Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). However, survival benefit is modest and platinum-containing regimens cause substantial toxic effects. We did a prospective randomised open-label phase III study to compare an experimental platinum-free, triplet, sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the standard platinum-containing, doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC.

Between March, 2001, and April, 2005, patients with stage IIIB (positive pleural effusion) or IV NSCLC, performance status 0 to 1, and adequate organ function, were randomly assigned to experimental treatment or to standard treatment. Randomisation was done centrally by use of a dynamic balancing algorithm. Patients were stratified by weight loss, lactate dehydrogenase concentration, and disease stage. Patients in the experimental group were scheduled to receive intravenous vinorelbine (25 mg/m²) plus gemcitabine (1000 mg/m²) on days 1 and 8 every 21 days for three cycles, followed by intravenous docetaxel (60 mg/m²) on day 1 every 21 days for three cycles. Patients in the standard group were scheduled to receive intravenous paclitaxel (225 mg/m²) plus carboplatin (area under the curve=6) for 3 h on day 1, every 21 days for six cycles. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response, and toxic effects. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00079287.

Of the 401 patients enrolled and randomised in the trial, five patients in the experimental group and three in the standard group were ineligible for analysis; thus 196 patients in the experimental group and 197 in the standard group were included in analyses. Patient characteristics were well-balanced between the two groups with regard to major prognostic factors. Median overall survival was 13·6 months (range 12·0–16·4) in the experimental group versus 14·1 months (11·9–17·5) in the standard group (p=0·97). 49 of 196 patients (25%) in the experimental group had a partial response compared with 73 of 197 patients (37%) in the standard group (p=0·012). There were no complete responses. Median progression-free survival was 5·5 months (95% CI 4·9–6·3) in the experimental group compared with 5·8 months (5·3–6·1) in the standard group (p=0·74). The incidence of grade 3 and 4 neutropenia, neuropathy, arthralgia, and myalgia was lower in the experimental group than in the standard group, although the incidence of pulmonary toxic effects was higher.

Although platinum-containing regimens remain the standard treatment for advanced NSCLC, non-platinum regimens could provide equivalent efficacy with a different toxicity profile.

Japan Multi-National Trial Organisation.