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Originally published as JCO Early Release 10.1200/JCO.2007.15.4286 on May 5 2008 © 2008 American Society of Clinical Oncology.
Molecular Selection of Patients for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time
Princess Margaret Hospital, Toronto, Ontario, Canada Blockade of the epidermal growth factor (EGF) pathway through inhibition of EGF receptor (EGFR) is now well established in the treatment of non–small-cell lung cancer (NSCLC).1 However, considerable debate remains regarding when to initiate EGFR inhibitor therapy, how best to select patients for treatment, and how EGFR markers should be incorporated into clinical decision making. With respect to this last issue, EGFR protein expression determined by immunohistochemistry (IHC), EGFR gene copy number determined by fluorescent in situ hybridization (FISH), and EGFR mutation status determined by gene sequencing or other more sensitive techniques may each contribute important information regarding which patients are likely to benefit from treatment. In NSCLC, small molecule inhibition of the EGFR tyrosine kinase pathway has been the most successful strategy to date, and two oral tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, have received approval for treatment in the second- and third-line setting.2,3 In contrast, the addition of these agents to systemic chemotherapy in the first-line setting does not result in improved response or survival rates.1 Barely 4 years have passed since Lynch et al4 and Pao et al5 first reported an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR TKI therapy. Lynch et al4 also showed that mutations were associated with in vitro enhanced TK activity in response to EGF, and increased sensitivity to gefitinib. Based on these early clinical and laboratory observations, the investigators hypothesized that EGFR mutations would be predictive of response to EGFR TKI therapy and that screening for these mutations might be useful to select patients for treatment. Subsequently, numerous studies confirmed the association between mutation status and response6; in addition, many authors reported that the presence of mutation was associated with longer survival in patients receiving EGFR TKI therapy.6 The early trials that led to the approval of EGFR TKIs for the second- and third-line treatment of advanced NSCLC did not select patients on the basis of any EGFR marker. After identification of the activating mutations on exons 19 and 21, some investigators speculated that the survival benefit seen in the placebo-controlled trials was due entirely to a small percentage of patients who had mutations, and some even went as far as to suggest that EGFR TKI therapy should be limited to patients with mutations. Subsequent studies clearly showed that patients with wild-type EGFR could also derive significant survival benefit from treatment even though they had lower response rates compared with patients with mutations.7,8 Furthermore, other EGFR markers including protein expression and high EGFR copy number have now been shown to be predictive of response,7,8 and in at least one trial, both of these markers were associated with a differentially greater survival benefit.8 In view of the unexpectedly high response rates seen in patients with mutations, several investigators postulated that it might be appropriate to treat these patients with first-line EGFR TKI therapy rather than chemotherapy. In this issue of the Journal of Clinical Oncology, Sequist et al9 report their experience in the first-line treatment of 34 patients with mutations (79% exon 19 deletions or exon 21 L858R point mutations) with gefitinib. As has been reported in almost all series, mutations were seen more frequently in females, lifetime nonsmokers, and patients with adenocarcinoma. Their overall response rate of 55% is in keeping with reports from other investigators, although no patient with atypical mutations achieved response. The authors reported a median progression-free survival of 9.2 months and overall survival of 17.5 months. As discussed by the authors, their results are similar to those of the other single arm phase II trials of either erlotinib or gefitinib in patients with mutations. Sequist et al also evaluated EGFR gene copy number by FISH, and concluded "FISH appeared to provide no additional clinical information." Undoubtedly this is because most patients who harbor EGFR mutations on exons 19 and 21 also have high gene copy number. However, patients with wild-type EGFR may have high copy number, and as shown by many authors now, these patients have a significantly higher chance of response than those with low copy number. This raises the question not addressed by Sequist et al as to whether other EGFR markers, particularly gene copy number, have the potential to guide patient selection for first-line EGFR targeted therapy. The Denver group has completed a 140 patient, randomized, phase II trial that compares first-line single-agent erlotinib to chemotherapy alternating with erlotinib in patients who are EGFR IHC or FISH positive. This trial, although not powered for definitive results, may provide an important signal that may guide the design of subsequent phase III trials. In their discussion, Sequist et al comment that their patients had "significant clinical benefit" and that their results were "two-fold greater than typical results with cytotoxic regimens in unselected NSCLC populations." The unselected NSCLC population is definitely not the appropriate comparator on which to judge their results. There have now been several publications in which the survival rates of patients with EGFR mutations treated with chemotherapy have been reported.1 Invariably, their survival has been significantly longer than that of patients with wild-type EGFR, and in several publications, the median survival has not been reached at 2 years. The first thing that this tells us is that the studies of first-line EGFR TKI therapy in mutation-positive patients likely have all been published prematurely, with median follow-up times less than half the expected survival time of patients treated with chemotherapy. With this in mind, does the 17.5-month median survival in the Sequist et al study really compare favorably to historical controls? The study, while demonstrating the feasibility of selecting patients based on their molecular profile, does not tell us that first-line treatment of patients with EGFR mutations should be with an EGFR TKI. Before this conclusion can be reached, we must await the survival results from randomized studies comparing chemotherapy to EGFR TKI therapy. Such a study in prospectively identified patients with EGFR mutations is ongoing now in Spain. In addition, although the analyses of mutation status will be retrospective, a 1,200-patient trial comparing gefitinib to chemotherapy in nonsmoking Asian patients with adenocarcinoma recently has completed accrual. It is expected that 30% to 50% of patients in this study will harbor EGFR mutations, and so the results are awaited with interest. Until the randomized studies confirm that first-line treatment of patients with EGFR mutations does not result in inferior survival (and this is possible in view of historical data), such treatment should be considered experimental. However, even if EGFR TKI therapy does not result in superior survival, equivalent or noninferior survival rates would make this an attractive treatment option, or even the treatment of choice in view of its extremely favorable toxicity profile. To date, the focus of EGFR profiling has been to select patients who should be treated with EGFR inhibitors. It may, however, be equally important to select patients for whom EGFR inhibitor therapy is not appropriate, and to date, some of the studies of negative predictors seem to be providing us with even stronger signals than the positive predictors. KRAS is a downstream effector of the EGFR pathway, and mutations occur in approximately 20% to 30% of NSCLC cases.10 Several studies have now reported that KRAS mutations are associated with lack of sensitivity to EGFR inhibitors, and in some studies, the survival of patients with KRAS mutations was shown to be significantly worse when treated with EGFR TKIs.1,10 Lack of response to the EGFR monoclonal antibodies cetuximab11 and panitumumab12 also have been reported in patients with colorectal cancer whose tumors harbor RAS mutations. KRAS and EGFR mutations seldom occur simultaneously in the same tumors, and undoubtedly, that is why Sequist et al have not reported on RAS mutation status in their study. A second EGFR point mutation in exon 20 (T790M), in patients who have developed resistance to treatment with erlotinib or gefitinib, has now been identified.13 Finally, MET, the protein product of the c-met proto-oncogene, is commonly overexpressed in NSCLC, and recently, resistance to gefitinib has been described as a result of amplification of MET.14 The identification of the T790M mutation and MET amplification in Sequist et al's patients with EGFR exon 19 and 21 mutations who did not respond to gefitinib supports the early observations, but larger studies of these potentially negative selection markers are needed. In summary, both clinical patient characteristics and molecular tumor markers may be used to predict the likelihood of response to EGFR TKI therapy. It is likely—indeed probably inevitable—that a panel of tests will be used in the not too distant future to determine which patients are likely to respond, and of almost equal importance, to determine which patients are unlikely to derive benefit from EGFR inhibitor therapy. At this time, molecular selection of patients for first-line therapy with EGFR TKIs is not quite ready for prime time and we eagerly await the results of the prospectively designed randomized trials. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: Frances A. Shepherd, AstraZeneca (C), Roche (C) Stock Ownership: Frances A. Shepherd, AstraZeneca Honoraria: Frances A. Shepherd, AstraZeneca, Roche Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on May 5, 2008. REFERENCES 1. Wheatley-Price P, Shepherd FA: Epidermal growth factor receptor inhibitors in the treatment lung cancer: Reality and hopes. Curr Opin Oncol 20:162-175, 2008[Medline] 2. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 3. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005[CrossRef][Medline] 4. 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 5. 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 6. Sakurada A, Shepherd FA, Tsao MS: Epidermal growth factor tyrosine kinase inhibitors in lung cancer: Impact of primary or secondary mutations. Clin Lung Cancer 7:S138-S144, 2006 (suppl 4)[CrossRef][Medline] 7. 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 8. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006 9. Sequist LV, Martins GM, Spigel D, et al: First-line gefitinib in patients with advanced non–small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26:2442-2449, 2008 10. Aviel-Ronen S, Blackhall FH, Shepherd FA, et al: K-ras mutations in non-small-cell lung carcinoma: A review. Clin Lung Cancer 8:30-38, 2006[Medline] 11. 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 12. Engelman JA, Zejnullahu K, Mitsudomi T, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043, 2007 13. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 14. Freeman D, Juan T, Meropol NJ, et al: Analysis of KRAS mutations in patients with metastatic colorectal cancer receiving panitumumab monotherapy. European Journal of Cancer Supplements 5:8, 2007 (abstr 3014; LBA 7)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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