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 randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of ...life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio HR 1·04; 97·5% repeated CI RCI –∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. Methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0–2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m2 on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1–14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov , number NCT00600340. Findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6–32·6 months) versus 26·1 months (22·3–29·0), respectively. The stratified HR was 1·02 (97·5% RCI –∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 97·5% RCI –∞ to 1·39; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 19% of 284 patients in the bevacizumab plus paclitaxel group vs 5 2% of 277 patients in the bevacizumab plus capecitabine group), hand–foot syndrome (1 <1% vs 43 16%), peripheral neuropathy (39 14% vs 1 <1%), leucopenia (20 7% vs 1 <1%), and hypertension (12 4% vs 16 6%). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. Interpretation Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. Funding Roche.
Summary Background Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival ...and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. Methods In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m2 on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m2 twice daily on days 1–14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov , number NCT00600340. Findings Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9–24·7), 181 patients in the per-protocol population had died (89 33% in the paclitaxel group; 92 35% in the capecitabine group). The hazard ratio HR for overall survival was 1·04 (97·5% repeated CI −∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 44% of 285 patients vs 76 27% of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months 95% CI 10·4–12·9 vs 8·1 months 7·1–9·2; HR 1·36 95% CI 1·09–1·68, p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 18%), peripheral neuropathy (39 14%), and leucopenia (20 7%) in the paclitaxel group and hand-foot syndrome (44 16%), hypertension (16 6%), and diarrhoea (15 5%) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. Interpretation In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. Funding Central European Cooperative Oncology Group; Roche.
Summary Background Pemetrexed maintenance therapy significantly improved overall survival and progression-free survival compared with placebo, and had a good safety profile in a phase 3 ...placebo-controlled study in patients with advanced non-small-cell lung cancer (NSCLC). Results for quality of life, symptom palliation, and tolerability are presented here. Methods After four cycles of platinum-based induction therapy, 663 patients with stage IIIB or stage IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (in a 2:1 ratio) from March 15, 2005, to July 20, 2007, using the Pocock and Simon minimisation method to receive pemetrexed (500 mg/m2 every 21 days; n=441) or placebo (n=222) plus best supportive care until disease progression. The primary efficacy data have been reported previously. Patients completed the Lung Cancer Symptom Scale (LCSS) at baseline, after each cycle, and post-discontinuation. Worsening of symptoms was defined as an increase of 15 mm or more from baseline on a 100 mm scale for each LCSS item. The primary outcome for these quality-of-life analyses was time to worsening of symptoms, analysed for all randomised patients. This study is registered with ClinicalTrials.gov , number NCT00102804. Findings Baseline characteristics, including LCSS scores, were well balanced between groups. Baseline LCSS scores were low, indicating low symptom burden for patients without disease progression after completion of first-line treatment. Longer time to worsening was recorded for pain (hazard ratio HR 0·76, 95% CI 0·59–0·99; p=0·041) and haemoptysis (HR 0·58, 95% CI 0·34–0·97; p=0·038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4·3 mm vs 0·2 mm; p=0·028). Rates of resource use were statistically higher for pemetrexed than for placebo: admissions to hospital for drug-related adverse events (19 4% vs none; p=0·001), transfusions (42 10% vs seven 3%; p=0·003), and erythropoiesis-stimulating agents (26 6% vs four 2%; p=0·017). Interpretation Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy. Funding Eli Lilly.
