Originally published as JCO Early Release 10.1200/JCO.2005.05.4692 on June 19 2006
Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3340-3346
© 2006 American Society of Clinical Oncology.
Prospective Phase II Study of Gefitinib for Chemotherapy-Naïve Patients With Advanced Non–Small-Cell Lung Cancer With Epidermal Growth Factor Receptor Gene Mutations
Akira Inoue,
Takuji Suzuki,
Tatsuro Fukuhara,
Makoto Maemondo,
Yuichiro Kimura,
Naoto Morikawa,
Hiroshi Watanabe,
Yasuo Saijo,
Toshihiro Nukiwa
From the Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University; and Department of Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Address reprint requests to Akira Inoue, MD, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1, Seiryomachi, Aoba-ku, Sendai 980-8575, Japan; e-mail: akinoue{at}idac.tohoku.ac.jp
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ABSTRACT
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PURPOSE: This study was undertaken to investigate the efficacy and the feasibility of gefitinib for chemotherapy-naïve patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.
PATIENTS AND METHODS: The EGFR gene status in various tumor samples obtained from chemotherapy-naïve advanced NSCLC patients was examined by DNA sequencing of EGFR exons 18 to 23. Patients harboring EGFR mutations received gefitinib (250 mg/d) alone. The response rate, progression-free survival (PFS), and toxicity profile were assessed prospectively.
RESULTS: Between June 2004 and October 2005, 75 patients were examined for the EGFR status, and 25 patients (33%) harbored EGFR mutations. EGFR mutations were significantly frequent in females (P < .01) and never or light smokers (P < .001). Sixteen patients with EGFR mutations were enrolled onto the study. The overall response rate in these patients was 75% (95% CI, 54% to 96%), and the disease control rate was 88% (95% CI, 71% to 100%). The median PFS time of these patients was 9.7 months (95% CI, 7.4 to 9.9 months). No life-threatening toxicity was observed.
CONCLUSION: Treatment with gefitinib alone for chemotherapy-naïve NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity. To assess the proper timing of gefitinib in such patients, a subsequent randomized trial comparing gefitinib with standard chemotherapy is warranted.
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INTRODUCTION
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Gefitinib (Iressa; AstraZeneca, Osaka, Japan) is an orally active, selective, tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that binds to the adenosine triphosphate–binding pocket of the EGFR kinase domain and blocks downstream signaling pathways; gefitinib showed novel antitumor activity in patients with advanced non–small-cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy.1,2 Several retrospective analyses have suggested that a high response to gefitinib can be found most frequently in women, never smokers, patients with adenocarcinoma, and Japanese patients.1-4
Recent studies proved that somatic mutations in exons 18 to 21, close to the region coding the adenosine triphosphate–binding pocket of the kinase domain of EGFR, are associated with response and survival in patients treated with gefitinib.5-23 Most of those mutations were observed in the following two hotspots: in-frame deletions including amino acids at codons 746 to 750 (E746 to A750) in exon 19 and an amino acid substitution at codon 858 (L858R) in exon 21. Those mutations were also observed more frequently among women, never smokers, patients with adenocarcinoma, and Japanese and East Asian patients, in agreement with the known clinical predictors of gefitinib sensitivity as well as the favorable prognosis of such patients.
However, there were some discrepancies about the association between EGFR mutations and the tumor response or survival in gefitinib-treated NSCLC patients in these studies. For example, the response rates of gefitinib varied from 23% to as high as 83%. These discrepancies can be attributed to the fact that all of the previous studies were retrospective analyses, so the patient characteristics, method of detection of gene mutations, and condition of tumor samples were quite different. To address these controversies, proper prospective trials are urgently needed.
Although gefitinib failed to show activity in chemotherapy-naïve patients with advanced NSCLC when used in combination with standard chemotherapy in large randomized trials,24,25 if NSCLC patients selected according to the EGFR gene mutation status were targeted, a more promising response to gefitinib alone may be found in a first-line setting. However, concern about gefitinib-induced interstitial lung disease (ILD) still exists in Japan.4,26 A previous study concluded that first-line treatment with gefitinib for nonselected NSCLC patients was not feasible because of lethal ILD observed in 10% of enrolled patients.27 However, the feasibility of gefitinib in a first-line setting for patients selected according to the EGFR mutation status is still unclear. In this context, we conducted this prospective phase II study to evaluate the efficacy and the feasibility of gefitinib treatment for chemotherapy-naïve patients with advanced NSCLC with EGFR mutations.
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PATIENTS AND METHODS
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Patient Selection
Chemotherapy-naïve patients with stage IIIB to IV or postoperative recurrent NSCLC who had EGFR gene mutations were eligible for this study. Other eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2 and an estimated life expectancy of more than 12 weeks. Laboratory requirements included hemoglobin  9 g/dL, WBC count 4,000/µL, platelets 100,000/µL, AST and ALT  2.0x the institutional upper limit of normal, serum creatinine 1.5 mg/dL, and arterial oxygen pressure 60 mmHg. Patients with symptomatic brain metastasis or severe comorbidity, such as symptomatic cardiovascular disease, uncontrolled diabetes, active gastric ulcer, or liver cirrhosis, were excluded. Patients with pulmonary fibrosis diagnosed by high-resolution computed tomography were also excluded from this study. The institutional review board of our hospital approved the analyses of the EGFR gene of the tumor and this study, and written informed consent was obtained from all enrolled patients.
EGFR Gene Analysis
Genomic DNA was extracted from tumor specimens using the DNeasy kit (Qiagen, Valencia, CA). EGFR gene (exons 18 to 23) mutations were determined by polymerase chain reaction (PCR) amplification using the intron-based primers according to a published method.6 PCR was performed using Gene Amp PCR System 9700 (Applied Biosystems, Foster City, CA), and its products were then sequenced directly using the Big Dye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems) and ABI PRISM 3100 (Applied Biosystems) according to the manufacturer's instructions. All sequencing reactions performed in both forward and reverse directions were analyzed by the Basic Local Alignment Search Tool (BLAST), and all electropherograms were reanalyzed by visual inspection to check for the mutations. All mutations were confirmed by PCR amplification of an independent DNA isolate.
Drug Administration
Gefitinib (250 mg/d) was orally administered once daily. The patients continued uninterrupted treatment until disease progression, intolerable toxicity, or withdrawal of consent. Second-line chemotherapy or other treatments after gefitinib were not prohibited by the protocol.
Treatment Assessment
We evaluated the objective tumor responses as complete response (CR), partial response (PR), stable disease, or progressive disease in accordance with the new WHO criteria (Response Evaluation Criteria in Solid Tumors). Disease control was defined as the best tumor response of CR, PR, or stable disease that was confirmed and sustained for 4 weeks or longer. Baseline assessments were performed within 14 days before the treatment. During the treatment, assessments were performed every 4 weeks for the first 4 months and then every 8 weeks until disease progression. All adverse events (AEs) were reported, and severity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0) grading system. Data were collected when gefitinib treatment was interrupted or withdrawn as a result of AEs. Routine clinical and laboratory assessments were performed at least every 4 weeks.
Statistical Analysis
The primary end point of this study was a response rate defined as the proportion of the patients whose best response was CR or PR among all per-protocol patients. Simon's two-stage minimax design28 was used to determine the sample size and interim decision criteria. Assuming that a response rate of 70% in eligible patients would indicate potential usefulness, whereas a rate of 40% would be the lower limit of interest, with  = .15 and ß = .10, the estimated accrual number was 14 patients. This regimen would be rejected when only five of the first nine patients had an objective response at the interim analysis.
Another end point of this study was the feasibility, as determined by the proportion of patients safely completing the first 28 days of therapy without any grade 3 or greater serious AEs. A minimax design was also used to test whether there was sufficient evidence to determine that the treatment completion rate was at least 95% (ie, clinically feasible) versus at most 80% (ie, clinically infeasible), with = .20 and ß = .20. In this setting, the estimated required accrual number was also 14 patients, and this regimen would be rejected when two of the first eight patients could not complete the first 28 days of therapy at the interim analysis.
Secondary end points of this study were toxicity and progression-free survival (PFS). PFS was defined as the interval between the start of the treatment and the date of the first observation of disease progression or death from any cause. The survival distribution was estimated by the Kaplan-Meier method. Patients alive without disease progression at the data cutoff point were censored at the last point when the patients were assessed to be progression free.
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RESULTS
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Patient Characteristics
From June 2004 to October 2005, we performed mutational analyses in various tumor samples from 99 chemotherapy-naïve NSCLC patients, and 75 patients were assessable for EGFR mutations. The median time from submission of tumor samples to receiving results of the EGFR mutation status was 7 days (range, 5 to 14 days). Among the 75 patients, EGFR mutations were detected in 25 patients (33%); 17 had E746 to A750 deletions in exon 19, and eight had L858R point mutation in exon 21 (Table 1). Relationships between the patient characteristics and the EGFR mutations are shown in Table 2. In agreement with the results of previous reports, EGFR mutations were significantly frequent in females (P = .0027) and never or light smokers (defined as < 10 pack years; P < .001). Patients with adenocarcinoma also had a tendency to harbor the EGFR mutations (P = .065). Finally, 16 patients with EGFR mutations (nine with deletions and seven with L858R) were enrolled onto this study, whereas nine patients (eight with deletions and one with L858R) received standard chemotherapy, such as a platinum doublet regimen, because gefitinib has been approved only for advanced NSCLC patients previously treated with chemotherapy in Japan (Fig 1). The characteristics of patients who received chemotherapy were not different from those of patients who received gefitinib (Table 3).
Table 4 lists all the patient characteristics in this study. Most of the patients were female and never smoked, and all the patients had adenocarcinoma. The median age at entry onto this study was 71 years (range, 33 to 82 years). All 16 patients were fully assessable for efficacy, but two patients were not assessable for feasibility as a result of early termination of gefitinib treatment because of rapid disease progression.
Response and Survival
The objective tumor responses are listed in Table 5. The overall response rate and disease control rate were 75% (95% CI, 54% to 96%) and 88% (95% CI, 71% to 100%), respectively. Some patients experienced a dramatic improvement of systemic advanced disease shortly after the initiation of gefitinib (Fig 2). The difference in the response rate between the two types of gene mutations (deletions and L858R) was not significant (67% v 86%, respectively; P = .585). In the samples from two patients with progressive disease, another EGFR mutation, T790M, which is known to be associated with resistance to gefitinib,29 was not detected. The K-Ras mutation was not examined in this study.
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Fig 2. Remarkable antitumor response observed in patients with epidermal growth factor receptor mutations. A primary tumor (left upper lobe) and multiple metastases of the lymph node, bone, and brain (left) detected by positron emission tomography scan and magnetic resonance imaging were dramatically improved a few months after the initiation of gefitinib (right).
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The median follow-up time was 7.6 months (range, 3.4 to 18.8 months), and 10 patients were still receiving gefitinib at the data cutoff point (middle of February 2006). The median PFS time was 9.7 months (95% CI, 7.4 to 9.9 months) in the 16 patients in this study, whereas the PFS time in the nine patients who received standard chemotherapy was 7.6 months (95% CI, 6.7 to 9.5 months; Fig 3).
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Fig 3. Progression-free survival curves of patients treated with first-line gefitinib (——) and of patients treated with standard chemotherapy (– – – –). Bars indicate censored patients at the data cutoff point.
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Feasibility
No severe AEs, such as ILD, were observed in the 16 patients on this study. The most frequent AEs seen in this study were grade 1 to 2 skin rash, stomatitis, and diarrhea (Table 6). Two patients experienced grade 2 skin rash, and one of these patients also suffered from grade 2 nail changes. Although one patient suffered from grade 3 elevation of hepatic enzyme, he was able to restart gefitinib after 1 month. There was no treatment-related death in this study.
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DISCUSSION
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This small prospective study of first-line treatment with gefitinib demonstrated a higher objective response rate (75%) and longer PFS time (9.7 months) in chemotherapy-naïve patients with advanced NSCLC compared with patients who received conventional chemotherapy,30,31 suggesting that the selection of NSCLC patients for gefitinib treatment according to the EGFR gene status is an adequate strategy. This study met its primary statistical end point for the efficacy that confirms retrospective observations linking the EGFR mutations and the efficacy of gefitinib. It also demonstrated the feasibility of first-line gefitinib for patients with EGFR mutations. Because we had observed severe ILD related to gefitinib,26,27 we carefully reviewed the AEs in this study. Patients in this study showed no life-threatening toxicity such as ILD.
Although gefitinib monotherapy had achieved clinically meaningful results in initial phase II studies (response rates for gefitinib 250 mg/d were 18.4% and 11.8% in Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2, respectively) of previously treated NSCLC patients,1,2 subsequent large, randomized, phase III trials (Iressa NSCLC Trial Assessing Combination Treatment I and II) failed to demonstrate the superiority of combining gefitinib with standard chemotherapy over chemotherapy alone in the first-line treatment for advanced NSCLC.24,25 Retrospective analyses of EGFR gene abnormalities in the IDEAL trials suggested that EGFR mutation–positive patients had higher response rates and longer time to progression, but not better overall survival, compared with mutation-negative patients. No statistical differences in response rate and overall survival were observed in patients treated with gefitinib plus chemotherapy when administered according to the EGFR genotype.21 These negative results may have resulted from the small number of EGFR mutation analyses performed in those studies. Therefore, we believe that the appropriate timing of gefitinib (first line with or without chemotherapy or second line) for NSCLC patients with EGFR mutations should be examined further.
Some studies of first-line treatment with gefitinib have been performed. A study performed in Japan concluded that first-line treatment with gefitinib was not feasible in nonselected NSCLC patients because of the high incidence of ILD.27 Lee et al32 selected patients with adenocarcinoma and patients who were lifetime never smokers to receive first-line gefitinib. These selected patients demonstrated dramatic antitumor activity (response rate of 69% and long time to progression of 7.6 months). In contrast to selection by clinical features (adenocarcinoma and never smoker), we selected patients according to the EGFR genotype and treated patients with gefitinib alone. Although most of the patients in our study also had adenocarcinoma and were never smokers, EGFR mutations have been detected in not only nonsmokers with adenocarcinoma, but also in heavy smokers and patients with other histologic types.8 Therefore, we believe that NSCLC patients should be examined for EGFR mutations to predict their gefitinib sensitivity. Because a high response rate does not directly correlate with longer survival for some agents, a large-scale, randomized, phase III study is needed to examine whether first-line treatment of gefitinib prolongs survival in NSCLC patients with EGFR mutations.
Some studies have indicated that the EGFR gene copy number by fluorescent in situ hybridization is also a favorable predictive marker of gefitinib sensitivity,23 and others suggested that the K-Ras mutation is a negative predictive factor.33 Studies of BR21 and Iressa Survival Evaluation in Lung Cancer (ISEL) concluded that EGFR copy number is a better predictor for outcome of EGFR TKI compared with EGFR mutation status.34 However, we assume that there are substantial misconstructions in the analyses in those studies about the relationship of the EGFR mutations and its efficacy because the investigators did not separate the active mutations well known to correlate with the response of TKI, such as exon 19 deletions, L858R, G719A, G719C, and G719S, from other nonspecific mutations. Moreover, these studies were conducted in mainly white patients, whereas our study was conducted in only Japanese patients. Thus, we believe that at least the active EGFR mutation is a good predictor of the efficacy of EGFR TKI.
Most of the reports about the relationship between EGFR mutations and gefitinib sensitivity analyzed patients with postoperative recurrence using surgical specimens retrospectively. However, many patients with advanced NSCLC at diagnosis can be initially indicated for gefitinib treatment in the first- or second-line setting. It is noteworthy that more than half of the patients in our study were successfully analyzed for the EGFR gene status without using surgical specimens but, instead, using various types of tumor samples such as pleural effusion and cytology. Regarding the sensitivity and the time required for the examination of EGFR mutations, new techniques, such as the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp method, should be used in the future instead of the direct sequence method.35
Two patients with relatively worse performance status and rapidly progressing tumors did not respond to gefitinib despite being positive for EGFR mutations. Subsequent examination revealed the absence of a mutation (T790M) related to resistance in both patients. Because one patient responded to subsequent standard chemotherapy (carboplatin and paclitaxel), a decision to withdraw gefitinib treatment should be carefully considered for such refractory patients.
In conclusion, first-line gefitinib treatment can achieve a high activity with acceptable toxicity in patients with advanced NSCLC and EGFR mutations. To assess the proper timing of gefitinib for the treatment of such patients, a large-scale randomized trial comparing gefitinib with standard chemotherapy in chemotherapy-naïve NSCLC patients with EGFR mutations is warranted.
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Authors' Disclosures of Potential Conflicts of Interest
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The authors indicated no potential conflicts of interest.
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Author Contributions
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| Conception and design: Akira Inoue
Financial support: Yasuo Saijo, Toshihiro Nukiwa
Administrative support: Akira Inoue, Takuji Suzuki, Tatsuro Fukuhara, Makoto Maemondo
Provision of study materials or patients: Makoto Maemondo, Yuichiro Kimura, Naoto Morikawa, Hiroshi Watanabe
Collection and assembly of data: Akira Inoue
Data analysis and interpretation: Akira Inoue, Takuji Suzuki, Tatsuro Fukuhara, Naoto Morikawa
Manuscript writing: Akira Inoue, Yasuo Saijo
Final approval of manuscript: Toshihiro Nukiwa
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NOTES
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Submitted December 23, 2005;
accepted March 20, 2006.
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TOP
ABSTRACT
INTRODUCTION
