帕博利珠单抗单挑晚期三阴性乳腺癌
众所周知，T淋巴细胞是重要的免疫细胞，可杀灭癌细胞等病原体，是人体自身主要的抗癌机制。而癌细胞可诱导T淋巴细胞表面的程序性死亡蛋白PD-1与程序性死亡蛋白配体PD-L1结合，引起免疫逃逸。一期临床研究KEYNOTE-012和二期临床研究KEYNOTE-086结果表明，PD-1抑制剂帕博利珠单抗（俗称K药）单药治疗晚期三阴性乳腺癌，抗肿瘤活性持久且安全性可控，故有必要进一步开展三期临床研究进行验证。
前情提要
2021年3月4日，英国《柳叶刀》肿瘤学分册在线发表美国默克、哈佛大学达纳法伯癌症研究所、俄罗斯联邦巴什科尔托斯坦共和国临床肿瘤医院、韩国首尔大学医院、国立癌症中心、法国马赛大学癌症研究中心保利卡梅特斯研究所、巴黎第十一大学古斯塔夫鲁西研究所、西班牙国际乳腺癌中心、巴塞罗那希伯伦谷肿瘤研究所、英国伦敦大学玛丽王后学院巴茨癌症研究所、皇家马斯登医院、日本国立癌症中心医院、广岛市立广岛市民医院、巴西圣保罗州立大学癌症研究所、德国汉堡大学医院、慕尼黑大学医院、意大利米兰圣拉斐尔大学医院、新加坡国立癌症中心的三期临床研究KEYNOTE-119结果报告，对帕博利珠单抗单药或研究者自选化疗方案二线或三线治疗晚期三阴性乳腺癌的有效性和安全性进行了比较。
KEYNOTE-119 (NCT02555657): A Randomized Open-Label Phase III Study of Single Agent Pembrolizumab Versus Single Agent Chemotherapy Per Physician's Choice for Metastatic Triple Negative Breast Cancer (mTNBC)
该国际多中心非盲随机对照三期临床研究于2015年11月25日～2017年4月11日从全球31个国家或地区150个医疗中心（学术医疗中心、社区癌症中心或社区医院）入组年龄≥18岁、已被集中确认为晚期三阴性乳腺癌、美国东部肿瘤协作组体力状态评分为0或1、转移后一线或两线蒽环类或紫杉类等全身治疗失败患者622例，按1∶1随机分为两组：
帕博利珠单抗组312例：每3周静脉注射帕博利珠单抗200毫克，共35次
化疗组310例：由研究者从卡培他滨、艾立布林、吉西他滨、长春瑞滨选择其中之一进行单药化疗（各药上限为60%）
根据每100个肿瘤细胞有多少肿瘤细胞＋淋巴细胞＋巨噬细胞为PD-L1阳性，计算联合阳性评分（CPS）。按肿瘤PD-L1状态为阳性（CPS≥1）还是阴性（CPS<1）以及既往早期乳腺癌术前新辅助或术后辅助治疗后复发转移还是首次诊断时就已转移进行亚组分析。主要终点为CPS≥10的患者、CPS≥1的患者、全部患者的总生存；如果帕博利珠单抗与化疗相比，CPS≥1的患者总生存比例显著较高，那么对全部患者进行对数秩检验。对意向治疗患者进行主要终点分析，对实际治疗患者进行安全性分析。
结果，两组患者的随访时间分别为中位31.4、31.5个月（四分位27.8～34.4、27.8～34.6）。
帕博利珠单抗组312例与化疗组310例意向治疗患者相比，总生存时间：
CPS≥10：中位12.7比11.6个月（95%置信区间：9.9～16.3、8.3～13.7；风险比：0.78，95%置信区间：0.57～1.06，对数秩P=0.057）
CPS≥1：中位10.7比10.2个月（95%置信区间：9.3～12.5、7.9～12.6；风险比：0.86，95%置信区间：0.69～1.06，对数秩P=0.073）
全部患者：中位9.9比10.8个月（95%置信区间：8.3～11.4、9.1～12.6；风险比：0.97，95%置信区间：0.82～1.15）
CPS≥20：中位14.9比12.5个月（95%置信区间：10.7～19.8、7.3～15.4；风险比：0.58，95%置信区间：0.38～0.88）
帕博利珠单抗组309例与化疗组292例实际治疗患者相比，3～4级治疗相关不良事件：
血色素减少：3例比10例（1%、3%）
白细胞减少：1例比14例（<1%、5%）
中性粒细胞数量减少：1例比29例（<1%、10%）
中性粒细胞减少：0例比39例（0、13%）
严重不良事件：61例比58例（20%、20%）
治疗相关不良事件所致死亡：1例（循环衰竭）比2例（1例全血细胞减少和脓毒症、1例血胸）
因此，该研究结果表明，对于转移后一线或两线蒽环类或紫杉类等全身治疗失败的晚期三阴性乳腺癌患者，帕博利珠单抗单药与化疗单药相比，二线或三线治疗的总生存并未显著改善，除非肿瘤细胞＋淋巴细胞＋巨噬细胞的PD-L1阳性百分比≥20%，这些结果可能为将来帕博利珠单抗单药治疗研究患者选择（PD-L1高表达）以及晚期三阴性乳腺癌患者联合治疗方案（帕博利珠单抗联合化疗或放疗）提供参考。
对此，加拿大多伦多大学玛格丽特公主癌症中心发表同期评论：帕博利珠单抗单药治疗晚期三阴性乳腺癌。
相关链接
Lancet Oncol. 2021 Mar 4. Online ahead of print.
Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.
Eric P Winer, Oleg Lipatov, Seock-Ah Im, Prof Anthony Goncalves, Eva Munoz-Couselo, Keun Seok Lee, Prof Peter Schmid, Kenji Tamura, Laura Testa, Prof Isabell Witzel, Shoichiro Ohtani, Nicholas Turner, Stefania Zambelli, Nadia Harbeck, Fabrice Andre, Rebecca Dent, Xuan Zhou, Vassiliki Karantza, Jaime Mejia, Javier Cortes; KEYNOTE-119 investigators.
Merck, Kenilworth, NJ, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Republican Clinical Oncology Dispensary, Ufa, Bashkortostan, Russia; Seoul National University, Seoul, South Korea; National Cancer Center, Goyang, South Korea; Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Aix-Marseille University, Centre National de la Recherche Scientifique, French National Institute of Health and Medical Research, Marseille, France; Faculté de Medicine Paris-Sud XI, Gustave Roussy, Villejuif, France; International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Barts Cancer Institute, Queen Mary University London, London, UK; Royal Marsden National Health Service Foundation Trust, London, UK; National Cancer Center Hospital, Tokyo, Japan; Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade do Estado do Sao Paulo, Sao Paulo, Brazil; University Medical Center Hamburg, Hamburg, Germany; Ludwig-Maximilians-University, University Hospital, Munich, Germany; Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy; National Cancer Centre Singapore, Singapore.
BACKGROUND: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.
METHODS: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.
FINDINGS: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31.4 months (IQR 27.8-34.4) for the pembrolizumab group and 31.5 months (27.8-34.6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12.7 months (95% CI 9.9-16.3) for the pembrolizumab group and 11.6 months (8.3-13.7) for the chemotherapy group (hazard ratio [HR] 0.78 [95% CI 0.57-1.06]; log-rank p=0.057). In participants with a CPS of 1 or more, median overall survival was 10.7 months (9.3-12.5) for the pembrolizumab group and 10.2 months (7.9-12.6) for the chemotherapy group (HR 0.86 [95% CI 0.69-1.06]; log-rank p=0.073). In the overall population, median overall survival was 9.9 months (95% CI 8.3-11.4) for the pembrolizumab group and 10.8 months (9.1-12.6) for the chemotherapy group (HR 0.97 [95% CI 0.82-1.15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).
INTERPRETATION: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.
FUNDING: Merck Sharp & Dohme
DOI: 10.1016/S1470-2045(20)30754-3
Lancet Oncol. 2021 Mar 4. Online ahead of print.
Pembrolizumab monotherapy in metastatic triple-negative breast cancer.
Eitan Amir, David W Cescon.
Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada.
Single-arm studies of PD-1 or PD-L1 inhibitors have shown modest rates of objective response in both oestrogen receptor-positive, HER2-negative breast cancer, and triple-negative breast cancer. However, when responses were observed, they were often durable, thereby supporting additional investigation in comparative trials using more definitive outcome measures, such as progression-free survival or overall survival.
DOI: 10.1016/S1470-2045(21)00019-X