TY - JOUR
T1 - Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4)
T2 - A randomised, placebo-controlled, phase 3 study
AU - Yao, James C.
AU - Fazio, Nicola
AU - Singh, Simron
AU - Buzzoni, Roberto
AU - Carnaghi, Carlo
AU - Wolin, Edward
AU - Tomasek, Jiri
AU - Raderer, Markus
AU - Lahner, Harald
AU - Voi, Maurizio
AU - Pacaud, Lida Bubuteishvili
AU - Rouyrre, Nicolas
AU - Sachs, Carolin
AU - Valle, Juan W.
AU - Fave, Gianfranco Delle
AU - Van Cutsem, Eric
AU - Tesselaar, Margot
AU - Shimada, Yasuhiro
AU - Oh, Do Youn
AU - Strosberg, Jonathan
AU - Kulke, Matthew H.
AU - Pavel, Marianne E.
N1 - Funding Information:
JCY has received consulting or advisory fees from Ipsen, Lexicon, and Novartis, and research funding from Novartis. NF has received honoraria from Ipsen and Novartis; consulting or advisory fees from Ipsen, Lexicon, Novartis, and Italfarmaco; research funding from Novartis; and travel and accommodation expenses from Ipsen and Novartis. SS has received honoraria, consulting or advisory fees, travel and accommodation expenses, and research funding from Novartis. RB has received research funding from Italfarmaco, Novartis, and Otsuka, and travel and accommodation expenses from Ipsen, Italfarmaco, and Novartis. EW has received consulting or advisory fees from Celgene, Ipsen, and Novartis. JT has received honoraria, research funding, and travel and accommodation expenses from Novartis. MR has received honoraria from Celgene, Ipsen, Novartis, and Roche and consulting or advisory fees from Celgene, Ipsen, Novartis, and Roche. HL has received honoraria from Ipsen, Novartis, and Pfizer; consulting or advisory fees from Novartis and Pfizer; research funding from Novartis; and travel and accommodation expenses from Ipsen, Novartis, and Pfizer. MV, LBP, NR, and CS are employees of and own shares in Novartis. JWV has received honoraria, consulting or advisory fees, and research funding from Novartis. GDF has received consulting or advisory fees and research funding from Novartis. EVC has received research funding from Novartis. YS has received research funding from Chugai Pharma, Lilly, Novartis, and Taiho Pharmaceutical. JS has received honoraria from Novartis; consulting or advisory fees from Ipsen, Lexicon, and Novartis; research funding from Novartis and Pfizer; and is on the speaker's bureau for Bayer and Genentech. MHK has received consulting or advisory fees from Ipsen and Novartis. MEP has received honoraria from Ipsen, Lexicon, Novartis, and Pfizer; consulting or advisory fees from Ipsen, Lexicon, Novartis, and Pfizer; research funding from Novartis; and travel and accommodation expenses from Ipsen and Novartis. CC, MT, and D-YO declare no competing interests.
Funding Information:
The study was sponsored by Novartis Pharmaceuticals Corporation. We thank the patients and investigators for their participation in the study; the worldwide network of research nurses, trial coordinators, and operations staff for their contributions; Du Lam for assistance with protocol development and study conduct; Valentine Jehl and Hélène Cauwel for their inputs into statistical aspects during protocol development; and Bhavik Shah and Rohit Kachhadiya (Novartis Healthcare Pvt Ltd) for providing medical editorial assistance with this Article.
Funding Information:
Novartis Pharmaceuticals Corporation. The study was sponsored by Novartis Pharmaceuticals Corporation. We thank the patients and investigators for their participation in the study; the worldwide network of research nurses, trial coordinators, and operations staff for their contributions; Du Lam for assistance with protocol development and study conduct; Valentine Jehl and Helene Cauwel for their inputs into statistical aspects during protocol development; and Bhavik Shah and Rohit Kachhadiya (Novartis Healthcare Pvt Ltd) for providing medical editorial assistance with this Article.
PY - 2016/3/5
Y1 - 2016/3/5
N2 - Summary Background Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. Methods In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. Funding Novartis Pharmaceuticals Corporation.
AB - Summary Background Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. Methods In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. Funding Novartis Pharmaceuticals Corporation.
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U2 - 10.1016/S0140-6736(15)00817-X
DO - 10.1016/S0140-6736(15)00817-X
M3 - Article
C2 - 26703889
AN - SCOPUS:84960112967
VL - 387
SP - 968
EP - 977
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10022
ER -