzo{at}ausl.bo.it).
Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR). Although approximately 10% of non–small-cell lung cancer (NSCLC) patients who received gefitinib had a dramatic response and increased long-term survival, patients not selected for any biologic characteristic who received the drug as a first-line therapy in combination with standard chemotherapy had no survival advantage (1,2). The mechanisms underlying gefitinib sensitivity have recently been discovered. It is now known that specific EGFR gene mutations can confer a gefitinib-sensitive phenotype (3), that a consequence of these mutations is the activation of the antiapoptotic protein Akt (4), and that patients whose tumors have activated Akt are more sensitive to the drug than patients whose tumors do not (5). In December 2004, AstraZeneca announced the results of the ISEL trial, a phase III randomized study comparing gefitinib with placebo in pretreated NSCLC patients. In this trial, the survival benefit observed in patients who received gefitinib was not statistically significant (hazard ratio of death = 0.89, P = .11). The negative results of the ISEL trial and those of all trials using a TKI in combination with chemotherapy clearly indicate that it is not possible to propose a TKI to all patients with NSCLC and that TKIs should be offered to patients selected for the presence of the drug target, i.e., the presence of EGFR gene mutations or amplification. Unfortunately, the problem of patient selection is further complicated because different mechanisms are involved in TKI sensitivity. For example, erlotinib was shown to improve survival compared with placebo in pretreated patients (6), but benefit was not confined to responders or to patients with EGFR gene mutations.
For several years, we have focused on identifying a biological predictor of gefitinib sensitivity. We observed that patients whose tumors had activated Akt had a statistically significantly higher response rate and disease control rate and longer time to progression than patients whose tumors did not have activated Akt, but the difference in overall survival was not statistically significant (5). Because several receptors can activate Akt, we hypothesized that patients with Akt activation would be sensitive to the inhibitory effect of gefitinib only if Akt activation was sustained by an EGFR-dependent mechanism. Therefore, as correctly suggested by de Braud et al., we recently performed EGFR and Akt analyses in a large cohort of NSCLC patients treated with gefitinib. The results of this study confirm that Akt activation is required for gefitinib sensitivity in patients with EGFR-positive tumors, irrespective of the method used for EGFR assessment, and support the idea of analyzing Akt status to aid in identifying patients for TKI therapy.
De Braud et al. also raised the issue of timing of Akt assessment. Although no trial to date has specifically addressed this question, preclinical data suggest that NSCLC tumors become more dependent on the EGFR signalling pathway and more sensitive to EGFR blocking strategies as they are exposed to different chemotherapies (7). Therefore, I agree that, because of the possible effects of previous therapies on EGFR pathways, it is possible that our results underestimated the true association between the molecular variables and response to gefitinib.
REFERENCES
(1) Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non–small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004;22:777–84.
(2) Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non–small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004;22:785–94.
(3) Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.
(4) Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163–7.
(5) Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non–small cell lung cancer. J Natl Cancer Inst 2004;96:1133–41.
(6) Shepherd FA, Pereira J, Ciuleanu TE, Tan EH, Hirsh V, Thongprasert S, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non–small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Trial Group (NCIC CTG) trial. Proc Am Soc Clin Oncol 2004;23:622.
(7) Perez-Soler R, Dai Q, Ling YH, Lee M, Kroog G, Zou Y, et al. Molecular mechanisms of sensitivity and resistance to the HER1/EGFR tyrosine kinase inhibitor erlotinib [abstract O-247]. Lung Cancer 2003;41:s72.
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J Natl Cancer Inst 2005 97: 461-462.
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