|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1184-1186 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.9351
In ReplyYonsei Cancer Center and the Department of Internal Medicine, Yonsei University College of Medicine; and the Lung Cancer Clinic Severance Hospital, Yonsei University Medical Center, Seoul, Republic of Korea We thank Dr Costa and his collaborators for their interest in our study. In their letter, they proposed a molecular explanation for response to erlotinib in non–small-cell lung cancer with acquired resistance to gefitinib. We do think that their work illustrated why patients in our phase II study and other anecdotal reports derived clinical benefit from erlotinib therapy after failure of gefitinib. T790M gatekeeper mutations represent approximately 50% of tumors from patients who initially responded and then relapsed.1 In T790M mutation, the substituted methionine at position 790 makes sterical hindrance. Because of profound gatekeeper effect, T790M mutation can not be overcome by erlotinib. One of the patients in our phase II study revealed T790M mutation in addition to an exon 19 deletion mutation in tumor tissue that became resistant to gefitinib.2 This patient showed progressive disease on subsequent erlotinib therapy, further supporting this hypothesis. Therefore, strategy for overcoming resistance due to T790M mutation is irreversible inhibitors that covalently bind to epidermal growth factor receptor (EGFR).3
Certain second mutations, such as L747S or D761Y, confer much less resistance to gefitinib or erlotinib compared with T790M mutation. Based on crystal structure, D761Y mutation, which occurs in So, why does the tumor that becomes resistant to gefitinib respond to erlotinib? The molecular structure of gefitinib and erlotinib are similar, but not identical. Much lower IC50 value of erlotinib against wild-type EGFR compared with gefitinib might be translated into the higher antitumor effect.7 Furthermore, in case of second mutations with less sterical hindrance for drug binding, small change in molecular structure might allow erlotinib to be fit in the catalytic pocket of EGFR and thus to overcome resistance to gefitinib. Regarding the authors’ prediction that an increase in doses of gefitinib or switching to erlotinib would lead to clinical benefit, we prefer the switch to erlotinib rather than high-dose of gefitinib because of poor tolerability. A similar example was described in chronic myeloid leukemia. Resistance frequently results from the emergence of point mutations within the kinase domain of the bcr/abl protein that reduce the binding affinity of imatinib.8 Interestingly, the degree of resistance ranges from a few fold for some of the mutation to complete resistance for the T315I mutation which is analogous to T790M in EGFR. Overcoming resistance to imatinib can be achieved through several approaches. These include escalating the dose of imatinib or using new inhibitors, such as nilotinib. Due to structural modifications, nilotinib is more potent in the killing of wild-type bcr/abl–expressing cells and also maintains activity against imatinib-resistant mutant, except T315I.9 In our article, we proposed prior response to gefitinib as a predictive marker for subsequent erlotinib therapy. However, based on the authors’ observation, molecular predictor can lead to better patient selection than clinical predictor. That is, although a tumor showed response to gefitinib and subsequently progressed, it may respond to erlotinib in the absence of T790M mutation. Therefore, it would be reasonable and probably important to perform rebiopsy of tumor tissue on acquisition of resistance in order to optimize and individualize subsequent targeted therapy. As a practical point, acquiring adequate tissue for EGFR mutation analysis, however, is often not feasible, particularly in heavily pretreated patients. We sincerely expect a highly sensitive and noninvasive method for the detection of EGFR mutation in serum DNA to become available as soon as possible.10 The authors’ observation did not address why erlotinib produced a response in our patient with wt EGFR who had stable disease (SD) on gefitinib. This important conclusion in our study may imply that these tumors have resistant mechanisms that could be overcome by erlotinib. In the BR.21 study, a significant prolongation of survival was achieved despite response rate of less than 10%, perhaps because of high proportion of the patients had durable SD while receiving treatment.11 Until today, however, little has been studied about the resistant mechanisms in this large group of patients. Further understanding of mechanism of resistance will facilitate more effective ways to overcome the acquired resistance. Several published data are now available regarding the clinical activity of erlotinib after the failure of gefitinib. We summarized 16 patients who achieved clinical benefit to erlotinib in Table 1.2,5,12-18 Consistent with our previous assertion, nine among 16 patients showed SD on gefitinib. Seven patients showed partial response (PR) on erlotinib, with time-to-progression of over 90 days in all patients. Most of patients contain wild-type EGFR. Brain lesions showed PR in patients 7 and 8. In patient 11, rebiopsy after progression on gefitinib showed only exon 19 deletion without T790M mutation. Among 17 patients who did not achieve clinical benefit, almost all had PR or progressive disease on gefitinib (Table 2).2,5,12-18 Rebiopsy in patient 5 after progression on gefitinib showed T790M mutation, together with exon 19 deletion.
In conclusion, clinical experiences of ours and several others encourage further evaluation of this approach as a potential therapeutic option in a selected subset of non–small-cell lung cancer patients previously treated with gefitinib. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. 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 2. Cho BC, Park M, Kim JH, et al: Phase II study of erlotinib in advanced non-small cell lung cancer after failure of gefitinib. J Clin Oncol 25:2528-2533, 2007 3. Kwak EL, Sordella R, Bell DW, et al: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665-7670, 2005 4. Balak MN, Gong Y, Riely GJ, et al: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor–mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494-6501, 2006 5. Chang JW, Chou Cl, Huang SF, et al: Erlotinib response of EGFR-mutant gefitinib-resistant non-small cell lung cancer. Lung Cancer 27:414-417, 2007 6. Arteaga CL: HER3 and mutant EGFR meet MET. Nat Med 13:675-677, 2007[CrossRef][Medline] 7. Polack VA, Savage DM, Baker DA, et al: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinoma with OSI-774: Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739-748, 1999 8. Kantarjian HM, Talpaz M, O'Brien S, et al: Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101:473-475, 2003 9. Weisberg E, Manley P, Mestan J, et al: AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94:1765-1769, 2006[CrossRef][Medline] 10. Kimura H, Kasahara K, Kawaishi M, et al: Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non–small-cell lung cancer. Clin Cancer Res 12:3915-3921, 2006 11. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123-132, 2005 12. Viswanathan A, Pillot G, Govindan R: Lack of response to erlotinib after progression on gefitinib in patients with advanced non-small cell lung cancer. Lung Cancer 50:417-418, 2005[CrossRef][Medline] 13. Walther JC, Khorshid M, Gaya A, et al: Cross-over response to erlotinib of brain metastatic disease from bronchial adenocarcinoma after gefitinib failure, and an unusual rash. Clin Oncol (R Coll Radiol) 18:637-639, 2006[Medline] 14. Garfield DH: Response to erlotinib after failure of gefitinib in a patient with advanced non small cell lung cancer. J Clin Oncol 23:7738-7740, 2005 15. Gridelli C, Maione P, Galetta D, et al: Three cases of long-lasting tumor control with erlotinib after progression with gefitinib in advanced non-small cell lung cancer. J Thorac Oncol 2:758-761, 2007[CrossRef][Medline] Related Correspondence
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
-helix of EGFR, is not predicted to result in bulky steric clash as with T790M mutation.
