Royal Marsden Hospital/The Institute of Cancer Research National Institute for Health and Care Research Biomedical Research Centre, London, United Kingdom.
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
JAMA Oncol. 2023 Jun 1;9(6):779-789. doi: 10.1001/jamaoncol.2023.0147.
IMPORTANCE: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). OBJECTIVE: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN. DESIGN, SETTING, AND PARTICIPANTS: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock). INTERVENTIONS: Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. MAIN OUTCOMES AND MEASURES: The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety. RESULTS: Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease. CONCLUSIONS AND RELEVANCE: The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02823574.
重要性：在复发性或转移性头颈部鳞状细胞癌（R/M SCCHN）患者中，仍需要改善临床结局。
目的：评估一线纳武利尤单抗联合伊匹单抗与纳武利尤单抗单药治疗 R/M SCCHN 患者的临床获益。
设计、地点和参与者：这项名为 CheckMate 714 的双盲、2 期随机临床试验于 2016 年 10 月 20 日至 2019 年 1 月 23 日在 21 个国家的 83 个地点进行。合格的参与者年龄在 18 岁或以上，患有铂类难治性或铂类适用的 R/M SCCHN，且无 R/M 疾病的先前系统治疗。数据于 2016 年 10 月 20 日（首位患者首次就诊）进行分析，至 2019 年 3 月 8 日（主要数据库锁定）和 2020 年 4 月 6 日（总生存数据库锁定）。
干预措施：患者以 2:1 的比例随机分配，接受纳武利尤单抗（3 mg/kg 静脉注射[IV]每 2 周一次）联合伊匹单抗（1 mg/kg IV 每 6 周一次）或纳武利尤单抗（3 mg/kg IV 每 2 周一次）联合安慰剂，最多治疗 2 年或直至疾病进展、不可接受的毒性作用或同意退出。
主要终点和测量指标：主要终点是铂类难治性 R/M SCCHN 患者中通过盲法独立中心评估的治疗臂之间的客观缓解率（ORR）和缓解持续时间。探索性终点包括安全性。
结果：在纳入的 425 名患者中，241 名（56.7%；中位年龄为 59 [范围，24-82] 岁；194 名男性[80.5%]）患有铂类难治性疾病（纳武利尤单抗联合伊匹单抗，n=159；纳武利尤单抗，n=82），184 名（43.3%；中位年龄为 62 [范围，33-88] 岁；152 名男性[82.6%]）患有铂类适用疾病（纳武利尤单抗联合伊匹单抗，n=123；纳武利尤单抗，n=61）。在主要数据库锁定时，铂类难治性疾病患者中纳武利尤单抗联合伊匹单抗的 ORR 为 13.2%（95%CI，8.4%-19.5%），纳武利尤单抗的 ORR 为 18.3%（95%CI，10.6%-28.4%）（比值比[OR]，0.68；95.5%CI，0.33-1.43；P=0.29）。纳武利尤单抗联合伊匹单抗的中位缓解持续时间未达到（NR）（95%CI，11.0 个月至 NR），纳武利尤单抗的中位缓解持续时间为 11.1 个月（95%CI，4.1 个月至 NR）。在铂类适用疾病患者中，纳武利尤单抗联合伊匹单抗的 ORR 为 20.3%（95%CI，13.6%-28.5%），纳武利尤单抗的 ORR 为 29.5%（95%CI，18.5%-42.6%）。铂类难治性疾病患者中，纳武利尤单抗联合伊匹单抗与纳武利尤单抗相关的 3 级或 4 级治疗相关不良事件发生率分别为 15.8%（25/158）和 14.6%（12/82），铂类适用疾病患者分别为 24.6%（30/122）和 13.1%（8/61）。
结论和相关性：CheckMate 714 随机临床试验未达到其主要终点，即一线纳武利尤单抗联合伊匹单抗与纳武利尤单抗单药治疗铂类难治性 R/M SCCHN 的 ORR 获益。纳武利尤单抗联合伊匹单抗具有可接受的安全性特征。有必要研究 R/M SCCHN 患者的亚群，以确定哪些患者从纳武利尤单抗联合伊匹单抗治疗中获益，而不是纳武利尤单抗单药治疗。
试验注册：ClinicalTrials.gov 标识符：NCT02823574。
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