免疫细胞表面的程序性死亡受体PD-1属于免疫检查点之一，与癌细胞表面的程序性死亡配体PD-L1结合以后，可以阻止免疫系统杀死癌细胞。帕博利珠单抗（俗称K药）可以抑制PD-1，阻断癌细胞的免疫逃避机制。
2019年11月20日，美国癌症学会《癌症》在线发表纽约纪念医院斯隆凯特林癌症中心、洛杉矶西达赛奈医学中心、麻省总医院的研究报告，探讨了帕博利珠单抗＋放疗对晚期三阴性乳腺癌患者的有效性和安全性，无论PD-L1表达水平如何。
NCT02730130: A Multicenter Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus Radiotherapy in Metastatic Triple Negative Breast Cancer Patients
该多中心单组二期西蒙两阶段设计临床研究于2016年6月～2017年5月从纽约纪念医院斯隆凯特林癌症中心和洛杉矶西达赛奈医学中心入组无论PD-L1表达水平如何的晚期三阴性乳腺癌患者17例，年龄范围37～73岁，中位52岁。放疗剂量为30戈瑞，5～7天内分5次进行。首次放疗3天内静脉注射帕博利珠单抗200毫克，随后每3周±3天，直至疾病进展。随访时间范围2.1～108.3周，中位34.5周。主要研究终点为第13周根据实体瘤疗效评价标准（RECIST）1.1版测量的放疗区域外病变总缓解率，次要研究终点包括安全性和无进展生存。探索目标为初步确定可以预测总缓解率和无进展生存的生物标志。
结果，17例患者队列的总缓解率为17.6%（3例，95%置信区间：4.7%～44.2%），其中完全缓解3例、疾病稳定1例、疾病进展13例。8例患者第13周之前死于疾病进展。
第13周根据RECIST对9例女性的放疗区域外病变进行测量，其中3例（33%）完全缓解，肿瘤体积缩小100%。完全缓解分别持续18周、20周、108周。
根据美国国家癌症研究所（NCI）不良事件通用术语标准（CTCAE）4.0版，发生率最高的1～2级毒性反应为皮炎（29%）。帕博利珠单抗相关3级不良事件4例：疲劳、淋巴细胞减少、感染。未报告4级不良事件或治疗相关死亡。
因此，根据该研究结果表明，无论PD-L1表达水平如何，对于预后不佳的晚期三阴性乳腺癌患者，帕博利珠单抗联合放疗的安全性和有效性令人鼓舞，故有必要进一步开展较大样本的临床研究，对免疫检查点抑制剂＋放疗与预测疗效的生物标志进行验证。
Cancer. 2019 Nov 20. [Epub ahead of print]
A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer.
Ho AY, Barker CA, Arnold BB, Powell SN, Hu ZI, Gucalp A, Lebron-Zapata L, Wen HY, Kallman C, D'Agnolo A, Zhang Z, Flynn J, Dunn SA, McArthur HL.
Memorial Sloan Kettering Cancer Center, New York, New York; Cedars-Sinai Medical Center, Los Angeles, California; Massachusetts General Hospital, Boston, Massachusetts.
The current phase 2, multi-institutional study evaluates whether the combination of the programmed cell death protein 1 immune checkpoint inhibitor pembrolizumab and radiotherapy (RT) is safe and effective in patients with metastatic triple-negative breast cancer (mTNBC). Among 17 women in the current study with pretreated mTNBC who received pembrolizumab and RT, the combination appears safe and demonstrates an encouraging signal within a poor-prognosis population, indicating that further study of the combination is warranted.
BACKGROUND: The current study was conducted to evaluate the efficacy and safety of pembrolizumab-mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic triple-negative breast cancer who were unselected for programmed death-ligand 1 expression.
METHODS: The current study was a single-arm, Simon 2-stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37-73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow-up was 34.5 weeks (range, 2.1-108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression-free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression-free survival.
RESULTS: The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%-44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment-related deaths reported.
CONCLUSIONS: The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor-prognosis, metastatic, triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed.
KEYWORDS: checkpoint blockade; immunotherapy; metastatic; radiotherapy (RT); triple-negative breast cancer (TNBC)
DOI: 10.1002/cncr.32599
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