Eligibility
The study was a phase II, open-label, non-randomized, multicenter study (a phase II study of Iressa versus Vinorelbine or gemcitAbine in chemo-naïve elderly patients with advanced Non-small-cell lung cancer based on epidermal growth factor receptor mutation status: IVAN Trial; University hospital Medical Information Network-clinical trial registration number, C000000436). Patients enrolled in the present study had measurable, pathologically confirmed stage IIIB or IV NSCLC and were aged 70 years or older. Availability of archived tumor tissue or pleural/pericardial fluid for evaluation of EGFR mutation status was required for enrollment. Other eligibility criteria included written informed consent; no prior chemotherapy; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; adequate bone marrow, renal, and hepatic function; and a life expectancy of at least 3 months. Exclusion criteria included symptomatic brain metastasis, any evidence of interstitial lung disease on chest computed tomography examination, other co-existing malignancies or malignancies diagnosed within the last 5 years other than carcinoma in situ, history of congestive heart failure, unstable angina pectoris or recent history (within 6 months) of acute myocardial infarction, uncontrolled cardiac arrhythmia, severe psychiatric illness, or concurrent disease or condition that would have made the patient inappropriate for study participation. The local ethical committees (the Research Ethics Committee of the Institute of Biomedical Research and Innovation, the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine, the Clinical Research Approval Committee and the Medical Ethics Committee of Kurashiki Central Hospital, the Ethics Committee for Clinical Research of Kobe City Medical Center General Hospital, the Research Ethics Committee of Kobe City Medical Center West Hospital, and the institutional review board at the Hyogo Prefectural Amagasaki Hospital) approved the study, and written informed consent was obtained from each patient. The study was conducted in accordance with the Helsinki declaration.
EGFR mutation screening
In the current open-label study, treatment was assigned based on
EGFR mutation status. First, the
EGFR gene mutational status of a biopsy specimen from each patient was evaluated. Initially, patients were screened for
EGFR mutations in a commercial central laboratory at SRL in Tokyo. Both the exon 19 deletion mutation and the L858R point mutation were screened by direct sequencing, as described previously [
13]. The T790M mutation, which was reported to be associated with resistance to EGFR-TKI therapy, was also checked, and the patient was excluded from the study if this mutation was detected [
24]. From June 1, 2007, outsourcing of EGFR genetic testing was covered by government insurance in Japan, and the protocol was amended to allow the outsourcing from each institution to commercial clinical laboratories, either at Mitsubishi Chemical Medience in Tokyo (peptide nucleic acid-locked nucleic acid PCR clamp method) [
25] or BML, Inc. in Tokyo (PCR-invader assay) [
26]. During the study period, the methodology for
EGFR mutation detection was substantially improved, and direct sequencing was substituted with highly-sensitive, advanced-generation detecting technology available in Japan.
Treatment plan
Patients whose tumor contained an EGFR activating mutation received gefitinib (250 mg per day orally). In the present study, gefitinib was selected as the EGFR-TKI. Gefitinib was first approved in Japan for treatment of patients with advanced NSCLC on July 5th, 2002, and Japanese oncologists had already acquired considerable experience with this drug at the beginning of the present study. Patients with no EGFR activating mutation were treated with cytotoxic chemotherapy: either vinorelbine 25 mg/m2 on Day 1 and 8 (the recommended dose in Japan) or gemcitabine 1000 mg/m2 on Day 1 and 8. The choice of the chemotherapy regimen was at the discretion of the attending physician, and a total of three to six cycles of treatment were required for either treatment regimen. Treatment was continued until progression of the disease (PD), development of unacceptable toxicity, patients’ request, or completion of the treatment. Further therapy after PD was permitted in the protocol.
Dose modification of gefitinib, vinorelbine, or gemcitabine was allowed according to the protocol. The gefitinib dosing schedule could be modified to every second day for patients with severe toxicity: pulmonary toxicity (except for cough, forced expiratory volume in 1 second, hiccoughs, interstitial pneumonitis/pulmonary infiltrates) ≥ grade 2, or grade 3/4 diarrhea, mucositis, liver dysfunction, hematologic toxicity, skin toxicity, or ocular toxicity. For vinorelbine, a maximum of one dose reduction (25 to 20 mg/m2) was allowed based on the following criteria: neutropenic fever, ileus ≥ grade 2, non-hematological toxicity (except for nausea, hyponatremia, body weight loss, anorexia, and alopecia) ≥ grade 3, grade 4 neutropenia and/or thrombocytopenia. Regarding gemcitabine, a maximum of one dose reduction (1000 to 800 mg/m2) was allowed based on the following criteria: neutropenic fever, interstitial pneumonitis or pulmonary fibrosis ≥ grade 1, non-hematological toxicity (except for nausea, hyponatremia, body weight loss, anorexia, and alopecia) ≥ grade 3, grade 4 neutropenia and/or thrombocytopenia.
The primary outcome of the study was the objective response rate (ORR): partial plus complete response based on the Response Evaluation Criteria in Solid Tumors [
27]. The present study was designed to detect a response rate of 65% in the gefitinib group compared with a minimal, clinically meaningful response rate of 30%. It was estimated before starting the present study that 20 eligible patients would allow the study to have 80% power to detect this difference, with an alpha level of 0.05. The drop rate was considered to be 10%, and a total of 22 patients would need to be enrolled in the gefitinib group. We estimated that the frequency of NSCLC with
EGFR mutations accounted for 25% of the total NSCLC population, based on the results of the pre-protocol survey regarding the number of newly referred advanced NSCLC patients to two hospitals (Kyoto University Hospital and the Institute of Biomedical Research and Innovation Hospital; data not shown). To enroll 22 patients in the gefitinib group, 88 patients would need to be screened, and 66 of the 88 patients were expected to have tumors with wild-type
EGFR. To detect a response rate of 20% compared with a minimal, clinically meaningful response rate of 5% in the single-agent chemotherapy group, 27 patients were required to maintain more than 80% power to detect this difference, with an alpha level of 0.05. Sixty-six patients, estimated in the pre-protocol period, were sufficient. We expected that patients who had predictive factors for containing an
EGFR mutation (
i.e. female, East-Asian origin, adenocarcinoma, and no history of smoking) were more likely to be recruited in our trial. In other words, patients with wild-type
EGFR would be less likely to be enrolled. In this case, 27 patients were minimally required to detect the difference in the single-agent chemotherapy group. The drop rate was considered to be 10%, and a total of 30 patients would need to be enrolled in the single-agent chemotherapy group.
Planned secondary outcomes included the disease control rate, 1-year survival rate, overall survival (OS), time to treatment failure (TTF), and toxicity. Disease control was defined as the best response out of complete response, partial response, or stable disease, which was confirmed and sustained for 4 weeks or longer. TTF was measured from the start date of treatment to the date of discontinuation of the study treatment, occurrence of PD, or death by any cause (whichever occurred earlier). If intolerable toxicity or discontinuation of treatment secondary to toxicity occurred, the patient was considered assessable but was classified as a treatment failure.
During treatment, assessments were performed every 6 weeks until disease progression. Events were confirmed twice via source-document verification at site visits or delivered radiographic data by members of the data center and the investigators.
Safety was monitored by clinical AEs, laboratory (hematology and clinical chemistry) testing, radiographic information, and collection of vital signs, weight, and ECOG PS status. AE severity was graded based on the National Cancer Institute Common Toxicity Criteria (version 3.0). Interstitial pneumonitis was the most serious concern related to gefitinib treatment because this event has been noted in patients taking gefitinib.
OS and TTF were estimated by the Kaplan–Meier method, and the therapy arms were compared by log-rank test. Categorical variables were analyzed by Fisher’s exact test or Χ
2 test. Continuous variables were assessed with unpaired t-tests or the Mann–Whitney U-test. Statistical analyses were performed using JMP version 6 (SAS Institute, Cary, NC, USA) and R software version 2.8.1 (R Foundation for Statistical Computing, Vienna, Austria).