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.

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

“…There were 2 phase II studies 20,21 and 5 phase III studies. [10][11][12]18,19 All studies had a comparator: in 3 10-12 the comparator was placebo, while in 1 was placebo plus octreotide LAR; 18 in 2 studies the comparator was pegylated (PEG)-interferon alfa-2b and interferon respectively 19,20 and everolimus in on trial. 21 The median Jadad score was 5, showing a good quality of the included studies (Table 1).…”

“…26,29 Thus, targeting these markers potentially arrest the NETs related-angiogenesis inducing, as a consequence, a tumor downstage and an improvement in PFS/ OS. 12,20,21 The present study is a systematic review and a meta-analysis of trials to assess the efficacy of targeted agents in patients with advanced NET. NETs are a heterogeneous disease arising from various primary sites such as the small intestine or other sites of the gastrointestinal tract, and the lung, 30,31 therefore their management is complicated by a different clinical presentations, clinical disease course, symptoms and degree of aggressiveness.…”

“…With regard to OS, data were obtained from 4 studies. [10][11][12]21 The pooled analysis revealed that the new target therapies definitely improved the OS compared with control arm (0.79, 95%CI: 0.63-0.98; P D 0.03, Fig. 2).…”

“…Food and Drug Administration (FDA) for the treatment of patients with progressive, well-differentiated pancreatic NET: sunitinib (a vascular endothelial growth factor receptor-tyrosine kinase inhibitor) and everolimus (a mammalian target of rapamycin (mTOR). Three phase III trials demonstrated an improved in progression-free survival (PFS) of both sunitinb and everolimus compared with placebo, [10][11][12] supporting their role in clinical practice.…”

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives

“…These findings were confirmed by a randomized, double-blind, placebo-controlled, phase 3 trial that investigated the efficacy and safety of everolimus in patients with non-functioning well-differentiated (G1 or G2) NETs of gastrointestinal (n = 175) or lung origin (n = 90). Treatment with everolimus reduced risk of progression by 44 and 50% in gastrointestinal and lung NETs, respectively (Yao et al 2016).…”