Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA.
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust National Institute of Health Research Biomedical Research Centre, London, UK.
Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1.
Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.
KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.
Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.
Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.
Merck Sharp & Dohme.
帕博利珠单抗在头颈部鳞状细胞癌（HNSCC）中具有活性，程序性死亡配体 1（PD-L1）的表达与改善反应相关。
KEYNOTE-048 是一项在 37 个国家的 200 个地点进行的、针对未经治疗的局部不可治愈的复发性或转移性 HNSCC 患者的随机、3 期研究。参与者按 PD-L1 表达、p16 状态和表现状态分层，并按 1:1:1 的比例随机分配至单独使用派姆单抗、派姆单抗联合铂类和 5-氟尿嘧啶（派姆单抗联合化疗）或西妥昔单抗联合铂类和 5-氟尿嘧啶（西妥昔单抗联合化疗）。研究者和参与者了解治疗分配。研究者、参与者和赞助者的代表对 PD-L1 联合阳性评分（CPS）结果不知情；研究入组不要求 PD-L1 阳性。主要终点是在意向治疗人群（所有随机分配至治疗组的参与者）中的总生存期（从任何原因死亡的时间）和无进展生存期（从随机分组到影像学确认疾病进展或任何原因死亡的时间，以先发生者为准）。共有 14 个主要假设：单独使用派姆单抗和派姆单抗联合化疗在 PD-L1 CPS 为 20 或更高、CPS 为 1 或更高以及总人群中，以及单独使用派姆单抗和派姆单抗联合化疗在总人群中的非劣效性（非劣效性边界：1.2）均优于西妥昔单抗联合化疗。每个假设的确定发现是在该假设的统计测试完成时获得的；这在 11 个假设的第二次中期分析和 3 个假设的最终分析时发生。安全性评估在治疗人群中（所有接受至少一剂分配治疗的参与者）进行。该研究在 ClinicalTrials.gov 注册，编号为 NCT02358031。
2015 年 4 月 20 日至 2017 年 1 月 17 日，882 名参与者被分配接受单独使用派姆单抗（n=301）、派姆单抗联合化疗（n=281）或西妥昔单抗联合化疗（n=300）；其中 754 名（85%）有 CPS 为 1 或更高，381 名（43%）有 CPS 为 20 或更高。在第二次中期分析中，单独使用派姆单抗在 CPS 为 20 或更高的人群中与西妥昔单抗联合化疗相比，改善了总生存期（中位数 14.9 个月 vs 10.7 个月，风险比 [HR] 0.61 [95%CI 0.45-0.83]，p=0.0007）和 CPS 为 1 或更高的人群（12.3 个月 vs 10.3 个月，0.78 [0.64-0.96]，p=0.0086），并且在总人群中具有非劣效性（11.6 个月 vs 10.7 个月，0.85 [0.71-1.03]）。派姆单抗联合化疗在总人群中与西妥昔单抗联合化疗相比，改善了总生存期（13.0 个月 vs 10.7 个月，HR 0.77 [95%CI 0.63-0.93]，p=0.0034），并且在 CPS 为 20 或更高的人群（14.7 个月 vs 11.0 个月，0.60 [0.45-0.82]，p=0.0004）和 CPS 为 1 或更高的人群（13.6 个月 vs 10.4 个月，0.65 [0.53-0.80]，p<0.0001）中也具有非劣效性。单独使用派姆单抗或派姆单抗联合化疗在第二次中期分析中均未改善无进展生存期。在最终分析中，在 300 名接受治疗的参与者中，164 名（55%）出现 3 级或更高级别的任何原因不良事件，在 276 名接受派姆单抗联合化疗的参与者中，235 名（85%）出现 3 级或更高级别的任何原因不良事件，在 287 名接受西妥昔单抗联合化疗的参与者中，239 名（83%）出现 3 级或更高级别的任何原因不良事件。在派姆单抗单独治疗组中，25 名（8%）参与者发生了 3 级或更高级别的治疗相关不良事件，在派姆单抗联合化疗组中，32 名（12%）参与者发生了 3 级或更高级别的治疗相关不良事件，在西妥昔单抗联合化疗组中，28 名（10%）参与者发生了 3 级或更高级别的治疗相关不良事件。
基于观察到的疗效和安全性，派姆单抗联合铂类和 5-氟尿嘧啶是复发性或转移性 HNSCC 的合适一线治疗药物，而派姆单抗单药治疗是 PD-L1 阳性复发性或转移性 HNSCC 的合适一线治疗药物。
默克夏普和多姆公司。
