Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms

Neuroendocrinology. 2018;107(1):24-31. doi: 10.1159/000487237. Epub 2018 Mar 8.


Background/aims: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3.

Methods: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1.

Results: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET.

Conclusion: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.

Keywords: Grade 3 neuroendocrine neoplasms; Ki-67; Sunitinib; p-AKT.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / analysis*
  • Female
  • Humans
  • Intestinal Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / drug therapy*
  • Pancreatic Neoplasms / drug therapy*
  • Prospective Studies
  • Proto-Oncogene Proteins c-akt / analysis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Stomach Neoplasms / drug therapy*
  • Sunitinib / pharmacokinetics
  • Sunitinib / therapeutic use*


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Proto-Oncogene Proteins c-akt
  • Sunitinib

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor