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

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

Author information

1
Medical Oncology, Hôpital Saint Antoine, AP-HP, Paris, France.
2
Biostatistics, Hôpital Bichat, AP-HP, Paris, France.
3
Gastroenterology, Hôpital Edouard Herriot, Lyon, France.
4
Medical Oncology, Hôpital Edouard Herriot, Lyon, France.
5
Medical Oncology, Hôpital La Timone, Marseille, France.
6
Gastroenterology and Digestive Oncology, Hôpital La Timone, Marseille, France.
7
Gastroenterology, Hôpital Beaujon, AP-HP, Clichy, France.
8
Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, Sorbonne Paris Cité, Paris, France.
9
Medical Oncology, Hôpital Beaujon, AP-HP, Paris, France.
10
Radiology, Hôpital Beaujon, AP-HP, Clichy, France.
11
Department of Pathology Beaujon-Bichat, AP-HP, DHU UNITY, Clichy, France.
12
Medical Oncology, Hôpital Saint Joseph, AP-HP, Paris, France.

Abstract

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

PMID:
29518779
DOI:
10.1159/000487237

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