Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with , , and is active but not recruiting. Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68–1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] 69 [17%]), anaemia (80 [20%] 61 [15%]), dysphagia (76 [19%] 62 [16%]), and decreased lymphocyte count (76 [19%] 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] 25 [6%]), acute kidney injury (33 [8%] 30 [8%]), and febrile neutropenia (24 [6%] seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

中文翻译：

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派姆单抗加同步放化疗与安慰剂加同步放化疗治疗局部晚期头颈鳞状细胞癌患者的比较 (KEYNOTE-412)：一项随机、双盲 3 期试验

尽管采用多种疗法，局部晚期头颈鳞状细胞癌 (HNSCC) 的 5 年总生存率约为 50%。我们评估了局部晚期 HNSCC 在同步放化疗中添加派姆单抗的情况。在随机、双盲、3 期 KEYNOTE-412 试验中，来自全球 130 个医疗中心的新诊断、高风险、未切除的局部晚期 HNSCC 参与者被随机分配 (1:1) 接受派姆单抗 (200 mg) 加放化疗或安慰剂加放化疗。随机化是使用交互式响应技术系统进行的，并根据研究者选择的放射治疗方案、肿瘤部位和 p16 状态以及疾病阶段进行分层，参与者随机分配为每层 4 人一组。参与者、研究人员和申办者人员对治疗分配情况不知情。当地药剂师知道支持治疗准备的任务。派姆单抗和安慰剂每 3 周静脉注射一次，最多 17 剂（放化疗前 1 剂，放化疗期间 2 剂，维持治疗 14 剂）。化放疗包括静脉注射顺铂 (100 mg/m)，每 3 周一次，持续两到三剂，以及加速或标准分割放疗（70 Gy，分 35 次）。主要终点是对所有随机分配的参与者进行无事件生存分析。对接受至少一剂研究治疗的所有参与者的安全性进行了分析。这项研究已在 、 、 注册，并且正在进行中，但尚未招募。 2017年4月19日至2019年5月2日期间，804名参与者被随机分配到派姆单抗组（n=402）或安慰剂组（n=402）。 804 名参与者中，660 名（82%）为男性，144 名（18%）为女性，622 名（77%）为白人。中位研究随访时间为 47·7 个月 (IQR 42·1–52·3)。派姆单抗组未达到中位无事件生存期（95% CI 44·7 个月 - 未达到），安慰剂组为 46·6 个月（27·5 - 未达到）（风险比 0·83 [95%] CI 0·68–1·03]；对数秩 p=0·043 [显着性阈值，p≤0·024]）。派姆单抗组 398 名受试者中有 367 名 (92%) 和安慰剂组 398 名受试者中有 352 名 (88%) 出现 3 级或更严重的不良事件。最常见的 3 级或更严重不良事件是中性粒细胞计数减少（派姆单抗组 398 名参与者中的 108 名 [27%]，安慰剂组 398 名参与者中的 100 名 [25%]）、口腔炎（80 名 [20%] 69 名[17] %]）、贫血（80 [20%] 61 [15%]）、吞咽困难（76 [19%] 62 [16%]）和淋巴细胞计数减少（76 [19%] 81 [20%]）。派姆单抗组有 245 名 (62%) 参与者发生严重不良事件，而安慰剂组有 197 名 (49%) 参与者发生严重不良事件，最常见的是肺炎 (43 [11%] 25 [6%])、急性肾损伤 (33 [8] %] 30 [8%]）和发热性中性粒细胞减少症（24 [6%] 7 [2%]）。治疗相关不良事件导致派姆单抗组四名 (1%) 参与者死亡（吸入性肺炎、终末期肾病、肺炎和硬化性胆管炎各一名参与者）和安慰剂组六名 (2%) 参与者（三名参与者因咽部出血，各一名参与者因口腔出血、术后出血和败血症）。在分子上未经选择的局部晚期 HNSCC 人群中，与单独放化疗相比，派姆单抗联合放化疗并未显着改善无事件生存期。没有看到新的安全信号。局部晚期头颈部鳞癌仍然是一种具有挑战性的疾病，需要更好的治疗方法。 Merck Sharp & Dohme 是 Merck & Co 的子公司，位于美国新泽西州拉威。