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

Abstract

Summary Background Effective systemic therapies for patients with progressive neuroendocrine tumours of lung or gastrointestinal tract are limited. We aimed to assess the efficacy and safety of everolimus in this patient population. Methods In RADIANT-4, a randomised, double-blind, placebo-controlled, phase 3 study, patients with advanced, progressive, well-differentiated, nonfunctional lung or gastrointestinal neuroendocrine tumours were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomised in a 2:1 ratio to everolimus 10 mg/day or placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and prior somatostatin analogue treatment. The primary endpoint was progression-free survival assessed by central radiology review. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings From April 2012 to August 2013, a total of 302 patients were enrolled, of whom, 205 were allocated to everolimus 10 mg/day and 97 to placebo. Median progression-free survival was 11.0 months (95% confidence interval [CI], 9.2–13.3) in the everolimus arm and 3.9 months (95% CI, 3.6–7.4) in the placebo arm. 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 statistically not significant, a trend towards improved survival was observed in the first pre-planned interim overall survival analysis (HR, 0.64; 95% CI: 0.40, 1.05; one-sided p=0.037; boundary for statistical significance, 0.0002). Grade 3 or 4 drug-related adverse events (everolimus vs placebo) were relatively infrequent and included stomatitis (9% vs 0), diarrhoea (7% vs 2%), infections (7% vs 0), anaemia (4% vs 1%), fatigue (4% vs 1%), and hyperglycaemia (4% 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.