PURPOSE The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors. PATIENTS AND METHODS Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR). RESULTS Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade. CONCLUSION A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.

中文翻译：

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Nivolumab 对错配修复缺陷的非结直肠癌有效：Arm Z1D 的结果——NCI-MATCH (EAY131) 研究的子协议

目的 美国国家癌症研究所治疗​​选择分子分析 (NCI-MATCH) 试验是迄今为止对复发或难治性恶性肿瘤患者进行的最大的国家精准肿瘤学研究（> 1,100 个部位），该试验将患者分配到基于平行 II 期研究的靶向治疗肿瘤分子改变。抗程序性死亡受体 1 抑制剂 nivolumab 先前在错配修复 (MMR) 缺陷型结肠癌中显示出活性。我们假设 nivolumab 对 MMR 缺陷的非结直肠肿瘤患者有效。患者和方法 具有复发或难治性肿瘤、良好的终末器官功能和东部肿瘤协作组体能状态≤1 的合格患者接受肿瘤活检以集中筛查分子改变。MMR 缺陷定义为通过免疫组织化学 (IHC) 完全丧失 MLH1 或 MSH2 MMR 基因产物的核表达。排除了 MMR 缺陷型结直肠癌患者。静脉注射纳武单抗，每 2 周 3 mg/kg（28 天周期）和第 4 周期后每 4 周 480 mg。每2个周期进行一次疾病重新评估。主要终点是 RECIST 1.1 客观缓解率 (ORR)。结果 IHC 筛查的 4,902 名筛查患者中有 2% 患有 MMR 缺陷型癌症。招募了 42 名可评估的患者，中位年龄为 60 岁，中位患者接受过 3 次治疗。最常见的组织学是子宫内膜样子宫内膜腺癌 (n = 13)、前列腺腺癌 (n = 5) 和子宫癌肉瘤 (n = 4)。ORR 为 36%（42 名患者中的 15 名）。另有 21% 的患者病情稳定。估计的 6、12 和 18 个月无进展生存率为 51.3%（90% CI，38.2% 至 64.5%）、46.2%（90% CI，33.1% 至 59.3%）和 31.4%（ 90% CI，18.7% 至 44.2%）。中位总生存期为 17.3 个月。毒性主要是低级的。结论 多种难治性癌症（筛选出的癌症中的 2.0%）具有 NCI-MATCH 中定义的 MMR 缺陷。Nivolumab 在多种组织病理学类型的 MMR 缺陷型非结直肠癌中具有良好的活性。0% 的筛选者）具有 NCI-MATCH 中定义的 MMR 缺陷。Nivolumab 在多种组织病理学类型的 MMR 缺陷型非结直肠癌中具有良好的活性。0% 的筛选者）具有 NCI-MATCH 中定义的 MMR 缺陷。Nivolumab 在多种组织病理学类型的 MMR 缺陷型非结直肠癌中具有良好的活性。