VEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous cell carcinoma (HNSCC). We aimed to determine the recommended phase 2 dose of ramucirumab, a selective VEGFR2 inhibitor, given with pembrolizumab and the objective response rate of this combination as first-line treatment for recurrent or metastatic HNSCC. In this single-centre, phase 1/2 trial, which was done at Washington University (St Louis, MO, USA), eligible patients were aged 18 years or older with incurable recurrent or metastatic HNSCC and an Eastern Cooperative Oncology Group performance status of 0–2. Patients in phase 2 were required to have had no previous systemic therapy for recurrent or metastatic disease. In a dose de-escalation phase 1 design, patients received ramucirumab (starting dose 10 mg/kg given intravenously) and pembrolizumab (200 mg intravenously) on day 1 of each 21-day cycle. The recommended phase 2 dose of ramucirumab was defined as the highest dose at which one or fewer of three patients had dose-limiting toxicity during cycle one (primary endpoint of phase 1). In a Simon's two-stage phase 2 design, patients received the recommended phase 2 dose of ramucirumab and pembrolizumab. Tumour response (primary endpoint of phase 2) was assessed by Response Evaluation Criteria in Solid Tumours (version 1.1). We hypothesised that there would be an objective response rate of 32% or higher (null ≤13%). Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for activity (80% power; one-sided α=0·05). Analyses were done per protocol. The trial is registered with , , and is closed to enrolment. Between June 18, 2019, and Feb 11, 2021, three patients enrolled and were treated in phase 1 and 37 patients in phase 2. Median age of all patients was 64 years (IQR 59–72). 36 (90%) of 40 patients were men and four (10%) were women, and 36 (90%) patients were White, three (8%) were Black or African American, and one (3%) was Asian. In phase 1, no dose-limiting toxicity event occurred. The recommended phase 2 dose of ramucirumab was 10 mg/kg. Median follow-up for patients on phase 2 was 14·8 months (IQR 4·9–31·0). In phase 2, 18 (55%; 95% CI 38–70) of 33 evaluable patients had an objective response, including confirmed complete response in 11 patients, confirmed partial response in six patients, and unconfirmed partial response in one patient. The most common grade 3 or worse adverse events were dysphagia (14 [38%] of 37 patients), lung infection (11 [30%]), lymphocyte count decrease (ten [27%]), hypophosphataemia (nine [24%]), and hypertension (eight [22%]). No treatment-related deaths were recorded. Ramucirumab and pembrolizumab were safe to administer to patients with recurrent or metastatic HNSCC, and the objective response rate with this combination as first-line treatment for recurrent or metastatic HNSCC was favourable. Further studies of ramucirumab and pembrolizumab in patients with recurrent or metastatic HNSCC are warranted. Lilly and the Joseph Sanchez Foundation.

中文翻译：

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Ramucirumab 联合 pembrolizumab 治疗复发性或转移性头颈鳞状细胞癌：单中心 1/2 期试验


VEGF 是血管生成和免疫治疗抵抗的关键介质，在头颈鳞状细胞癌 (HNSCC) 中过度表达。我们的目的是确定 ramucirumab（一种选择性 VEGFR2 抑制剂）与 pembrolizumab 联用的推荐 2 期剂量，以及该组合作为复发性或转移性 HNSCC 一线治疗的客观缓解率。在华盛顿大学（美国密苏里州圣路易斯）进行的这项单中心 1/2 期试验中，符合条件的患者年龄为 18 岁或以上，患有无法治愈的复发性或转移性 HNSCC，并且东部肿瘤合作组的表现状态为0–2。第二阶段的患者要求之前没有接受过针对复发或转移性疾病的全身治疗。在剂量递减第一阶段设计中，患者在每个 21 天周期的第一天接受雷莫芦单抗（静脉注射起始剂量 10 mg/kg）和派姆单抗（静脉注射 200 mg）。推荐的 ramucirumab 2 期剂量定义为在第 1 周期（第 1 期的主要终点）期间三名患者中的一名或更少出现剂量限制性毒性的最高剂量。在 Simon 的两阶段 2 期设计中，患者接受了推荐的 2 期剂量的雷莫芦单抗和派姆单抗。肿瘤反应（第 2 阶段的主要终点）通过实体瘤反应评估标准（1.1 版）进行评估。我们假设客观缓解率为 32% 或更高（零≤13%）。 33 名可评估患者（至少进行过一项反应评估的患者）中的 8 项或更多反应是活动的证据（80% 功效；单侧 α=0·05）。根据方案进行分析。该试验已在 、 、 注册，并且已停止招募。 2019年6月18日至2021年2月11日期间，3名患者入组并接受第一阶段治疗，37名患者接受第二阶段治疗。所有患者的中位年龄为64岁（IQR 59-72）。 40 名患者中，36 名 (90%) 为男性，4 名 (10%) 为女性，36 名 (90%) 名患者为白人，3 名 (8%) 为黑人或非裔美国人，1 名 (3%) 为亚洲人。在第一阶段，没有发生剂量限制性毒性事件。 ramucirumab 的推荐 2 期剂量为 10 mg/kg。第 2 期患者的中位随访时间为 14·8 个月（IQR 4·9–31·0）。在第 2 阶段，33 名可评估患者中有 18 名（55%；95% CI 38-70）获得客观缓解，其中 11 名患者确认完全缓解，6 名患者确认部分缓解，1 名患者未确认部分缓解。最常见的 3 级或更严重不良事件是吞咽困难（37 名患者中的 14 名 [38%]）、肺部感染（11 名 [30%]）、淋巴细胞计数减少（10 名 [27%]）、低磷酸盐血症（9 名 [24%]） ）和高血压（8 [22%]）。没有记录与治疗相关的死亡。雷莫芦单抗和派姆单抗对复发性或转移性 HNSCC 患者使用是安全的，并且该组合作为复发性或转移性 HNSCC 一线治疗的客观缓解率良好。有必要对复发性或转移性 HNSCC 患者进行雷莫芦单抗和派姆单抗的进一步研究。礼来公司和约瑟夫·桑切斯基金会。