新英格兰：Ｋ药治疗早期三阴性乳腺癌
免疫检查点抑制剂一家可谓日益壮大，从原本双雄争霸到现在老三、老四、老五都已正式出道。目前，美国已批准5个免疫检查点抑制剂，中国内地已批准其中4个。
程序性细胞死亡蛋白-1（PD-1）抑制剂
帕博利珠单抗：可瑞达，俗称K药，默克或默沙东出品，2014年12月美国批准、2018年7月中国批准
纳武利尤单抗：欧狄沃，俗称O药，百时美施贵宝出品，2014年9月美国批准、2019年8月中国批准
程序性细胞死亡蛋白配体-1（PD-L1）抑制剂
阿特利珠单抗：泰圣奇，俗称T药，罗氏基因泰克出品，2016年10月美国批准、2020年2月中国批准
度伐利尤单抗：英飞凡，俗称I药，阿斯利康出品，2017年5月美国批准、2019年12月中国批准
阿维鲁单抗：Bavencio，俗称B药，默克和辉瑞出品，2017年3月美国批准
一期临床研究KEYNOTE-173、二期临床研究I-SPY2结果表明，早期三阴性乳腺癌患者术前新辅助化疗＋帕博利珠单抗的抗肿瘤活性鼓舞人心、安全性可接受。
相关链接
2020年2月27日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》发表英国伦敦大学玛丽王后学院、西班牙马德里凯龙医疗集团、巴塞罗那大学、美国默克、耶鲁大学癌症中心、洛杉矶西达赛奈医学中心、贝勒大学、德克萨斯肿瘤学协作组、德国埃森中心医院、马尔堡大学、慕尼黑大学、埃尔朗根纽伦堡大学、柏林赫利俄斯医院、瑞典卡罗林学院、韩国成均馆大学三星首尔医院、澳大利亚悉尼大学、日本北海道癌症中心、葡萄牙尚帕利莫基金会临床中心、新加坡国家癌症中心、新加坡国立大学的KEYNOTE-522三期临床研究报告，比较了早期三阴性乳腺癌术前新辅助化疗±帕博利珠单抗至最终手术时的病理完全缓解（无乳腺浸润癌且淋巴结阴性）患者比例。
KEYNOTE-522 (Study of Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer): A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (NCT03036488)
该国际多中心随机双盲安慰剂对照三期临床研究于2017年3月～2018年9月从21个国家181家医院入组II或III期三阴性乳腺癌患者1174例，按2∶1的比例随机分为两组进行术前新辅助治疗：帕博利珠单抗＋化疗组784例、安慰剂＋化疗组390例。帕博利珠单抗每3周200毫克×24周，化疗方案包括紫杉醇＋卡铂×12周→多柔比星或表柔比星＋环磷酰胺×12周，最多用药27周。主要终点为意向治疗人群无事件生存以及最终手术时的病理完全缓解。
结果，经过2.7～25.0个月（中位15.5个月）随访，截至2018年9月24日首次中期分析时，随机入组患者602例，帕博利珠单抗＋化疗组401例与安慰剂＋化疗组201例相比：
病理完全缓解比例：64.8%比51.2%（95%置信区间：59.9～69.5、44.1～58.3）
病理完全缓解相差：13.6%（95%置信区间：5.4～21.8，P<0.001）
进展复发死亡比例：7.4%比11.8%（风险比，0.63，95%置信区间：0.43～0.93）
治疗相关不良事件：78.0%比73.0%（≥3级）
治疗相关死亡比例：0.4%比0.3%
因此，该研究结果表明，对于早期三阴性乳腺癌患者，无论PD-L1是否阳性，帕博利珠单抗＋新辅助化疗与安慰剂＋新辅助化疗相比，病理完全缓解比例显著较高。
相关链接
N Engl J Med. 2020 Feb 27;382(9):810-821.
Pembrolizumab for Early Triple-Negative Breast Cancer.
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators.
Queen Mary University of London, London; Quirón Group, Madrid; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Yale School of Medicine, Yale Cancer Center, New Haven, CT; Cedars-Sinai Medical Center, Los Angeles; Kliniken Essen-Mitte, Essen; University of Marburg, Marburg; University of Munich, Munich; University Hospital Erlangen, Erlangen; Helios Klinikum Berlin-Buch, Berlin, Germany; Karolinska InstitutetKarolinska University Hospital, Solna, Sweden; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; University of Sydney, Sydney; National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan; Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal; Merck, Kenilworth, NJ; National Cancer Center Singapore, Duke-National University of Singapore Medical School, Singapore; Baylor University Medical Center, Texas Oncology and US Oncology, Dallas.
BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.
METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.
RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.
CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.
Funded by Merck Sharp & Dohme [a subsidiary of Merck
KEYNOTE-522 ClinicalTrials.gov number: NCT03036488
PMID: 32101663
DOI: 10.1056/NEJMoa1910549