Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, placebo-controlled, phase 3 study

James C. Yao, Nicola Fazio, Simron Singh, Roberto Buzzoni, Carlo Carnaghi, Edward Wolin, Jiri Tomasek, Markus Raderer, Harald Lahner, Maurizio Voi, Lida Bubuteishvili Pacaud, Nicolas Rouyrre, Carolin Sachs, Juan W. Valle, Gianfranco Delle Fave, Eric Van Cutsem, Margot Tesselaar, Yasuhiro Shimada, Do Youn Oh, Jonathan StrosbergMatthew H. Kulke, Marianne E. Pavel

Research output: Contribution to journalArticle

394 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)968-977
Number of pages10
JournalThe Lancet
Volume387
Issue number10022
DOIs
StatePublished - Mar 5 2016
Externally publishedYes

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Neuroendocrine Tumors
Gastrointestinal Tract
Placebos
Lung
Disease-Free Survival
Therapeutics
Everolimus
Safety
Stomatitis
Risk Reduction Behavior
Survival Analysis
Somatostatin
Drug-Related Side Effects and Adverse Reactions
Radiology
Hyperglycemia
Fatigue
Anemia
Pancreas
Diarrhea
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4) : A randomised, placebo-controlled, phase 3 study. / Yao, James C.; Fazio, Nicola; Singh, Simron; Buzzoni, Roberto; Carnaghi, Carlo; Wolin, Edward; Tomasek, Jiri; Raderer, Markus; Lahner, Harald; Voi, Maurizio; Pacaud, Lida Bubuteishvili; Rouyrre, Nicolas; Sachs, Carolin; Valle, Juan W.; Fave, Gianfranco Delle; Van Cutsem, Eric; Tesselaar, Margot; Shimada, Yasuhiro; Oh, Do Youn; Strosberg, Jonathan; Kulke, Matthew H.; Pavel, Marianne E.

In: The Lancet, Vol. 387, No. 10022, 05.03.2016, p. 968-977.

Research output: Contribution to journalArticle

Yao, JC, Fazio, N, Singh, S, Buzzoni, R, Carnaghi, C, Wolin, E, Tomasek, J, Raderer, M, Lahner, H, Voi, M, Pacaud, LB, Rouyrre, N, Sachs, C, Valle, JW, Fave, GD, Van Cutsem, E, Tesselaar, M, Shimada, Y, Oh, DY, Strosberg, J, Kulke, MH & Pavel, ME 2016, 'Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, placebo-controlled, phase 3 study', The Lancet, vol. 387, no. 10022, pp. 968-977. https://doi.org/10.1016/S0140-6736(15)00817-X
Yao, James C. ; Fazio, Nicola ; Singh, Simron ; Buzzoni, Roberto ; Carnaghi, Carlo ; Wolin, Edward ; Tomasek, Jiri ; Raderer, Markus ; Lahner, Harald ; Voi, Maurizio ; Pacaud, Lida Bubuteishvili ; Rouyrre, Nicolas ; Sachs, Carolin ; Valle, Juan W. ; Fave, Gianfranco Delle ; Van Cutsem, Eric ; Tesselaar, Margot ; Shimada, Yasuhiro ; Oh, Do Youn ; Strosberg, Jonathan ; Kulke, Matthew H. ; Pavel, Marianne E. / Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4) : A randomised, placebo-controlled, phase 3 study. In: The Lancet. 2016 ; Vol. 387, No. 10022. pp. 968-977.
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abstract = "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.",
author = "Yao, {James C.} and Nicola Fazio and Simron Singh and Roberto Buzzoni and Carlo Carnaghi and Edward Wolin and Jiri Tomasek and Markus Raderer and Harald Lahner and Maurizio Voi and Pacaud, {Lida Bubuteishvili} and Nicolas Rouyrre and Carolin Sachs and Valle, {Juan W.} and Fave, {Gianfranco Delle} and {Van Cutsem}, Eric and Margot Tesselaar and Yasuhiro Shimada and Oh, {Do Youn} and Jonathan Strosberg and Kulke, {Matthew H.} and Pavel, {Marianne E.}",
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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.

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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