Supplementary Material for: Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms

<b><i>Background/Aims:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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, <i>p</i> = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. <b><i>Conclusion:</i></b> 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.

**背景与目的：** 血管生成在高分化胰腺神经内分泌瘤（pancreatic neuroendocrine tumours, PanNET）中广泛存在，既往研究证实舒尼替尼可延长该类患者的无进展生存期，因此获批上市。然而，针对3级胃肠胰神经内分泌肿瘤（grade 3 gastroenteropancreatic neuroendocrine neoplasms, GEPNEN-G3）患者的临床应用经验仍较为有限。本前瞻性II期临床试验旨在评估晚期GEPNEN-G3患者中舒尼替尼抗肿瘤活性的潜在预测生物标志物。**方法：** 受试者接受舒尼替尼37.5mg每日一次持续给药，直至出现疾病进展或不可接受的毒性反应。采用实体瘤疗效评价标准1.1版（RECIST1.1）评估抗肿瘤活性，依据美国国家癌症研究所常见不良反应事件评价标准4.0版（NCI-CTCAE v4）评价安全性。同时检测舒尼替尼及其主要活性代谢产物SU12662的药代动力学特征。对所有肿瘤标本进行组织学肿瘤分化程度复核。采用免疫组化法检测血小板衍生生长因子受体β（PDGFRβ）、碳酸酐酶9（carbonic anhydrase 9）、Ki-67、血管内皮生长因子受体2（VEGFR2）及磷酸化AKT（p-AKT）的表达水平，并分析其与RECIST1.1标准评估的治疗响应的相关性。**结果：** 本研究共纳入31例患者，其中26例具备可用的组织学标本。分别有6例为高分化神经内分泌瘤（NET-G3），20例为神经内分泌癌（NEC）。18例患者对舒尼替尼产生治疗响应，其中4例达到部分缓解，14例出现疾病稳定。高p-AKT表达与舒尼替尼较低的治疗响应率显著相关（比值比（odds ratio, OR）0.94，95%置信区间（confidence interval, CI）0.89~0.99，*p*=0.04）。本研究中患者的舒尼替尼及SU12662的安全性与药代动力学暴露特征与既往PanNET相关研究报道一致。**结论：** 舒尼替尼在GEPNEN-G3患者中显示出明确的抗肿瘤活性，且毒性谱符合预期。在NET-G3和NEC亚组中，分别有4/6和11/20的患者获得治疗响应。高p-AKT表达可预测舒尼替尼治疗响应率降低。本研究明确了侵袭性GEPNEN-G3患者中与舒尼替尼耐药/敏感性相关的潜在生物标志物。