未登录

开通VIP,畅享免费电子书等14项超值服

开通VIP
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陆批准上市,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


本站仅提供存储服务,所有内容均由用户发布,如发现有害或侵权内容,请点击举报
打开APP阅读全文并永久保存 更多类似文章
猜你喜欢
类似文章
靶向药物Pembrolizumab治疗三阴性乳腺癌
三阴性乳腺癌的免疫治疗
[ASCO2017]乳腺专家圆桌会:乳腺癌分子靶向和免疫治疗重要进展
小癌种、大希望:PD1治疗这十类肿瘤,展露锋芒
多种治疗齐开花能否啃下三阴性乳腺癌这块硬骨头?
三阴性乳腺癌新方案
更多类似文章 >>
生活服务
搜索
绑定账号成功
后续可登录账号畅享VIP特权!
如果VIP功能使用有故障,
可点击这里联系客服!