Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial
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DOI：
10.1016/s1470-2045(17)30065-7
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发表时间：
2017-03-01
期刊：
影响因子：
51.1
通讯作者：
Galsky, Matthew D.
中科院分区：
文献类型：
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作者：
Sharma, Padmanee;Retz, Margitta;Galsky, Matthew D.
背景转移性尿路上皮癌患者的预后很差，一线化疗后的治疗选择很少。二线治疗的反应是罕见的。我们评估了nivolumab（一种全人IgG 4 PD-1免疫检查点抑制剂抗体）在转移性或手术不可切除的尿路上皮癌患者中的安全性和活性，这些患者的疾病进展或复发，尽管先前接受过至少一种基于铂的化疗方案的治疗。年龄≥ 18岁的转移性或手术不可切除的局部晚期尿路上皮癌患者，可测量疾病（根据实体瘤缓解评价标准v1.1），东部肿瘤协作组体能状态评分为0或1，用于生物标志物分析的可用肿瘤样品每2周静脉内接受nivolumab 3 mg/kg，直到疾病进展和临床恶化、不可接受的毒性或其他方案定义的原因。主要终点是由设盲独立审查委员会在所有接受治疗的患者中以及肿瘤PD-L1表达（>= 5%和>= 1%）确认的总体客观缓解。本试验已在ClinicalTrials.gov注册，编号为NCT 02387996，并已完成。在2015年3月9日至2015年10月16日期间，来自11个国家63个研究中心的270名患者接受了纳武利尤单抗治疗，其中265名患者接受了活性评估。总生存期的中位随访时间为7.00个月（IQR 2.96-8.77）。265例患者中有52例（19.6%，95% CI 15.0-24.9）达到了确认的客观缓解。23例患者达到了确认的客观缓解（28.4%，95% CI 18.9-39.5）81例PD-L1表达≥ 5%的患者中，29例PD-L1表达≥ 1%的122例患者中有23例（23.8%，95%CI 16.5-32.3），PD-L1表达<1%的143例患者中有23例（16.1%，95%CI 10.5-23.1）。270例患者中有48例（18%）发生了3-4级治疗相关不良事件，最常见的是3级疲劳和腹泻，各有5例患者发生。三例死亡归因于治疗（肺炎、急性呼吸衰竭和心血管衰竭）。解释Nivolumab单药治疗提供了有意义的临床益处，与PD-L1表达无关，并且与先前治疗的转移性或手术不可切除的尿路上皮癌患者的可接受的安全性特征相关。
Background Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen.Methods In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (>= 5% and >= 1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing.Findings Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7.00 months (IQR 2.96-8.77). Confirmed objective response was achieved in 52 (19.6%, 95% CI 15.0-24.9) of 265 patients. Confirmed objective response was achieved in 23 (28.4%, 95% CI 18.9-39.5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23.8%, 95% CI 16.5-32.3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16.1%, 95% CI 10.5-23.1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).Interpretation Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.