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发表于 2008-5-6 12:46:12
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来自: 美国
In Reply<br/>Byoung Chul Cho, Joo Hang Kim<br/><br/>Yonsei 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<br/><br/>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.<br/><br/>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<br/><br/>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 {alpha}-helix of EGFR, is not predicted to result in bulky steric clash as with T790M mutation.4 The importance of presence of T790M mutation as a negative predictor for salvage use of erlotinib after gefitinib therapy was also reported by Chang et al.5 They demonstrated a deletion mutation without T790M mutation in rebiopsied tumor sample from a patient who responded to erlotinib after gefitinib failure. Just as suggested by the authors, erlotinib might be able to overcome resistance due to these second mutations other than T790M mutation. It appears that precise position of mutation within the kinase domain of EGFR could be an important factor in determining which patients might respond to erlotinib. The tumor microenvironment and pharmacokinetics of the drug may influence the type of mutations.4,6<br/><br/>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.<br/><br/>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<br/><br/>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<br/><br/>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.<br/><br/>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.<br/><br/>Table 1. Summary of Patients Who Derived Benefit From Erlotinib After Failure of Gefitinib<br/><br/>Case     Histology     Sex     Smoking     No. of Prior Chemotherapy     Response to Gefitinib     TTP to Gefitinib (days)     Response to Erlotinib     TTP to Erlotinib (days)     EGFR Mutation<br/>1     Ad     F     Never     3     SD     181     R     180     No<br/>2     Ad     M     Never     3     SD     204     R     140     No<br/>3     BAC     F     Never     3     SD     549     SD     150+     No<br/>4     BAC     F     Never     NR     SD     681     SD     192     No<br/>5     Ad     F     Never     NR     SD     117     R     99     No<br/>6     Ad     F     Never     0     SD     540     R     390+     N/A<br/>7*     Ad     F     Never     2     SD     360     SD     390+     N/A<br/>8*     Ad     F     Never     2     SD     720     SD     210+     N/A<br/>9     Ad     M     Former     2     SD     120     SD     90     No<br/>10     Ad     F     Never     0     R     420     R     360+     N/A<br/>11{dagger}     Ad     M     Former     1     R     270     R     540     Yes<br/>12     Ad     F     Never     3     R     496     SD     111     Yes<br/>13     SCC     M     Current     3     R     180     SD     101     N/A<br/>14     Ad     M     Current     2     PD     63     SD     104     No<br/>15     Ad     F     Never     NR     PD     81     SD     96     No<br/>16     Ad     M     Former     2     PD     60     PR     210+     N/A<br/><br/>Abbreviation: EGFR, epidermal growth factor receptor; M, male; F, female; NR, not reported; N/A, not available; Ad, adenocarcinoma; BAC, bronchioloalveolar carcinoma; SCC, squamous-cell carcinoma; TTP, time to progression; PR, partial response; SD, stable disease; PD, progressive disease.<br/><br/>* Brain lesions showed PR.<br/><br/>{dagger} Rebiopsy after progression on gefitinib showed only exon 19 deletion without T790 M mutation.<br/><br/>Table 2. Summary of Patients Who Did Not Derive Benefit From Erlotinib After Failure of Gefitinib<br/><br/>Case     Histology     Sex     Smoking     No. of Prior Chemotherapy     Response to Gefitinib     TTP to Gefitinib (days)     EGFR Mutation<br/>1     Ad     F     Ever     2     PR     540     N/A<br/>2     Ad     F     Never     1     PR     1,200     N/A<br/>3     Ad     F     Ever     3     PR     660     N/A<br/>4     Ad     F     Never     0     PR     300     N/A<br/>5*     Ad     F     Never     3     PR     365     Yes<br/>6     Ad     F     Never     2     PR     120     Yes<br/>7     Ad     F     Never     2     PR     344     N/A<br/>8     Ad     F     Current     2     PR     145     N/A<br/>9     Ad     F     Never     2     PR     80     Yes<br/>10     SCC     M     Current     0     PD     14     N/A<br/>11     Ad     M     Never     2     PD     30     N/A<br/>12     MEC     M     Current     2     PD     63     Yes<br/>13     Ad     F     Never     2     PD     60     No<br/>14     Ad     F     Never     2     PD     60     No<br/>15     Ad     M     Current     2     PD     60     Yes<br/>16     Ad     M     Former     2     PD     60     No<br/>17     Ad     M     Current     2     PD     60     No<br/>18     SCC     M     Former     2     PD     60     No<br/>19     SCC     F     Never     2     PD     60     No<br/>20     Ad     M     Current     2     PD     80     No<br/>21     Ad     M     Former     2     PD     60     No<br/>22     Ad     F     Never     2     SD     122     N/A<br/><br/>Abbreviation: EGFR, epidermal growth factor receptor; NR, not reported; N/A, not available; Ad, adenocarcinoma; BAC, bronchioloalveolar carcinoma; SCC, squamous-cell carcinoma; MEC, mucoepidermoid carcinoma; TTP, time to progression; PR, partial response; SD, stable disease; PD, progressive disease.<br/><br/>* Rebiopsy after progression on gefitinib showed T790 M mutation, together with exon 19 deletion. |
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