eUpdate – Neuroendocrine Tumours Treatment Recommendations

eUpdate – Neuroendocrine Tumours Treatment Recommendations

Published: 20 September 2016. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

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.

Section

Management of advanced/metastatic disease

Text update

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.

Recommendation

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.

Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in neuroendocrine tumours (bronchial, thymic and gastro-entero-pancreatic)*

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 [1]
 
Phase III
 
NCT01524783
Placebo
 
Median PFS: 3.9 months
PFS gain: 7.1 months
 
OS benefit, not statistically significant yet
PFS HR: 0.48
 
(0.35-0.67)
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 [2]
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

References

  1. Yao JC, Fazio N, Singh S et al. 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. Lancet 2016; 387: 968–977.
  2. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.