Medical Oncology, Hôpital Saint Antoine, AP-HP, Paris, France.
Biostatistics, Hôpital Bichat, AP-HP, Paris, France.
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.
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.
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.
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.
背景/目的：血管生成在分化良好的胰腺神经内分泌肿瘤（PanNET）中广泛发展，舒尼替尼已被证明可延长无进展生存期，从而在全国范围内获得批准。然而，在 3 级胃肠胰神经内分泌肿瘤（GEPNEN-G3）患者中的临床经验仍然有限。本前瞻性 II 期试验评估了舒尼替尼在晚期 GEPNEN-G3 患者中的潜在预测生物标志物。
舒尼替尼的剂量为 37.5mg/天，作为连续每日剂量给药，直到进展或不可接受的毒性。根据 RECIST1.1 评估活性。根据 NCI-CTCAE v4 评估安全性。评估了舒尼替尼及其主要活性代谢物 SU12662 的药代动力学。所有肿瘤标本均进行组织学检查以评估肿瘤分化。使用免疫组织化学定量测定 PDGFRβ、碳酸酐酶 9、Ki-67、VEGFR2 和 p-AKT 的表达，并根据 RECIST1.1 将其表达与反应相关联。
共纳入 31 例患者，其中 26 例有可供分析的组织学标本。6 例和 20 例患者分别表现为分化良好的肿瘤（NET-G3）和神经内分泌癌（NEC）。18 例患者对舒尼替尼有反应（4 例部分缓解，14 例肿瘤稳定）。高 p-AKT 表达与舒尼替尼反应降低相关（OR 0.94，95%CI 0.89-0.99，p=0.04）。这些患者中舒尼替尼和 SU12662 的安全性和 PK 暴露与 PanNET 中的报道一致。
舒尼替尼在 GEPNEN-G3 患者中表现出活性，具有预期的毒性特征。在 NET-G3 和 NEC 组中，分别有 6/6 和 20/20 例患者为应答者。高 p-AKT 表达预示着对舒尼替尼的反应较低。我们的研究确定了一种潜在的生物标志物，可用于预测侵袭性 GEPNEN-G3 对舒尼替尼的耐药性/敏感性。
