PURPOSE Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity. RESULTS Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events. CONCLUSIONS Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.

中文翻译：

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非胰腺神经内分泌肿瘤患者罕见肿瘤 (DART SWOG 1609) 中双重抗 CTLA-4 和抗 PD-1 阻断的 II 期篮子试验。

目的 免疫检查点阻断改善了各种肿瘤类型的结果；关于这些药物在罕见肿瘤中的疗效知之甚少。我们报告了 SWOG S1609 双重抗 CTLA-4 和抗 PD-1 阻断罕见肿瘤 (DART) 的（非胰腺）神经内分泌肿瘤队列的结果。患者和方法 我们在多个罕见肿瘤队列中进行了一项前瞻性、开放标签、多中心 II 期临床试验，其中报告了（非胰腺）神经内分泌队列。没有预先指定按年级进行的反应评估。主要终点是总体反应率 [ORR; RECIST v1.1；完全反应（CR）和部分反应（PR）]；次要终点包括无进展生存期（PFS）、总生存期（OS）、疾病稳定>6个月和毒性。结果 32 名符合条件的患者接受了治疗；18 人 (56%) 患有高级别疾病。最常见的原发部位是胃肠道（47%；N = 15）和肺（19%；N = 6）。总体 ORR 为 25% [95% 置信区间 (CI) 13-64%；CR，3%，N = 1；PR，22%，N = 7]。高级别神经内分泌癌患者的 ORR 为 44%（8/18 患者），而低/中级别肿瘤患者的 ORR 为 0%（0/14 患者；P = 0.004）。6 个月 PFS 为 31%（95% CI，19%-52%）；中位 OS 为 11 个月（95% CI，6-∞）。最常见的毒性是甲状腺功能减退 (31%)、疲劳 (28%) 和恶心 (28%)，丙氨酸氨基转移酶升高 (9%) 是最常见的 3/4 级免疫相关不良事件，没有 5 级事件。结论 Ipilimumab 加 nivolumab 在非胰腺高级别神经内分泌癌患者中的 ORR 为 44%，