Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
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DOI：
10.1016/s1470-2045(17)30422-9
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
André T
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作者：
Overman MJ;McDermott R;Leach JL;Lonardi S;Lenz HJ;Morse MA;Desai J;Hill A;Axelson M;Moss RA;Goldberg MV;Cao ZA;Ledeine JM;Maglinte GA;Kopetz S;André T
转移性DNA错配修复缺陷/微卫星不稳定性高（dMMR/MSI-H）结直肠癌（mCRC）在常规化疗后预后不良，并表现出高水平的肿瘤新抗原、肿瘤浸润淋巴细胞和检查点调节因子，所有特征均与其他肿瘤类型中对程序性细胞死亡受体-1（PD-1）阻断的反应相对应。因此，在该人群中评价了nivolumab（一种PD-1免疫检查点抑制剂）。在这项正在进行的多中心、开放标签、非随机、II期试验中，入组了经组织学证实的复发性或mCRC局部评估为dMMR/MSI-H的成人患者（年龄≥18岁），这些患者在接受至少一种既往治疗（包括氟尿嘧啶和奥沙利铂或伊立替康）期间/之后发生疾病进展或不耐受。患者每2周给予nivolumab 3 mg/kg，直至疾病进展、死亡、不可接受的毒性或退出研究。主要终点是根据实体瘤疗效评价标准v1·1评估的客观缓解率（ORR）。接受至少一剂研究药物的所有患者均纳入主要和安全性分析。本试验注册于ClinicalTrials.gov，编号NCT 02060188。在2014年3月12日至2016年3月16日期间入组的74例患者中，大多数（54.1%）接受过≥3种既往治疗。在中位随访12.0个月（四分位距8.57 - 18.00个月）时，74例患者中有23例（31.1%[95%CI 20.8%-42.9%]）达到了经评估的客观缓解; 68.9%（95%CI 57.1%-79.2%）的患者疾病控制≥12周。尚未达到中位缓解持续时间;所有缓解者均存活，8例（34.8%）缓解时间≥12个月。最常见的（≥10%的患者）药物相关不良事件为疲乏（n=16 [21.6%]）、腹泻（n=15 [20.3%]）、瘙痒（n=10 [13.5%]）和皮疹（n=8 [10.8%]）。最常见的3级或4级药物相关不良事件为脂肪酶（n=6 [8.1%]）和淀粉酶（n=2 [2.7%]）水平升高。5例患者（6.8%）因丙氨酸氨基转移酶升高、结肠炎、十二指肠溃疡、急性肾损伤和口腔炎（各1例）而停止治疗。23例患者（31.1%）在研究期间死亡;研究者认为这些死亡均与治疗无关。Nivolumab为dMMR/MSI-H mCRC预治疗患者提供了持久的缓解和疾病控制以及长期生存，是这些患者的新治疗选择。
Metastatic DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) colorectal cancer (mCRC) has a poor prognosis following conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all features that correspond with response to programmed cell death receptor-1 (PD-1) blockade in other tumour types. Thus, nivolumab, a PD-1 immune checkpoint inhibitor, was evaluated in this population. In this is ongoing, multicentre, open-label, nonrandomised, phase 2 trial, adult patients (aged ≥18 years) with histologically confirmed recurrent or mCRC locally assessed as dMMR/MSI-H who had progressed on/after or been intolerant of at least one prior line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan, were enrolled. Patients were given nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors v1·1. All patients who received at least one dose of study drug were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02060188. Among the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, most (54·1%) had received ≥3 prior therapies. At a median follow-up of 12·0 months (interquartile range 8·57–18·00 months), 23 of 74 patients (31·1% [95% CI 20·8%–42·9%]) achieved an investigator-assessed objective response; 68·9% (95% CI 57·1%–79·2%) of patients had disease control for ≥12 weeks. Median duration of response was not yet reached; all responders were alive, and 8 (34·8%) had responses of ≥12 months. The most common (≥10% of patients) drug-related adverse events was fatigue (n=16 [21·6%]), diarrhoea (n=15 [20·3%]), pruritus (n=10 [13·5%]) and rash (n=8 [10·8%]). The most common grade 3 or 4 drug-related adverse events were increased lipase (n=6 [8·1%]) and amylase (n=2 [2·7%]) levels. Five patients (6·8%) discontinued treatment because of increased alanine aminotransferase, colitis, duodenal ulcer, acute kidney injury, and stomatitis (n=1 each). Twenty-three patients (31·1%) died during the study; none of these deaths was considered to be treatment related by the investigator. Nivolumab provided durable responses and disease control, as well as long-term survival in pre-treated patients with dMMR/MSI-H mCRC, and is a new treatment option for these patients.