Summary Background Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed—an antifolate antineoplastic agent—in patients with advanced non-small-cell lung ...cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m2 , day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B12 , folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00102804. Findings All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months 95% CI 4·1–4·7 vs 2·6 months 1·7–2·8; hazard ratio HR 0·50, 95% CI 0·42–0·61, p<0·0001) and overall survival (13·4 months 11·9–15·9 vs 10·6 months 8·7–12·0; HR 0·79, 0·65–0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 5% vs three 1%). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 16% vs nine 4%; p<0·0001), specifically fatigue (22 5% vs one 1%, p=0·001) and neutropenia (13 3% vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 51% vs 149 67%; p=0·0001). Interpretation Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding Eli Lilly.
Summary Background The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes ...years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2 =0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level ( R2 =0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level ( R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2 =0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2 =0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good ( R2 =0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2 =0·95, 0·91–0·98 for modified vs standard radiotherapy). Interpretation We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
Although several new chemotherapeutic agents are promising as primary therapy in non-small-cell lung cancer (NSCLC), few have demonstrated activity in platinum-refractory disease. Based on ...encouraging results reported in two single-institution studies of docetaxel in this setting, we performed a multicenter phase II trial evaluating this novel taxane in previously treated NSCLC patients prospectively categorized by platinum response status.
Eighty patients with NSCLC previously treated with platinum-based chemotherapy received docetaxel at a dose of 100 mg/m(2) intravenously over 1 hour, repeated every 21 days, accompanied by dexamethasone 8 mg orally twice daily for 5 days. Forty-seven patients (59%) were defined as platinum-refractory based on response status to prior therapy.
The median number of cycles delivered per patient was four (range, one to 21 cycles). Partial response was observed in 13 (16%) of 80 of patients, with similar response rates in platinum-sensitive and platinum-refractory patients. The median survival time was 7 months, and the 1-year survival rate was 25%. Docetaxel was relatively well tolerated in this previously treated population. Grade IV neutropenia was common in patients (77%) but typically of brief duration. Febrile neutropenia was observed in 11 patients (14%), with no fatal infections. Severe fluid retention was rare (4% of patients).
This multicenter phase II trial confirms antitumor activity and encouraging survival with docetaxel therapy in platinum-treated and platinum-refractory NSCLC. To validate these results, a phase III trial randomizing platinum-treated patients to docetaxel or best supportive care is underway.
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