the Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan

    ABSTRACT

    PURPOSE: We conducted a phase II study of single agent treatment with gefitinib in chemotherapy-nave patients with advanced non–small-cell lung cancer (NSCLC) to assess its efficacy and toxicity.

    PATIENTS AND METHODS: Patients received 250 mg doses of gefitinib daily. Administration of gefitinib was terminated if partial response (PR) was not achieved within 8 weeks or if tumor reduction was not observed within 4 weeks. In these cases, platinum-based doublet chemotherapy was given as a salvage treatment. We evaluated mutation status of the epidermal growth factor receptor (EGFR) gene in cases with available tumor samples.

    RESULTS: Forty-two patients were enrolled between March and November 2003, with 40 of these patients being eligible. The response rate was 30% (95% CI, 17% to 47%). The most common toxicity included grade 1 or 2 acne-like rash (50%) and grade 1 diarrhea (18%). Grade 2 or 3 hepatic toxicity was observed in 8% of patients. Four patients developed grade 5 interstitial lung disease (ILD). Thirty patients received second-line chemotherapy. Median survival time was 13.9 months (95% CI, 9.1 to 18.7 months), and the 1-year survival rate was 55%. Tumor samples were available in 13 patients, including four cases of PR, six cases of stable disease, and three cases of progressive disease. EGFR mutations (deletions in exon 19 or point mutations [L858R or E746V]) were detected in four tumor tissues. All four patients with EGFR mutation achieved PR with gefitinib treatment.

    CONCLUSION: Single agent treatment with gefitinib is active in chemotherapy-nave patients with advanced NSCLC, but produces unacceptably frequent ILD in the Japanese population.

    INTRODUCTION

    Previous meta-analysis demonstrated that cisplatin-based chemotherapy yielded a modest but significant survival benefit over best supportive care in advanced non–small-cell lung cancer (NSCLC).1-4 In the 1990s, new agents, including vinorelbine, gemcitabine, paclitaxel, docetaxel, and irinotecan became available for the treatment of NSCLC. Several phase III trials comparing doublet platinum-based chemotherapies demonstrated no significant difference with respect to response rate, survival, or quality of life.5,6 Nonplatinum or triplet platinum-based combination chemotherapies have been investigated, but none of these produced longer survival than standard doublet platinum-based chemotherapy.7-9

    Recently, molecular-targeted agents have been introduced for the treatment of NSCLC. Gefitinib is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which displays activity against recurrent NSCLC after platinum-based chemotherapy. Two international, randomized phase II trials in patients with advanced or metastatic NSCLC after platinum-based chemotherapy demonstrated response rates of 12% to 18% (28% in the Japanese population).10,11 Two international, randomized, double-blinded, placebo-controlled phase III trials investigated the role of gefitinib combined with platinum-based chemotherapy regimens, including carboplatin and paclitaxel, or cisplatin and gemcitabine in chemotherapy-nave patients with advanced NSCLC.12,13 Surprisingly, there were no improvements in overall survival, time to progression, or response rate. There are no data available regarding first-line treatment with single agent gefitinib against NSCLC in the Japanese population. Here, we conducted a phase II study of single agent treatment with gefitinib in chemotherapy-nave patients with advanced NSCLC. If a failure with gefitinib treatment was perceived, standard platinum-based doublet chemotherapy was performed as salvage. The primary end point of this phase II trial was response rate, and the secondary end points were toxicity, survival, and response rate of salvage chemotherapy.

    PATIENTS AND METHODS

    Patient Population

    Patients were required to have histologically or cytologically confirmed stage IIIB (malignant pleural or pericardial effusion and/or metastasis in the same lobe) or stage IV NSCLC. Recurrences after surgical resection were permitted. Other criteria included: (1) age 20 years or older, but younger than 75 years; (2) Eastern Cooperative Oncology Group performance status (PS) 0 or 1; (3) measurable disease; (4) PaO2  60 mmHg; (5) adequate organ function (ie, total bilirubin  2.0, AST and ALT  100 U/L, serum creatinine  1.5 mg/dL, leukocyte count 4,000 to 12,000/mm3, neutrophil count  2,000/mm3, hemoglobin  9.5 g/dL, and platelets  100,000/mm3); (6) no prior chemotherapy or thoracic radiotherapy; (7) no interstitial pneumonia or pulmonary fibrosis, as determined by chest x-ray; (8) no paralytic ileus or vomiting, (9) no symptomatic brain metastases, (10) no active infection; (11) no active concomitant malignancy; (12) no pregnancy or breast-feeding; (13) no severe allergy to drugs. Patients with PaO2 less than 60 mmHg were excluded, because those patients might have pulmonary fibrosis, which is a risk factor of interstitial lung disease (ILD).14 All patients were required to provide written informed consent and the institutional review board at the National Cancer Center approved the protocol.

    Treatment Plan

    Treatment was started within a week after enrollment in the study. Patients received 250 mg of gefitinib orally daily. In the event of grade 3 or more and/or unacceptable toxicities, gefitinib was postponed until these toxicities were improved to grade 2 or less. Dose reduction was not performed. If treatment was postponed four times or more, the treatment was terminated. Therapy was continued unless the patient experienced unacceptable toxicity or progressive disease, partial response (PR) was not achieved within 8 weeks, or the sum of the longest diameters of the target lesions decreased less than 10% within 4 weeks. If the gefitinib treatment failed according to these criteria, platinum-based doublet chemotherapy was performed as a salvage regimen.

    Previous trials of gefitinib for pretreated patients with NSCLC reported that most responding patients showed rapid tumor regression within 4 or 8 weeks.11 Furthermore, most responses by gefitinib were extreme shrinkage of the tumor. Minor response, as frequently seen by the treatment with cytotoxic agents, was seldom experienced. Stable disease with gefitinib corresponded to no tumor reduction or slight progression. If patients with stable disease continued the treatment with gefitinib until progressive disease became obvious, those patients might not be able to receive platinum-based salvage chemotherapy because of poor PS due to progressive disease. Platinum-based combination chemotherapy is the standard care for patients with advanced NSCLC and good PS. Platinum-based chemotherapy was thought to be essential for patients with no response from the first-line single agent treatment with gefitinib. Therefore, we implemented these early stopping criteria for treatment with gefitinib.

    Study Evaluations

    Pretreatment evaluations consisted of a complete medical history, determination of performance status, physical examination, hematologic and biochemical profiles, arterial blood gas examination, ECG, chest x-ray, bone scan, and computed tomography (CT) scan of the chest, ultrasound or CT scan of the abdomen, and magnetic resonance imaging or CT scan of the whole brain. Evaluations performed included a weekly chest x-ray for 4 weeks, and once every 2 weeks for biochemistry, complete blood cell, platelet, leukocyte differential counts, physical examination, determination of performance status, and toxicity assessment. Imaging studies were scheduled to assess objective response every month.

    Response and Toxicity Criteria

    Response evaluation criteria in solid tumors (RECIST) guidelines were used for evaluation of antitumor activity.15 The target lesions were defined as  2 cm in the longest diameter on CT scans. A complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A PR was defined as an at least 30% decrease in the sum of the longest diameters of the target lesions for more than 4 weeks with no new area of malignant disease. Progressive disease (PD) indicated at least a 20% increase in the sum of the longest diameter of the target lesions or a new malignant lesion. Stable disease was defined as insufficient shrinkage to qualify for PR and insufficient increase to qualify for PD. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.

    Mutation Analysis of the EGFR Gene

    Tumor specimens were obtained during diagnostic or surgical procedures. Biopsied or surgically resected specimens were fixed with formalin or 100% methanol, respectively. Tumor genomic DNA was prepared from paraffin-embedded sections using laser capture microdissection in biopsied specimens or macrodissection in surgically resected specimens at Mitsubishi Chemical Safety Institute LTD. Exons 18, 19, and 21 of the EGFR gene were amplified and sequenced as previously described.16

    Statistical Analysis

    In accordance with the minimax two-stage phase II study design by Simon,17 the treatment program was designed to refuse response rates of 10% (P0) and to provide a significance level of .05 with a statistical power of 80% in assessing the activity of the regimen as a 25% response rate (P1). The upper limit for first-stage drug rejection was two responses in the 22 assessable patients; the upper limit of second-stage rejection was seven responses within the cohort of 40 assessable patients. Overall survival was defined as the interval between enrollment in this study and death or the final follow-up visit. Median overall survival was estimated by the Kaplan-Meier analysis method.18 Fisher's exact test was used in a contingency table.

    RESULTS

    Patient Population

    A total of 42 patients were enrolled in this study between March and November, 2003, with 40 of these patients being eligible. One patient was found ineligible due to anemia, the other because spinal magnetic resonance imaging could not confirm a positive bone scan. Patient characteristics are listed in Table 1. Sixty percent of patients were male; median age was 61 years. The most common histologic subtype was adenocarcinoma (75%). Most patients (93%) had stage IV disease or recurrence after surgical resection. Eighty percent of patients were current or former smokers.

    Efficacy

    One patient (3%) has been receiving gefitinib after 22 months. Four patients suspended gefitinib for 11, 14, 27, or 29 days, because of liver dysfunction (n = 3) and fever due to urinary tract infection (n = 1). Thirty-nine patients terminated gefitinib because of progressive disease (n = 20), no tumor reduction within 4 weeks (n = 12), not achieving PR within 8 weeks (n = 1), toxicities including pulmonary (n = 3), nausea and vomiting (n = 1), rash (n = 1), or hepatic dysfunction (n = 1).

    There were 12 PRs in 40 eligible patients, and the objective response rate was 30% (95% CI, 17% to 47%; Table 2). All but one patient from this subgroup achieved PR within 4 weeks, with the remaining patient achieving PR within 8 weeks. The background of the 12 responding patients was as follows: nine females, three males; 11 adenocarcinomas, one large-cell carcinoma; six individuals who never smoked, five current smokers, and one former smoker. Response rates based on patient characteristics were as follows: three of 24 (13%) males, nine of 16 (56%) females (P = .0050); 11 of 30 (37%) individuals with adenocarcinoma, one of 10 (10%) individuals with squamous or large-cell carcinoma (P = .0048); six of 32 (19%) current or former smokers, and six of eight (75%) individuals who never smoked (P = .0048).

    The median follow-up time was 23 months, and nine patients were still alive at the most recent follow-up. The median survival time was 13.9 months (95% CI, 9.1 to 18.7 months), and the 1-year survival rate was 55% (Fig 1).

    Safety and Toxicity

    Toxicity was evaluated in all eligible patients. The most common toxicity was rash (Table 3). Thirty-eight percent and 13% of patients experienced grade 1 or 2 rash, respectively. One patient experienced grade 3 nausea and vomiting, leading to gefitinib treatment being terminated. Grade 3 hepatic toxicity was observed in one patient, also causing termination of gefitinib treatment.

    The most problematic toxicity was ILD. We reviewed the medical records, chest x-rays, and CT films of all the cases, which were suspected as ILD by the physician in charge. ILD was diagnosed on the basis of standard or high-resolution CT findings of the chest (diffuse ground-glass opacity, consolidation, or infiltrate) and no response to antibiotics. We diagnosed that four patients experienced grade 5 ILD during or after first-line treatment with gefitinib. The first patient was a 61-year-old man. He developed dyspnea and fever elevation (38.1°C) on day 23 of the treatment with gefitinib and administration of gefitinib was terminated. Chest CT demonstrated bilateral diffuse ground-glass opacity, and PaO2 was 43.7mmHg in the room air. KL-6 antigen, a serum marker of interstitial pneumonia, was not elevated (351 U/mL) on day 24, but elevated on day 31 (1,400 U/mL). Beta-D-glucan, a serum marker of fungal infection and Pneumocystis carinii pneumonia, was also negative. Methylprednisolone and antibiotics were administered, with temporal improvement of ILD. However, subsequently, pulmonary function gradually deteriorated, leading to death. Autopsy revealed alveolar damage with organization around the bronchus and vessels in both neoplastic and non-neoplastic lesions, compatible with drug-induced ILD. The second patient was a 64-year-old man. Chest CT on day 27 showed stable disease, but administration of gefitinib was continued (protocol violation). Periodic chest x-ray film on day 45 showed abnormal shadow in the left lung field. High-resolution CT of the chest on the same day revealed reticular shadow on bilateral upper lobe. The treatment with gefitinib was terminated on day 45. KL-6 antigen was not elevated on day 49 (276 U/mL). Methylprednisolone and antibiotics were administered, but were not effective, leading to death. The third patient was a 67-year-old man. Chest CT on day 30 demonstrated enlargement of primary lesion and bilateral reticular shadow in subpleural lesions. Gefitinib was terminated on day 30. The patient developed dyspnea without fever elevation on day 37. Pao2 in the room air fell to 61.0 mmHg from 82.4 mmHg at pretreatment. Chest x-ray showed that the bilateral diffuse reticular shadow deteriorated. Methylprednisolone and antibiotics were administered, but were not effective, leading to death. Autopsy revealed severe fibrotic thickness of alveolar septum, compatible with severe interstitial pneumonia. There was no pathological evidence of carcinomatous lymphangiosis. The fourth patient was a 59-year-old woman. Chest x-ray showed consolidation in the left lung on day 21. Slight fever (37.9°C) developed on day 22. Blood culture was negative. Antibiotics were administered, but consolidation deteriorated and spread to both lungs on day 25. Gefitinib was terminated on day 25. KL-6 antigen was elevated to 3,590 U/mL. Methylprednisolone was administered, but was not effective, leading to death (Table 4). Four other patients experienced ILD after second-line or third-line chemotherapy. Two patients received second-line treatment with cisplatin plus vinorelbine (one and four courses), one patient received treatment with cisplatin plus gemcitabine (one course), and one patient received third-line treatment with docetaxel (four courses). Three of four patients received steroids, with temporal improvement of ILD being observed in two patients. However, ILD deteriorated during tapering of steroid treatment, with three patients subsequently dying. One patient stopped the third-line treatment with docetaxel, with the associated ILD showing improvement in this case without steroid treatment (Table 4).

    We retrospectively reviewed the pretreatment chest x-rays and CT films of all patients. Interstitial shadow was not detected on pretreatment chest x-ray films in any patients. However, six patients showed evidence of interstitial shadow on pretreatment chest CT films. Three of the six patients with interstitial shadow, as determined by pretreatment chest CT, experienced ILD either during or following administration of gefitinib or second-line chemotherapy. None of the six patients responded to gefitinib treatment. On the other hand, four of 34 patients who showed no interstitial shadow on pretreatment chest CT films experienced ILD. Interstitial shadow as determined by pretreatment chest CT was not a statistically significant risk factor of ILD (P = .0819; Table 5).

    Second-Line Chemotherapy

    A total of 30 patients received second-line chemotherapy. Twenty-seven patients received platinum-based chemotherapy (cisplatin plus vinorelbine; n = 17), carboplatin plus paclitaxel (n = 5), cisplatin plus gemcitabine (n = 3), cisplatin plus docetaxel (n = 1), and cisplatin plus irinotecan (n = 1). The remaining three patients received vinorelbine plus gemcitabine or vinorelbine alone. Nine of 30 patients achieved PR with these second-line chemotherapies. The objective response rate of second-line chemotherapy was 30% (95% CI, 15% to 50%).

    Mutation Status of the EGFR Gene

    Out of 42 enrolled patients, 16 patients were diagnosed pathologically, 22 were diagnosed cytologically, and four patients recurred after surgical resection. Biopsied specimens were available in nine patients. Therefore, tissue samples were available in a total of 13 patients. These 13 patients included four PRs, six with stable disease, and three PDs. EGFR mutations were detected in four tumor tissues, including the in-frame nucleotide deletions in exon 19 (n = 3) and an L858R mutation in exon 21 (n = 1). One tumor had an in-frame deletion and an E746V mutation in exon 19. All four PR patients had EGFR mutations (Table 6).

    DISCUSSION

    This phase II study was designed to evaluate the efficacy and safety of first-line single agent treatment with gefitinib in patients with advanced NSCLC. There is no other paper that evaluates single agent treatment with gefitinib prospectively in patients with advanced NSCLC. The observed response rate of 30% (95% CI, 17% to 47%), median survival of 13.9 months and 1-year survival of 55% are promising. However, grade 5 ILD occurred in 10% (95% CI, 3% to 24%) of patients. This high rate of ILD was not acceptable. The incidence of ILD was seen to be less than 1% in two randomized controlled studies comparing gefitinib with placebo in combination with gemcitabine and cisplatin or paclitaxel and carboplatin.12,13 The reason for the high incidence of ILD observed in our study is unknown. The West Japan Thoracic Oncology Group analyzed 1,976 patients receiving gefitinib retrospectively. In this case, the incidence of ILD was 3.2% (95% CI, 2.5% to 4.6%) and the death rate due to ILD was 1.3% (95% CI, 0.8% to1.9%). Multivariate analyses found that risk factors included being male, individuals who smoked, and complication of interstitial pneumonia.14 Our retrospective analyses revealed that three of six patients with interstitial shadow on pretreatment chest CT films, but not detected on chest x-ray films developed ILD; on the other hand, five of 34 patients without interstitial shadow developed ILD. Interstitial shadow on pretreatment chest CT was a marginally significant risk factor of ILD (P = .0819). It might be suggested that patients with interstitial shadow on pretreatment chest CT films be excluded from administration of gefitinib; however, our analyses were biased because we analyzed retrospectively and did not blind patient clinical information. Prospective analysis is needed to evaluate interstitial shadow by chest CT before treatment with gefitinib.

    The Southwest Oncology Group conducted a phase II trial to evaluate gefitinib in patients with advanced bronchioloalveolar carcinoma (SWOG 0126). Previously untreated (n = 102) and treated (n = 36) patients were entered and eligible in SWOG 0126. The response rate was 19% and the median survival time was 12 months in the untreated population.19 These subset analyses were comparable to our results.

    Recently, mutations in the tyrosine kinase domain of EGFR were found to be associated with gefitinib sensitivity in patients with NSCLC.16,20,21 Our retrospective analyses demonstrated that EGFR mutations were detected in four of 13 patients, and those four patients achieved PR in the single agent treatment of gefitinib. These results were compatible with previous reports.16,20,21

    Thirty patients received second-line chemotherapy, including platinum-based (n = 27) and nonplatinum-based (n = 3) regimens; the response rate was 30%. Pretreatment with gefitinib does not seem to adversely affect the response of second-line chemotherapy. However, our small-scale study does not suggest the best second-line regimen. Platinum combined with any third-generation agents including paclitaxel, docetaxel, vinorelbine, gemcitabine, or irinotecan is probably acceptable as the current standard first-line chemotherapy.

    First-line single agent with gefitinib is active, but produces unacceptably frequent ILD in the Japanese population. Being female, as well as adenocarcinoma, those who never smoked, and EGFR mutation were associated with response to gefitinib. Patients who responded to gefitinib did not experience ILD during gefitinib chemotherapy. Further research via genetics and image analysis is needed to avoid ILD and identify a subgroup of patients that benefit from gefitinib treatment. If this is realized, single agent treatment with gefitinib could be an option as first-line chemotherapy in selected patients with advanced NSCLC. Furthermore, randomized trials are warranted to compare first-line single agent treatment with gefitinib followed by second-line platinum-based chemotherapy with first-line platinum-based chemotherapy followed by second- or third-line gefitinib treatment.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma, Nagahiro Saijo, Yutaka Nishiwaki

    Financial support: Yutaka Nishiwaki

    Provision of study materials or patients: Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma, Yutaka Nishiwaki

    Collection and assembly of data: Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma

    Data analysis and interpretation: Seiji Niho, Nagahiro Saijo, Yutaka Nishiwaki

    Manuscript writing: Seiji Niho

    Final approval of manuscript: Seiji Niho, Kaoru Kubota, Koichi Goto, Kiyotaka Yoh, Hironobu Ohmatsu, Ryutaro Kakinuma, Nagahiro Saijo, Yutaka Nishiwaki

    Acknowledgment

    This work was supported in part by a grant from the Ministry of Health and Welfare for the second and third term, Comprehensive Strategy for Cancer Control, and a grant in aid for cancer research from the Ministry of Health and Welfare, Japan.

    NOTES

    Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

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

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