高风险早期三阴性乳腺癌术前免疫化疗
程序性细胞死亡蛋白1（PD-1）是主要表达于T淋巴细胞表面的免疫检查点，与癌细胞表面的程序性细胞死亡配体1（PD-L1）结合以后，可以抑制T淋巴细胞杀死癌细胞。帕博利珠单抗是用于癌症免疫治疗的人源化PD-1单克隆抗体，通过抑制T淋巴细胞的PD-1，能够阻断癌细胞的免疫逃避机制，从而允许T淋巴细胞杀死癌细胞。2014年和2018年，帕博利珠单抗先后被美国和中国内地批准上市，主要用于黑色素瘤、非小细胞肺癌等实体肿瘤。KEYNOTE-086研究证实帕博利珠单抗单药可以有效治疗晚期三阴性乳腺癌。
2020年2月14日，欧洲肿瘤内科学会《肿瘤学报》在线发表英国伦敦大学玛丽王后学院巴特癌症研究所、澳大利亚墨尔本大学彼得·麦卡伦癌症中心、韩国成均馆大学三星首尔医院、蔚山大学首尔峨山医院、延世大学癌症中心、西班牙巴塞罗纳肿瘤研究所、瑞典卡罗林医学院、德国埃森米特医院、新加坡国家癌症中心、美国默克的研究报告，探讨了高风险早期三阴性乳腺癌术前新辅助化疗＋帕博利珠单抗的安全性和初步抗肿瘤活性。
MK-3475-173/KEYNOTE 173 (Safety and Efficacy Study of Pembrolizumab in Combination With Chemotherapy as Neoadjuvant Treatment for Participants With Triple Negative Breast Cancer): A Phase 1b Study to Evaluate Safety and Clinical Activity of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast Cancer (NCT02622074)
该国际多中心多队列非盲一期临床研究于2016年2月18日～2017年2月28日从8个国家19家医院入组高风险早期三阴性乳腺癌患者60例，分为6个队列（A～F），对6种帕博利珠单抗＋化疗方案进行评估。各个队列术前第1周期的帕博利珠单抗剂量均为200毫克，再予8个周期的帕博利珠单抗＋紫杉类±卡铂化疗12周，随后多柔比星＋环磷酰胺化疗12周，最后进行手术。主要终点为安全性和推荐二期剂量；次要终点为病理完全缓解、客观缓解率、无事件生存、总生存。探索终点为结局与潜在生物标志之间的关系，例如肿瘤PD-L1表达（全部阳性比例）和基质肿瘤浸润淋巴细胞水平。
结果，限制剂量的毒性反应发生于22例患者，主要为中性粒细胞减少相关发热9例。
2个方案（A、E，白蛋白紫杉醇每周每平方米体表面积125毫克、紫杉醇每周每平方米体表面积80毫克＋卡铂每3周血药浓度时间曲线下面积5）达到二期剂量临界值，4个方案（B、C、D、F）未达到。
≥3级治疗相关不良事件主要为中性粒细胞减少（73%）。
免疫相关不良事件和输液反应发生于18例患者（30%），其中≥3级发生于6例患者（10%）。
全部队列的病理完全缓解率（ypT0/TisypN0）为60%（范围：30%～80%）。
全部队列的12个月无事件生存率和总生存率为80%～100%，其中4个队列为100%。
病理完全缓解率较高的显著相关因素包括：
治疗前肿瘤PD-L1全部阳性比例较高（P=0.0127）
治疗前基质肿瘤浸润淋巴细胞水平较高（P=0.0059）
治疗中基质肿瘤浸润淋巴细胞水平较高（P=0.0085）
因此，该研究结果表明，高风险早期三阴性乳腺癌术前新辅助化疗＋帕博利珠单抗的毒性反应可控、抗肿瘤活性令人鼓舞，初步分析表明病理完全缓解率与肿瘤PD-L1全部阳性比例和基质肿瘤浸润淋巴细胞水平成正比。
相关链接
Ann Oncol. 2020 Feb 14. [Epub ahead of print]
Pembrolizumab plus chemotherapy as neoadjuvant treatment for high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study.
P. Schmid, R. Salgado, Y.H. Park, E. Munoz-Couselo, S.B. Kim, J. Sohn, T. Foukakis, S. Kuemmel, R. Dent, L. Yin, A. Wang, K. Tryfonidis, V. Karantza, J. Cortés, S. Loi.
Barts Cancer Institute, London, United Kingdom; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; Karolinska Institute and University Hospital, Stockholm, Sweden; Clinics Essen-Mitte, Essen, Germany; National Cancer Centre, Singapore; Merck & Co., Inc., Kenilworth, NJ, USA; IOB Institute of Oncology, Quiron Group, Barcelona, Spain.
HIGHLIGHTS
Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC
2 chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 QW; paclitaxel 80 mg/m2 QW + carboplatin AUC5 Q3W
pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80-100% across cohorts
pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels
BACKGROUND: The phase 1b KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC).
PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary endpoints were safety and recommended phase 2 dose (RP2D); secondary endpoints were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory endpoints were the relationship between outcome and potential biomarkers, such as tumour programmed death ligand 1 (PD-L1) expression (combined positive score [CPS]) and stromal tumor-infiltrating lymphocyte levels (sTILs).
RESULTS: Sixty patients were enrolled between February 18, 2016, and February 28, 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 9 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 30%-80%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 CPS, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively).
CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, pCR rate showed positive correlation with tumour PD-L1 expression and sTIL levels.
KEYWORDS: neoadjuvant therapy, pembrolizumab, chemotherapy, triple-negative breast cancer, immune checkpoint inhibitor, programmed death ligand 1
DOI: 10.1016/j.annonc.2020.01.072