Research in context
Evidence before this study
We searched MEDLINE for reports on clinical trials in advanced neuroendocrine tumours, with “mTOR” and “NET” as our primary search terms, limiting the findings to include “non-functional”, “non-pancreatic”, or “non-syndromic” neuroendocrine tumours. We did not limit our search by date but we searched only for articles published in English. We identified no studies of mammalian target of rapamycin (mTOR) inhibitors as monotherapy in patients with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin. We found that the phase 3 RADIANT-2 study assessed the mTOR inhibitor everolimus in combination with octreotide longacting repeatable versus placebo plus octreotide longacting repeatable in patients with advanced neuroendocrine tumours and a history of carcinoid symptoms (Pavel et al, 2011). Although the RADIANT-2 study did not meet its primary endpoint, the results provided an initial indication of the potential antitumour effect of everolimus in the patients with non-pancreatic neuroendocrine tumours. Additionally, RAMSETE (RAD001 [everolimus] in Advanced and Metastatic Silent neuroEndocrine Tumours in Europe)—a single-arm, multicentre, single-stage phase 2 trial—showed that everolimus might be effective in non-syndromic, non-pancreatic neuroendocrine tumours with diverse tumour origin sites (Pavel et al, 2012). We identified no phase 3 studies with mTOR inhibitors as monotherapy in patients with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin.
Added value of this study
Advanced neuroendocrine tumours are incurable. Targeted treatments, such as everolimus and sunitinib, are approved for advanced, progressive, pancreatic neuroendocrine tumours. Effective antineoplastic therapy options for patients with advanced, progressive, non-functional neuroendocrine tumours of the lung or gastrointestinal tract are very scarce. To our knowledge, RADIANT-4 is the first, large, randomised, placebo-controlled, phase 3 study to assess the efficacy and safety of the mTOR inhibitor everolimus as monotherapy in this patient population. Everolimus was associated with a clinically meaningful almost threefold prolongation of progression-free survival versus placebo, indicating a statistically significant 52% risk reduction in favour of everolimus. The benefit of treatment with everolimus was maintained across most of the prespecified subgroups. The adverse event findings were consistent with the known safety profile of everolimus.
Implications of all the available evidence
Taken together with results from the previous RADIANT-3 study in pancreatic neuroendocrine tumours (Yao et al, 2011), the findings from RADIANT-4 study provide robust, practice-changing evidence to support the antitumour efficacy of everolimus across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, or gastrointestinal tract.