Published: 20 September 2016. Authors: ESMO Guidelines Committee
This update refers to the Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Öberg K, Hellman P, Ferolla P and Papotti A, Ann Oncol 2012; 23 (Suppl 7): vii120-vii123; and the Neuroendocrine gastro-entero-pancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Öberg K, Knigge U, Kwekkeboom D and Perren A, Ann Oncol 2012; 23 (Suppl 7): vii124-vii130.
Management of advanced/metastatic disease
In the randomised, double-blind, placebo-controlled, phase III RADIANT-4 trial, 302 patients with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were randomised in a 2:1 ratio to everolimus 10 mg per day orally or placebo, both with supportive care. The primary endpoint was progression-free survival (PFS), while overall survival (OS) and quality of life were secondary endpoints. Median PFS 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 (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 OS 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). Grade 3 or 4 drug-related adverse events were infrequent and manageable, though more numerous in the everolimus group.
In patients with unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin with progressive disease, everolimus, as compared with placebo, is associated with a statistically and clinically significant improvement in PFS.In the absence of mature OS and quality of life data, the observed PFS benefit is associated with an ESMO Magnitude of Clinical Benefit Scale (MCBS) score of 3.
|Therapy||Disease setting||Trial||Control||Absolute survival gain||HR (95% CI)||QoL/toxicity||MCBS score**|
|Everolimus, an mTOR inhibitor||Unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease||
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 
Median PFS: 3.9 months
PFS gain: 7.1 months
OS benefit, not statistically significant yet
PFS HR: 0.48
Deteriorated toxicity profile.
QoL was a secondary endpoint, however no data are available yet.
|3 (Form 2b; mature data on OS not available, data on QoL assessment not available)|
*EMA approvals in 2016 to end August 2016.
**ESMO-MCBS version 1.0 
HR, hazard ratio; CI, confidence interval; QoL, quality of life; mTOR, mammalian target of rapamycin; PFS, progression-free survival; OS, overall survival, EMA, European Medicines Agency