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Specific EGFR Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy

Chih-Hsin Yang, Chong-Jen Yu, Jin-Yuan Shih, Yeun-Chung Chang, Fu-Chang Hu, Meng-Chin Tsai, Kuan-Yu Chen, Zhong-Zhe Lin, Ching-Ju Huang, Chia-Tung Shun, Chin-Lun Huang, James Bean, Ann-Lii Cheng, William Pao, Pan-Chyr Yang

From the Graduate Institute of Clinical Medicine, College of Medicine; Departments of Oncology, Internal Medicine, and Medical Imaging, National Center of Excellence for General Clinical Trial and Research and Department of Pathology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan; and the Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY

Corresponding author: Chih-Hsin Yang, MD, PhD, Department of Oncology, National Taiwan University Hospital. 7, Chung-Shan South Rd, Taipei, Taiwan, 10016; e-mail: chihyang{at}ntu.edu.tw

	ABSTRACT

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Purpose To explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non–small-cell lung cancer (NSCLC) patients receiving gefitinib treatment.

Patients and Methods We designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis.

Results One hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations.

Conclusion In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

	INTRODUCTION

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Inhibition of tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has been successful in the treatment of selected advanced-stage non–small-cell lung cancer (NSCLC) patients who experienced treatment failure with chemotherapy. Erlotinib was established as a second-line or third-line treatment for chemotherapy-treated patients.¹ A preplanned 342 East Asian subset analysis in the Iressa Survival Evaluation in Lung Cancer (ISEL) study demonstrated a 4-month advantage of median survival in patients treated with gefitinib compared with placebo.²

Several factors were known to predict the tumor response or overall survival (OS) benefit of gefitinib treatment. East Asian ethnicity, female sex, nonsmoking status, adenocarcinoma pathology, and good performance status (PS) predicted response to gefitinib.³ East Asian ethnicity and nonsmoking status predicted survival benefit using gefitinib versus placebo.⁴ Molecular markers such as mutation in the tumor EGFR gene^5,6 predicted gefitinib response, whereas amplification of EGFR gene might predict survival benefit after gefitinib⁷ or erlotinib⁸ treatment versus placebo.

In a retrospective analysis of 76 poor-PS, chemotherapy-naive NSCLC patients who received gefitinib as first-line treatment, female sex, adenocarcinoma, or nonsmoking status were good predictive factors of long survival time.⁹ The use of gefitinib in good-PS patients who refuse chemotherapy is controversial because platinum-based combination chemotherapy has proven survival benefit. Several small phase II studies of gefitinib in NSCLC patients reported diverse results.^10-16 The wide range of tumor response (between 26.5% and 61.1%) was mainly the result of a mixture of predictive factors for response and small sample sizes. In addition, response durations, time to treatment failure (TTF) and OS were not completely reported.

Deletions in exon 19 and exon 21L858R mutation of EGFR predicted for good response to EGFR tyrosine kinase inhibitors (TKIs) in several retrospective studies.^17-21 Additional T790M mutations account for approximately half of cases of acquired resistance.^22,23 MET gene amplification also seems to be a possible mechanism for acquired resistance to gefitinib or erlotinib.^24,25 MET gene copy number in cancer cells may be an important factor in determining gefitinib response duration in chemotherapy-naive NSCLC patients, but this has not yet been studied. We performed this prospective study and evaluated clinical and molecular predictors of response and TTF of first-line gefitinib-treated NSCLC patients.

	PATIENTS AND METHODS

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Phase II Clinical Trial Design
A single center phase II study was designed to establish the anticancer efficacy of gefitinib as a first-line treatment for good PS stage IIIB/IV NSCLC patients (ClinicalTrials.gov Identifier: NCT00173875 [ClinicalTrials.gov] ). This study was approved by the Research Ethics Committee of the National Taiwan University Hospital (Taipei, Taiwan). The inclusion criteria were histologically or cytologically proven NSCLC, stage IIIB/IV and not amenable for curative treatment, measurable tumor in image studies, Eastern Cooperative Oncology Group (ECOG) PS of 0 to 2, adequate liver (bilirubin < 2.0 mg/dL, transaminases < 2.5x the upper limit of normal, alkaline phosphatase < 5x the upper limit of normal), renal (serum creatinine < 2 mg/dL) and bone marrow function (hemoglobin > 10g/dL, neutrophils > 2.0 x 10⁹/L and platelets > 100 x 10⁹/L), no prior systemic anticancer treatment, no immediate need for palliative radiotherapy, candidacy for cisplatin-based combination chemotherapy, and life expectancy of more than 6 months. Major exclusion criteria included CNS metastasis unless patients were clinically stable 6 weeks after radiotherapy, secondary malignancies, and major systemic diseases. The eligible patients after signing informed consent and completing screening procedures received gefitinib 250 mg/d. Computed tomography of all of the measurable tumors sites was performed every 8 weeks, and lesions were evaluated using Response Evaluation Criteria in Solid Tumor (RECIST).²⁶ Patients continued to receive gefitinib until disease progression documented by imaging studies, until clinical progression as judged by treating investigators, or until development of unacceptable toxicity. Adverse events were recorded every month according to National Cancer Institute Common Toxicity Criteria version 3. After patients had documented treatment failure to gefitinib, they were withdrawn from this study and were advised to receive chemotherapy after the discontinuation of gefitinib treatment. As an exploratory approach, in patients who received at least two cycles of salvage chemotherapy or radiotherapy, had at least stable disease documented by radiologic studies and agreed to continue gefitinib treatment, gefitinib was administered as maintenance treatment afterward until disease progression was again documented. All patients were followed until death. The primary end point of the study was overall response rate. Secondary end points included response rates in specific subsets of patients, progression-free survival (PFS), and OS at 1 year. Correlative studies prospectively planned included tumor and somatic gene sample collections for EGFR or other related gene testing. Exploratory MET tumor testing was not originally planned. Simon's optimal two stage design was used to calculate the sample size. Under an alpha error of 5%, power of 80%, response rate between 10% to 19%, more than five responders were needed in the first 44 assessable patients for continuing to second stage. Another 62 patients were planned to complete the second stage.

Patients who signed consent and took at least one dose of gefitinib were included in all efficacy and safety analysis. Tumor response and progression time were determined by an independent radiologist (Y.-C.C.) at the end of the study. PFS was defined as the time from day 1 of gefitinib to independently reviewed documented progression or to the date of patients’ receiving chemotherapy or radiotherapy as a result of clinical progression or to patient's death. TTF was defined as day 1 to the criteria for PFS, plus withdrawal from toxicity of treatment. OS was defined as the time from day 1 of gefitinib treatment to patient's death. The study was sponsored, conducted, and analyzed by the National Center of Excellence for General Clinical Trial and Research at the National Taiwan University Hospital. AstraZeneca Taiwan (Taipei, Taiwan) provided gefitinib and a partial grant to conduct the study.

EGFR and K-ras Gene Mutation Tests
Most tumor samples were obtained from paraffin-embedded blocks made on initial diagnosis. Alternatively, DNA extracted from pleural fluid-derived cancer cells were also used for analysis. DNA sequence of exons 18 to 21 of EGFR were determined by direct forward and reverse sequencing of the polymerase chain reaction (PCR) product from nested PCR reactions as described previously.²¹ K-ras exon 2 sequence was determined in some tumor samples using PCR and direct sequencing as previously described.²⁷ Positive mutation results were confirmed by sequencing an independent PCR product.

Quantitative Real-Time PCR to Estimate MET Gene Copy Number
Relative MET gene copy numbers were determined by quantitative real-time PCR as previously described.²⁵ In short, for MET and MTHFR (endogenous control), 10 to 50 ng of genomic DNA was amplified for 40 cycles (15 seconds at 95°C, 60 seconds at 60°C) in a ABI 7500 real-time PCR system (Applied Biosystems, Foster City, CA), using the QIAGEN QuantiTect SYBR Green PCR kit (Qiagen, Hilden, Germany) and 400 nm of primers. Triplicates cycle time values were averaged. MET relative amounts were normalized to MTHFR.

Statistical Analysis
Kaplan-Meier estimates of survival curves computed for PFS, TTF, and OS. Log-rank tests were used to compare the survival curves between different subsets of patients. Multivariate analyses were carried out in 90 patients whose tumors were tested for EGFR mutations. Variables included sex, smoking status, pathology, stage, PS, EGFR mutation types, and the potential interactions of any two factors were used by fitting multiple Cox's proportional hazard models to predict patient's hazard rates of TTF (Table A1, online only). In statistical testing, two-sided P .05 was considered statistically significant.

	RESULTS

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Patient Characteristics and Conduct of the Study
All 106 patients signed informed consent before entering onto the trial and were recruited between May 2005 and April 2006. Median age was 66.7 years (range, 32.3 to 86.2 years). Patient characteristics are listed in Table 1. Investigators tended to select patients who had better clinical predictive factors for gefitinib response to enter onto this study. Most patients were never smokers or had quit smoking for more than 1 year (defined as former smokers). All patients were East Asian. The first 44 patients were analyzed for response, and the result was presented previously in the abstract form.²⁸ Because the response rate (54.5%) in the first stage of the trial exceeded the predetermined goal, the study completed accrual of 106 patients. Final analysis was performed when the last accrued patient was followed for 12 months. Median follow-up duration was 18.3 months (range, 12 to 24 months).

TTF and OS
At the time of analysis, 95 patients (89.6%) experienced treatment failure and 58 patients (54.7%) were still alive. The median TTF and OS time are listed in Table 1 and the survival curves are shown in Figure 1. In log-rank tests, patients with a PS of 1 had statistically significant longer TTF than patients with a PS of 2. On the other hand, patients of female sex, PS of 1, or with adenocarcinoma pathology had statistically significant longer OS time than patients of male sex, PS of 2, or nonadenocarcinoma pathology. In the 90 patients who underwent EGFR mutation tests, patients with gefitinib-sensitive EGFR mutations (deletion in exon 19 or L858R exon 21 mutation) had better TTF and OS than did the patients with wild-type EGFR. Patients with other types of EGFR mutations had the worst TTF and OS (Table 1).

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A-D) Time to treatment failure (TTF) and (E-H) overall survival (OS) of patients grouped by (A, E) pathology, (B, F) smoking status, (C, G) sex, and (D, H) performance status (PS).

Sex Differences of TTF or OS in Patients With Mutant or Wild-Type EGFR
It is not clear whether sex is a predictor for response, TTF, or OS, in gefitinib-treated patients with gefitinib-sensitive EGFR mutations. In the 43 patients with these mutations, there were no differences in TTF among pathology, PS, smoking status (data not shown), or sex (Fig 2B). However, female patients seemed to live longer than male patients (Fig 2E; P = .0654). Similarly, there were no differences in TTF between female and male in 35 patients with wild-type EGFR. However, female patients again seemed to live longer than male patients (Fig 2F; P = .0943)

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Time to treatment failure and (D) overall survival of patients grouped by EGFR status. (B, C) Time to treatment failure and (E, F) overall survival grouped by sex for (B, E) 43 patients with EGFR exon 19 deletion or exon 21 L858R mutation or (C, F) 35 patients with wild-type EGFR.

MET Gene Copy Number and TTF
MET copy number was determined in 39 patients (Table A2). One patient had de novo L858R and T790M mutation and high copy number of MET (38). She had a short TTF and OS. No other patients had MET copy numbers more than 5.5. For seven patients whose MET copy numbers were more than 3.5, three had partial response, one stable disease, and two progressive disease, and one was not assessable after gefitinib treatment. MET copy number was plotted against TTF of all 39 tested patients and the 14 patients who had either L858R or deletion exon 19 mutations (Fig 3). In simple logistic regression, there was a trend for high MET copy number to predict for short TTF (all tested, P = .3978; L858R or exon 19 deletion, P = .5198). However, the sample size was too small to make any definitive conclusions.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Scatter plot of time to treatment failure versus MET copy number in (A) 38 patients (one patient with high MET copy number was not included in the figure) and (B) 14 patients with EGFR exon 19 deletion or exon 21 L858R mutation.

	DISCUSSION

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High response rate in patients with gefitinib-sensitive EGFR mutations is not the only parameter to select EGFR-TKI treatment over conventional combination chemotherapy. The duration of response or TTF after EGFR-TKI treatment is equally important. Prior studies of EGFR-TKI treatment in NSCLC patients with EGFR mutations reported median PFS of 9 to 12 months.^12,30,31 OS was not reported in full in those studies because of short follow-up periods. The results of this study provide more accurate TTF and OS for NSCLC patients, with specific EGFR mutations after first-line gefitinib treatment.

The most important independent predictive factors for long TTF in this study were the presence of gefitinib-sensitive EGFR mutations in tumor samples. However, the TTF of 43 patients with gefitinib-sensitive EGFR mutations in this study varied from 0.8 months to more than 23.5 months. Exploration of the predictive factors for duration of disease control is important. Recently, MET gene amplification has been implicated as a mechanism of action for acquired EGFR-TKI resistance^24,25 through the activation of ERBB3 pathway. Overexpression of MET in lung cancer tumor samples has been associated with poor prognosis.^35,36 In this study, a negative correlation between MET gene copy number and TTF was found in patients who had deletion exon 19 or L858R EGFR mutations. However, since the sample numbers of these patients were small, statistical significance was not reached. EGFR gene amplification in tumor samples may predict for survival advantage for NSCLC receiving EGFR-TKI treatment in retrospective studies.^8,37 However, the role of EGFR gene amplification to predict for response and survival seems to be less important in Asian patients³⁸ and was not examined in this study.

Two retrospective analyses on tumors samples from the patients receiving combination chemotherapy and placebo as the first-line treatment have shown that NSCLC patients who have EGFR mutations may have longer survival compared with the NSCLC patients with wild-type EGFR.^39,40 The presence of gefitinib-sensitive EGFR mutation is the best predictor for gefitinib response, TTF, and OS in this study. However, it is possible that patients whose tumors have an EGFR mutation also have a longer OS than those with EGFR wild-type tumors. To establish EGFR-TKI as the first-line treatment, a phase III randomized study comparing EGFR-TKI to standard chemotherapy is needed. One such study has completed accrual in Asia (N = 1,212; ClinicalTrials.gov Identifier: NCT00322452 [ClinicalTrials.gov] ).

In the present study, female sex and adenocarcinoma pathology predicted long OS but not TTF in log-rank tests. A similar trend for sex differences in prognosis was demonstrated in the patients with gefitinib-sensitive EGFR mutations or EGFR gene wild-type patients. (Fig 2). These findings suggest that second-line treatment with chemotherapy or inherent factors such as lower tumor growth rates may influence final OS. Factors such as sex and pathology may be more important as prognostic factors rather than predictive factors in patients receiving gefitinib as first-line treatment.

Patients with EGFR mutations other than gefitinib-sensitive mutations did not respond well to gefitinib. We have prospectively shown in this study that only two of 12 patients with atypical EGFR mutations (mutations other than exon 19 deletions and L858R mutation) responded to gefitinib. The median TTF (2.1 months) and OS (6.7 months) were poor. One retrospective report had similar findings.⁴¹ Patients with this kind of mutations in their tumor should consider chemotherapy or using experimental irreversible EGFR-TKIs as their primary treatment. On the contrary, seven patients with wild-type EGFR responded to gefitinib in this study (response rate, 20%). One of the reasons for the wild-type EGFR patients to respond to EGFR-TKI is the limitation of the current method to detect a small percentage of mutation cells in a group of wild-type EGFR cancer or normal cells. In a population with a high incidence of EGFR mutation such as patients from East Asia, the effectiveness of EGFR-TKI in NSCLCs deemed negative for EGFR mutations should not be ignored, and should be further explored in the future. Methods to decrease false-negative rates in conventional sequence methodology should be explored.⁴²

In conclusion, EGFR mutation types were the most important predictors of tumor response and longer TTF in gefitinib-treated, chemotherapy-naive NSCLC patients. MET gene amplification might be a predictor for gefitinib treatment durations. Prospective studies to confirm this observation are needed.

	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: Chih-Hsin Yang, AstraZeneca (C) Stock Ownership: None Honoraria: Chih-Hsin Yang, AstraZeneca; Chong-Jen Yu, AstraZeneca; Jin-Yuan Shih, AstraZeneca Research Funding: Chih-Hsin Yang, AstraZeneca Expert Testimony: None Other Remuneration: William Pao, Molecular MD

	AUTHOR CONTRIBUTIONS

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Conception and design: Chih-Hsin Yang, Chong-Jen Yu, Jin-Yuan Shih, Meng-Chin Tsai, Pan-Chyr Yang

Financial support: Chih-Hsin Yang

Administrative support: Chih-Hsin Yang, Ann-Lii Cheng, Pan-Chyr Yang

Provision of study materials or patients: Chih-Hsin Yang, Chong-Jen Yu, Jin-Yuan Shih, Kuan-Yu Chen, Zhong-Zhe Lin

Collection and assembly of data: Chih-Hsin Yang, Yeun-Chung Chang, Meng-Chin Tsai, Ching-Ju Huang, Chin-Lun Huang

Data analysis and interpretation: Chih-Hsin Yang, Yeun-Chung Chang, Fu-Chang Hu, Chia-Tung Shun, James Bean, William Pao

Manuscript writing: Chih-Hsin Yang, Fu-Chang Hu, William Pao

Final approval of manuscript: Chih-Hsin Yang, Chong-Jen Yu, Jin-Yuan Shih, Yeun-Chung Chang, Fu-Chang Hu, Meng-Chin Tsai, Kuan-Yu Chen, Zhong-Zhe Lin, Ching-Ju Huang, Chia-Tung Shun, Chin-Lun Huang, James Bean, Ann-Lii Cheng, William Pao, Pan-Chyr Yang

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Chia-Chi Cheng for her assistance in statistical computation.

	NOTES

 
Supported by the Taiwan National Science Council Grant No. NSC95-2314-B-002-227-MY3 and Department of Health Grant No. DOH94-TD-B-111-001, and partially supported by AstraZeneca Taiwan.

Presented in part 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and the 12th World Conference on Lung Cancer Research, Seoul, Korea, Septmber 2-6, 2007.

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

Clinical trial information can be found for the following: NCT00173875 [ClinicalTrials.gov] .

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Submitted December 11, 2007; accepted February 14, 2008.

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