Johns Hopkins University, Baltimore, MD.
Dana-Farber Cancer Institute, Boston, MA.
J Clin Oncol. 2020 Jan 20;38(3):214-222. doi: 10.1200/JCO.19.00818. Epub 2019 Nov 25.
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.
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 or 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).
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.
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.
国家癌症研究所分子分析用于治疗选择（NCI-MATCH）试验是迄今为止最大的全国精准肿瘤学研究（超过 1100 个地点），针对复发性或难治性恶性肿瘤患者，根据肿瘤分子改变将患者分配到靶向治疗的平行 II 期研究中。抗程序性死亡受体 1 抑制剂纳武利尤单抗先前在错配修复（MMR）缺陷型结直肠癌中显示出活性。我们假设纳武利尤单抗在 MMR 缺陷型非结直肠癌肿瘤患者中具有活性。
符合条件的复发性或难治性肿瘤患者，良好的终末器官功能，东部合作肿瘤学组表现状态为≤1，接受肿瘤活检，进行集中筛选分子改变。MMR 缺陷定义为免疫组织化学（IHC）检测到或 MMR 基因产物的核表达完全缺失。排除 MMR 缺陷型结直肠癌患者。纳武利尤单抗，3 mg/kg，每 2 周（28 天周期），第 4 周期后每 4 周 480mg，静脉注射。每 2 个周期进行一次疾病再评估。主要终点是 RECIST 1.1 客观缓解率（ORR）。
在 4902 名筛选患者中，有 2%的患者通过 IHC 检测出 MMR 缺陷型癌症。42 名可评估患者入组，中位年龄为 60 岁，中位治疗次数为 3 次。最常见的组织学类型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 例患者中有 15 例）。另外 21%的患者疾病稳定。估计 6、12 和 18 个月无进展生存率分别为 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。毒性主要为低级别。
在 NCI-MATCH 中定义的，各种难治性癌症（筛选患者的 2.0%）存在 MMR 缺陷。纳武利尤单抗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。
