晚期三阴性乳腺癌一线化疗＋免疫治疗
程序性死亡蛋白配体PD-L1主要表达于活化的抗原提呈细胞表面，其受体为T淋巴细胞表面程序性死亡蛋白PD-1，二者是重要的免疫检查点，可抑制T淋巴细胞增殖和细胞因子产生，对免疫应答起抑制作用，三阴性乳腺癌等恶性肿瘤可刺激这些免疫检查点，防止自己受到人体免疫系统攻击。KEYNOTE-012、KEYNOTE-086、KEYNOTE-119研究已经证实，PD-1抑制剂帕博利珠单抗（可瑞达，俗称K药）单药对晚期三阴性乳腺癌患者具有持久的抗肿瘤活性和可控的安全性。KEYNOTE-522研究也已证实，帕博利珠单抗＋化疗还可显著提高早期三阴性乳腺癌术前患者的病理完全缓解率。不过，帕博利珠单抗＋化疗对晚期三阴性乳腺癌患者的有效性和安全性尚不明确。
2020年12月5日，国际四大医学期刊之一、英国《柳叶刀》正刊发表西班牙国际乳腺癌中心、加泰罗尼亚健康研究院癌症研究所、加拿大玛格丽特公主癌症中心、美国默克、旧金山加利福尼亚大学综合癌症中心、波兰华沙居里夫人纪念癌症中心肿瘤研究所、韩国首尔大学医学院附属医院癌症研究所、马来西亚吉隆坡班台医院、智利圣地亚哥癌症治疗中心、俄罗斯巴什科尔托斯坦共和国肿瘤医院、巴西南里奥格兰德天主教大学圣卢卡斯医院、日本爱知癌症中心医院、国立大阪医院、哥伦比亚蒙特里亚肿瘤医院、土耳其埃格大学医学院、澳大利亚墨尔本大学彼得麦卡伦癌症中心、英国伦敦大学玛丽王后学院的KEYNOTE-355研究报告，比较了帕博利珠单抗＋化疗或安慰剂＋化疗一线治疗局部复发不可手术或远处转移三阴性乳腺癌的抗肿瘤活性和安全性。
NCT02819518: Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs. Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (MK-3475-355/KEYNOTE-355)
该国际多中心双盲安慰剂随机对照三期临床研究于2017年1月9日～2018年6月12日从欧洲、北美、亚洲、大洋洲、拉丁美洲29个国家地区209家医院对1372例患者进行筛选，入组年龄≥18岁、经中心确认三阴性乳腺癌局部复发不可手术或远处转移尚未治疗、至少一个病灶可测量、中心实验室提供新获得肿瘤标本用于免疫组织化学测定三阴性乳腺癌状态和PD-L1状态、美国东部肿瘤学协作组体力状态评分0或1、器官功能良好患者847例，通过交互式语音反馈系统＋网络反馈，采用区组法（每个区组6例）按2∶1随机分为两组：
可瑞达组566例：帕博利珠单抗每3周200毫克＋化疗（白蛋白紫杉醇、紫杉醇或吉西他滨＋卡铂）
安慰剂组281例：生理盐水＋化疗（白蛋白紫杉醇、紫杉醇或吉西他滨＋卡铂）
根据化疗类型（紫杉类或吉西他滨＋卡铂）、治疗前肿瘤细胞+免疫细胞PD-L1表达（联合阳性评分≥1或<1）以及既往术前新辅助或术后辅助化疗类型是否相同，对随机分组进行分层。申办者、研究者、其他研究地点工作者（除了非盲药剂师）和患者对帕博利珠单抗或生理盐水安慰剂分组双盲。此外，申办者、研究者、其他研究地点工作者和患者对患者个人肿瘤PD-L1生物标志结果双盲。双重主要疗效终点为PD-L1联合阳性评分≥10、≥1以及全部愿意治疗患者的无进展生存和总生存。本文为中期分析，对无进展生存进行最终评定；总生存随访仍在继续。对于无进展生存，采用分级检验策略，首先对联合阳性评分≥10的患者进行检验（中期分析预设α=0.00411），随后对联合阳性评分≥1的患者进行检验（中期分析预设α=0.00111，联合阳性评分≥10的患者无进展生存部分α通过），最后对全部愿意治疗患者进行检验（中期分析预设α=0.00111）。
结果，截至2019年12月11日第二次中期分析时，可瑞达组与安慰剂组的中位随访时间分别为25.9个月比26.3个月（四分位：22.8～29.9、22.7～29.7）。
可瑞达组与安慰剂组相比，中位无进展生存：
联合阳性评分≥10：9.7个月比5.6个月，进展或死亡风险低35%（风险比：0.65，95%置信区间：0.49～0.86，单侧P=0.0012，达到主要终点）
联合阳性评分≥1 ：7.5个月比5.6个月，进展或死亡风险低26%（风险比：0.74，95%置信区间：0.61～0.90，单侧P=0.0014，不显著）
全部愿意治疗患者：7.6个月比5.6个月，进展或死亡风险低18%（风险比：0.82，95%置信区间：0.69～0.97，未检验）
帕博利珠单抗的治疗效果随着治疗前肿瘤细胞+免疫细胞PD-L1表达水平提高而提高。
亚组分析表明，无论年龄、地理区域、体力状态评分、本次化疗方案、既往化疗类型、既往术前新辅助或术后辅助化疗、无转移间期、转移部位数量如何，可瑞达组与安慰剂组相比，无进展生存都较好。
可瑞达组与安慰剂组的3～5级治疗相关不良事件发生率分别为68%和67%，死亡率分别为0.35%和0%。
因此，该研究结果表明，对于PD-L1高表达晚期三阴性乳腺癌患者，帕博利珠单抗＋化疗与安慰剂＋化疗相比，无进展生存显著改善，标准化疗＋帕博利珠单抗对晚期三阴性乳腺癌一线治疗有效。
相关链接
Lancet. 2020 Dec 5;396(10265):1817-1828.
Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial.
Javier Cortes, David W Cescon, Hope S Rugo, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos H Barrios, Esther Holgado, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Jing Zhao, Gursel Aktan, Vassiliki Karantza, Peter Schmid; KEYNOTE-355 Investigators.
International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Princess Margaret Cancer Centre, Toronto, ON, Canada; University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; Merck, Kenilworth, NJ, USA; Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Pantai Hospital, Kuala Lumpur, Malaysia; Arturo Lopez Perez Foundation, Santiago, Chile; Republican Clinical Oncology Dispensary, Republic of Bashkortostan, Russia; Hospital Sao Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; Aichi Cancer Center Hospital, Nagoya, Japan; National Hospital Organization, Osaka National Hospital, Osaka, Japan; Oncomedica, Monteria, Colombia; Ege University Medical Faculty, Izmir, Turkey; Peter McCallum Cancer Centre, Melbourne, VIC, Australia; Queen Mary University of London, London, UK.
BACKGROUND: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer.
METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0.00411 at this interim analysis), then in patients with CPS of 1 or more (α=0.00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0.00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing.
FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25.9 months (IQR 22.8-29.9) in the pembrolizumab-chemotherapy group and 26.3 months (22.7-29.7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9.7 months with pembrolizumab-chemotherapy and 5.6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0.65, 95% CI 0.49-0.86; one-sided p=0.0012 [primary objective met]). Median progression-free survival was 7.6 and 5.6 months (HR, 0.74, 0.61-0.90; one-sided p=0.0014 [not significant]) among patients with CPS of 1 or more and 7.5 and 5.6 months (HR, 0.82, 0.69-0.97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.
INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.
FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
DOI: 10.1016/S0140-6736(20)32531-9