Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers
Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers
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DOI：
10.1158/1078-0432.ccr-20-0621
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发表时间：
2020-09-01
影响因子：
11.5
通讯作者：
Cebon, Jonathan
中科院分区：
文献类型：
--
作者：
Klein, Oliver;Kee, Damien;Cebon, Jonathan
目的：抗CTLA-4和抗PD-1阻断剂的联合免疫疗法已在几种肿瘤类型中表现出显著的临床活性。神经内分泌肿瘤（NET）是一组异质性罕见肿瘤，治疗选择有限。CA 209 -538是一项在罕见癌症（包括晚期NETs）中使用伊匹单抗和纳武单抗的联合免疫疗法的临床试验。患者和方法：CA 209 -538是一项在晚期罕见癌症患者中进行的前瞻性多中心临床试验。患者每三周接受3 mg/kg剂量的nivolumab和1 mg/kg ipilimumab治疗四次，然后每两周接受3 mg/kg nivolumab治疗，持续长达96周，直至疾病进展或出现不可接受的毒性。根据RECIST 1.1每12周评估一次缓解。主要终点为临床获益率（CBR;完全缓解+部分缓解+病情稳定）。3例（10%）患者为低度恶性肿瘤，13例（45%）为中度恶性肿瘤，13例（45%）为高度恶性肿瘤;肺是最常见的原发部位（39%）。客观缓解率为24%，CBR为72%; 43%的胰腺神经内分泌肿瘤（NEN）患者和33%的非典型支气管类癌患者达到客观缓解。中位无进展生存期为4.8个月[95%置信区间（CI）：2.7-10.5]，总生存期为14.8个月（95% CI：4.1-21.3）。免疫相关毒性的报告，在66%的患者与3/4%的经历3/4级events.Conclusions：与ipilimumab和nivolumab的组合免疫治疗表现出显着的临床活性，在亚组的患者与先进的NETs，包括非典型支气管类癌和高级别胰腺NEN的患者。
Purpose: Combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).Results: Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7-10.5] and overall survival was 14.8 months (95% CI: 4.1-21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.