Originally published as JCO Early Release 10.1200/JCO.2008.16.7254 on September 15 2008

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EGFR Mutations Predict Survival Benefit From Gefitinib in Patients With Advanced Lung Adenocarcinoma: A Historical Comparison of Patients Treated Before and After Gefitinib Approval in Japan

Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Hiroshi Nokihara, Noboru Yamamoto, Ikuo Sekine, Hideo Kunitoh, Koh Furuta, Tomohide Tamura

From the Division of Internal Medicine; Clinical Laboratory Division; Statistics and Cancer Control Division, Research Center for Cancer Prevention and Screening; and Clinical Support Laboratory, National Cancer Center Hospital; and the Department of Medical Oncology, Teikyo University School of Medicine, Tokyo, Japan

Corresponding author: Yuichiro Ohe, MD, Division of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: yohe{at}ncc.go.jp

	ABSTRACT

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Purpose This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma.

Patients and Methods Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis.

Results EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50).

Conclusion EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.

	INTRODUCTION

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Gefitinib (Iressa; AstraZeneca, Osaka, Japan) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Gefitinib was approved for the treatment of patients with advanced non–small-cell lung carcinoma (NSCLC) in Japan in July 2002, after its antitumor activity had been demonstrated in two phase II studies.^1,2 The response rate to gefitinib was higher among women, patients with adenocarcinoma, never-smokers, and Japanese or East Asians.^1-3 In April 2004, somatic mutations in the kinase domain of EGFR, mainly in-frame deletions including amino acids at codons 747 to 749 (DEL) in exon 19 and a missense mutation at codon 858 (L858R) in exon 21, were suggested to be determinants of gefitinib sensitivity.^4,5 Since then, retrospective studies have consistently revealed a strong association between EGFR mutations and clinical outcomes in NSCLC patients treated with gefitinib.^6-9 Although these studies showed that overall survival (OS) was much longer among patients with EGFR mutations, they did not intrinsically prove a survival benefit of gefitinib in patients with EGFR mutations because there remained the possibility that the differences in OS were merely caused by prognostic differences independent of gefitinib treatment.

Eight large-scale, randomized, phase III trials were conducted to evaluate the survival benefits of gefitinib or erlotinib (Tarceva; OSI Pharmaceuticals Inc, Melville, NY), another EGFR-TKI, in patients with advanced NSCLC. The Iressa NSCLC Trial Assessing Combination Treatment (INTACT) –1, INTACT-2, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin (TRIBUTE), and Tarceva Lung Cancer Investigation (TALENT) trials tested the concurrent combination of platinum-based chemotherapy and EGFR-TKIs in a first-line setting but failed to show a survival benefit from the addition of the EGFR-TKIs.^10-13 The Iressa Survival Evaluation in Lung Cancer (ISEL) trial tested the role of second- or third-line gefitinib monotherapy but also failed to show a significant survival benefit over a placebo,¹⁴ whereas the BR.21 trial showed a significant survival benefit of second- or third-line erlotinib monotherapy.¹⁵ The Iressa NSCLC Trial Evaluating Response and Survival against Taxotere (INTEREST) and V15-32 trials compared OS after second-line gefitinib monotherapy and docetaxel monotherapy, which is a standard second-line treatment; the former study proved the noninferiority of gefitinib to docetaxel, whereas the latter study failed to do so.^16,17

In subgroup analyses of some of these trials, significant survival benefits were observed for never-smokers^12,14 and Asian patients.¹⁴ In the BR.21 trial, no history of smoking was a significant predictor of a survival benefit from erlotinib.¹⁵ Because never-smokers and Asian patients are known to have higher frequencies of EGFR mutations,^4-9,18,19 these results suggested an association between EGFR mutations and a survival benefit from EGFR-TKIs. However, in all of these trials, mutational analyses failed to show a significant survival benefit from EGFR-TKIs in EGFR-mutant patients,^20-23 partly because of the small sample sizes that were used.

In the INTACT and TRIBUTE trials, patients with EGFR mutations lived longer than those without EGFR mutations, irrespective of treatment with EGFR-TKIs^20,21; this result suggested that EGFR mutations may have prognostic value in patients with advanced NSCLC who were treated with standard chemotherapy. However, these trials were inconclusive regarding this point because of the small number of EGFR-mutant patients who were examined. As for early-stage NSCLC patients, several large-scale retrospective studies have been reported; some studies showed no significant association between the presence of EGFR mutations and OS after surgery,^19,24 whereas others showed that the presence of EGFR mutations was associated with a favorable prognosis in a univariate analyses, but the association disappeared when adjustments for patient characteristics like sex and smoking history were made.^25,26

To evaluate whether gefitinib provides a survival benefit to patients with lung adenocarcinoma and whether the mutational status of EGFR is a predictor of a survival benefit from gefitinib and/or a prognostic factor, we analyzed data obtained on patients with advanced lung adenocarcinoma who were treated before and after gefitinib approval.

	PATIENTS AND METHODS

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Patients
We performed all the analyses in this study using a protocol approved by the institutional review board of the National Cancer Center Hospital (NCCH; Tokyo, Japan). Consecutive patients with advanced lung adenocarcinoma who had been pathologically diagnosed at NCCH and began first-line systemic therapy without thoracic radiotherapy between July 2002 and December 2004 (after gefitinib approval; group A) or between January 1999 and July 2001 (at least 1 year before gefitinib approval; group B) were identified using the databases of NCCH. Patients for whom appropriate pathologic samples were available and a mutational analysis could be successfully performed were included in this study.

Mutational Analysis
DNA was extracted from archived paraffin-embedded tissues and/or Papanicolaou-stained cytologic slides, and the two major hotspots of EGFR mutations, DEL and L858R, were analyzed using high-resolution melting analysis according to a previously described method.^9,27 Briefly, polymerase chain reaction (PCR) was performed using primers designed to amplify a region containing E746-I759 or L858 of EGFR and the dye LCGreen I (Roche Diagnostics, Indianapolis, IN). Melting curves were obtained using HR-1 (Idaho Technology, Salt Lake City, UT), and the curves of the samples and controls were compared. All of the mutational analyses were performed in a blinded fashion.

Clinical Outcomes
OS was defined as the time from the start of first-line systemic therapy until death. In patients with measurable lesions, tumor response to first-line cytotoxic chemotherapy, including second-line therapy after first-line gefitinib therapy, was evaluated using standard bidimensional measurements.²⁸ The response rate was defined as the proportion of complete and partial responses compared with the total number of patients.

Statistical Analysis
The differences in OS for the patients in group A and those in group B were compared using Kaplan-Meier curves and log-rank tests. To assess the interaction between the groups and the mutational status of EGFR, interaction terms were included in the Cox proportional hazards models. The interaction was considered significant if P < .10. The impact of EGFR mutations on tumor response to chemotherapy and prognosis was assessed using a ² test and a log-rank test, respectively. These analyses were performed with or without adjustments for the following baseline characteristics: age, sex, smoking history (never-smokers v others), performance status (PS), and disease stage (recurrence after surgery v stage III/IV). All the statistical analyses were performed using SAS software, version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Mutational Analysis
Medical and pathologic records were reviewed for 414 clinically eligible patients (255 in group A and 159 in group B), and the mutational status was successfully determined in 330 patients (200 in group A and 130 in group B). Appropriate pathologic samples were not available in 68 patients (49 in group A and 19 in group B), and indeterminate results were obtained because of incomplete PCR in 16 patients (six in group A and 10 in group B). Of the 330 successfully analyzed patients, 193 were analyzed using only cytology samples, 106 were analyzed using only tissue samples, and 31 were analyzed using both samples. DEL and L858R mutations were detected in 77 (23%) and 59 patients (18%), respectively, and these mutations were mutually exclusive.

Patient Characteristics
The patient characteristics of the 330 patients are listed in Table 1. All of the patients were Japanese except for one Korean patient and one Chinese patient. When groups A and B were compared, group A had a significantly higher percentage of patients with recurrence after surgery and patients with a poor PS. Age, sex, and smoking history were similar between the two groups. In group A, most of the patients were treated with EGFR-TKIs. However, 15 patients (8%) were not treated with EGFR-TKIs, and in 12 patients (6%), the EGFR-TKI treatment history was unknown because the patients had been transferred to another hospital and the subsequent treatment data was not available. In group B, all but 19 patients (15%) had no history of EGFR-TKI treatment; six patients had been treated with gefitinib in clinical trials before gefitinib approval, one patient had been treated with erlotinib in a phase II trial, and 12 patients had been treated with gefitinib in a clinical practice setting after gefitinib approval.

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Comparison of overall survival between patients who began first-line systemic therapy after gefitinib approval and patients who began treatment before gefitinib approval. (A) All patients included in the current study. (B) Patients with epidermal growth factor receptor (EGFR) mutations. (C) Patients without EGFR mutations. (D) Patients with deletional mutations in exon 19. (E) Patients with L858R mutation. MST, median survival time; HR, hazard ratio.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Comparison of overall survival between patients with and without epidermal growth factor receptor (EGFR) mutations among patients treated before gefitinib approval; and (B) the same comparison when the start of EGFR tyrosine kinase inhibitor administration is treated as a censoring event. MST, median survival time; HR, hazard ratio.

	DISCUSSION

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In this study, we clearly showed an improvement in the survival of patients with EGFR mutations after gefitinib approval. In fact, the MST doubled (13.6 to 27.2 months), a feat that has never before been achieved in the history of NSCLC treatment. Even in patients without EGFR mutations, a nonsignificant improvement in survival was obtained (MST, 10.4 to 13.2 months); this result might be a result of the efficacy of gefitinib, period effects other than the approval of gefitinib therapy, or selection biases. Nevertheless, a significant interaction between the presence of EGFR mutations and an improvement in survival was obtained, meaning that the mutational status of EGFR is a predictor of a survival benefit from gefitinib.

To our knowledge, this is the first study to show a significant interaction between EGFR mutations and a survival benefit from EGFR-TKI therapy. Although this study was a retrospective historical comparison conducted only in East Asian patients and some biases could not be excluded, the number of patients with EGFR mutations analyzed in this study (n = 136) was much larger than those in phase III trials (INTACT, n = 32; TRIBUTE, n = 29; ISEL, n = 26; BR.21, n = 34),^20-22,29 and we believe that the results of this study have a certain amount of importance to clinical practice.

The current study also showed that, among the patients treated with chemotherapy before gefitinib approval (group B), the OS was significantly longer in the patients with EGFR mutations than in those without EGFR mutations. As with the INTACT and TRIBUTE trials,^20,21 this result suggested that the presence of EGFR mutations was a favorable prognostic factor in patients with advanced NSCLC. However, this result is not conclusive because the difference was marginal when the effects of EGFR-TKIs, which were used in a small number of patients, were excluded.

As for the patients who were treated after gefitinib approval (group A), the difference in OS between the patients with and without EGFR mutations can be partly explained by the prognostic value of the EGFR mutations themselves. However, this study indicated that the difference was mainly caused by the mutations’ predictive value for a survival benefit from gefitinib.

The difference in OS according to the mutational status of EGFR in group B can also be explained by the predictive value for chemotherapy efficacy other than the pure prognostic value. In INTEREST and V15-32, which were phase III trials comparing docetaxel and gefitinib, the HRs for OS were almost the same between patients with and without EGFR mutations,^16,30 suggesting that EGFR mutations might be a predictive factor for a survival benefit from both docetaxel and gefitinib. In the current study, response rate to taxane monotherapy tended to be higher in patients with EGFR mutations, although the number of patients was small. These results are inconclusive, and further investigation is needed.

We detected no significant difference in the predictive and prognostic values of DEL and L858R in the current study. Some researchers, including ourselves, have reported that patients with DEL had better outcomes after EGFR-TKI treatment than those with L858R^9,31,32; however, the current study showed that gefitinib yielded almost the same survival benefit to both patients with DEL and patients with L858R, and we think that the two EGFR mutations should be treated equally when making clinical decisions.

In the ISEL and BR.21 trials, the EGFR copy number (evaluated using fluorescence in situ hybridization), rather than the EGFR mutation status, was suggested to predict a survival benefit from EGFR-TKIs,^22,23,29 and the authors concluded that a mutational analysis was not necessary to select patients for treatment with EGFR-TKIs. In contrast, the current study indicated that the EGFR mutation status was a determinant of a survival benefit from gefitinib, although EGFR copy numbers were not evaluated in this study. Our previous study showed that the EGFR copy number, as evaluated using quantitative PCR, was associated with a response to gefitinib; however, an increased EGFR copy number tended to be seen in patients with EGFR mutations and was not an independent predictor of response or OS in gefitinib-treated patients.⁶ These discrepancies may be a result of the ethnic difference, the methodologic difference between fluorescence in situ hybridization and quantitative PCR, or the accuracy of biomarker analyses. Although controversy still remains, we believe that the EGFR mutation status is the most useful biomarker for patient selection, at least in East Asian patients who have EGFR mutations more frequently than non-Asian patients.

In conclusion, gefitinib yielded a survival benefit among Japanese patients with lung adenocarcinoma, and the survival benefit was significantly greater in patients with EGFR mutations than in those without EGFR mutations. The presence of EGFR mutations may also be a favorable prognostic factor in advanced lung adenocarcinoma independent of gefitinib treatment. We need to consider appropriate treatment strategies for patients with NSCLC based on their EGFR mutation status.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: None Stock Ownership: None Honoraria: Toshimi Takano, AstraZeneca; Yuichiro Ohe, AstraZeneca; Noboru Yamamoto, AstraZeneca; Hideo Kunitoh, AstraZeneca; Tomohide Tamura, AstraZeneca Research Funding: None Expert Testimony: Hideo Kunitoh, AstraZeneca (U) Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Koh Furuta

Administrative support: Yuichiro Ohe, Tomohide Tamura

Provision of study materials or patients: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Hiroshi Nokihara, Noboru Yamamoto, Ikuo Sekine, Hideo Kunitoh, Tomohide Tamura

Collection and assembly of data: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Koh Furuta

Data analysis and interpretation: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Koh Furuta

Manuscript writing: Toshimi Takano

Final approval of manuscript: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Hiroshi Nokihara, Noboru Yamamoto, Ikuo Sekine, Hideo Kunitoh, Koh Furuta, Tomohide Tamura

	ACKNOWLEDGMENTS

 
We thank Kiyoaki Nomoto, Karin Yokozawa, Chizu Kina, and Sachiko Miura for their technical support.

	NOTES

 
published online ahead of print at www.jco.org on September 15, 2008.

Supported by a program for the Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency; a Health and Labor Science Research Grant from the Ministry of Health, Labor and Welfare, Japan; and a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 11, 2008; accepted April 17, 2008.

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