Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
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DOI：
10.1016/s1470-2045(16)30066-3
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发表时间：
2016-07-01
期刊：
影响因子：
51.1
通讯作者：
Chow, Laura Q.
中科院分区：
文献类型：
--
作者：
Seiwert, Tanguy Y.;Burtness, Barbara;Chow, Laura Q.
头颈部复发或转移性鳞状细胞癌患者的治疗选择很少。我们的目的是评估的安全性，耐受性和抗肿瘤活性pembrolizumab，人源化抗程序性死亡受体1（PD-1）抗体，PD-L1阳性复发性或转移性鳞状细胞癌的患者的头部和颈部。方法这项研究是一项开放标签，多中心，1b期临床试验的患者复发性或转移性鳞状细胞癌的头部和颈部。如果患者年龄≥ 18岁，确诊为头颈部复发性或转移性鳞状细胞癌，并且具有任何水平的PD-L1表达（即，至少1%的肿瘤细胞或基质通过免疫组织化学检测为PD-L1阳性），则有资格入组。患者接受帕博利珠单抗10 mg/kg静脉给药，每2周一次。主要结局为符合方案人群的安全性和根据实体瘤疗效评价标准（RECIST，第1.1版）中心审查的总体缓解患者比例。在全分析集中分析了总体缓解，全分析集定义为接受至少一剂帕博利珠单抗治疗、基线时有可测量疾病和一次基线后扫描的所有患者或因疾病进展或药物相关不良事件而停止治疗的未进行基线后扫描的患者。该研究在www.example.com注册，编号NCT 01848834，目前正在进行中，但不再招募患者。结果在2013年6月7日至2013年10月3日期间筛选的104名患者中，有81名（78%）为PD-L1阳性。其中，60例PD-L1阳性头颈部鳞状细胞癌患者入组并接受治疗：23例（38%）HPV阳性，37例（62%）HPV阴性。Pembrolizumab耐受性良好，60例患者中有10例（17%）发生3 - 4级药物相关不良事件，其中最常见的是丙氨酸转氨酶和天冬氨酸转氨酶升高，以及低钠血症，每例发生在60例患者中的2例中; 1例患者发生3级药物相关皮疹。60例患者中有27例（45%）发生了严重不良事件。无药物相关死亡。中心影像学审查显示总体缓解的患者比例为18%（45例患者中的8例; 95% CI 8 - 32），（16例患者中的4例; 7 - 52）HPV阳性患者和14%（29例患者中的4例; 4 - 32）在HPV-解释派姆单抗耐受性良好，并在复发性或转移性鳞状细胞癌中表现出临床上有意义的抗肿瘤活性。头颈部细胞癌，支持pembrolizumab作为晚期头颈部癌症抗癌疗法的进一步研究。
Background Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck.Methods This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling patients.Findings Of the 104 patients screened between June 7, 2013, and Oct 3, 2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3-4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (eight of 45 patients; 95% CI 8-32) in all patients and was 25% (four of 16 patients; 7-52) in HPV-positive patients and 14% (four of 29 patients; 4-32) in HPV-negative patients.Interpretation Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of pembrolizumab as anticancer therapy for advanced head and neck cancers.