一期临床研究KEYNOTE-28结果表明，T淋巴细胞
程序性死亡蛋白PD-1
抑制剂
帕博利珠单抗（可瑞达，俗称K药）单药
仅对难治型激素受体阳性HER2阴性且
程序性死亡蛋白配体PD-L1
阳性晚期乳腺癌安全有效。二期临床研究I-SPY2结果发现，
帕博利珠单抗＋术前新辅助化疗
可显着提高激素受体阳性HER2阴性或三阴性早期乳腺癌的病理完全缓解率。此外，三期临床研究EMBRACE证实，
艾立布林单药
与其他治疗方案相比，可显着延长难治型晚期乳腺癌患者的总生存。不过，
艾立布林＋帕博利珠单抗
对难治型激素受体阳性HER2阴性晚期乳腺癌的效果尚不明确。
9月3日，《美国医学会杂志》肿瘤学分册在线发表
美国哈佛大学达纳法伯癌症研究所、麻省理工学院布罗德研究所、贝丝以色列女执事医疗中心、麻省总医院、布莱根医院和波士顿妇女医院、达纳法伯布莱根妇女癌症中心、巴西叙利亚黎巴嫩医院、法国古斯塔夫鲁西研究所
的研究报告，对艾立布林±帕博利珠单抗治疗难治型激素受体阳性HER2阴性晚期乳腺癌的有效性和安全性进行了比较。
NCT03051659
: A Randomized Phase II Study Of Eribulin Mesylate With Or Without Pembrolizumab For Metastatic Hormone Receptor Positive Breast Cancer
该多中心非盲随机对照二期临床研究于4月6日～8月28日从哈佛大学三家教学医院（麻省总医院癌症中心、贝丝以色列女执事医疗中心、达纳法伯布莱根妇女癌症中心）入组至少二线内分泌治疗失败、最多二线化疗失败的激素受体阳性HER2阴性晚期乳腺癌患者
88例
（年龄30～76岁，中位57岁；既往化疗中位一线、最多二线失败，既往内分泌治疗中位二线、最多五线失败）按1∶1的比例随机分为两组各44例，分别给予
艾立布林＋帕博利珠单抗
或艾立布林单药。对于病情恶化的艾立布林单药治疗患者，可给予帕博利珠单抗单药治疗。主要终点为无进展生存，次要终点为客观缓解率和总生存。探索分析无进展生存、PD-L1状态、肿瘤浸润淋巴细胞、肿瘤突变数量、基因组变化的相关性。
结果，中位随访
10.5个月
（95%置信区间：0.4～22.8），
艾立布林＋帕博利珠单抗
与艾立布林单药治疗相比：
无进展生存相似：中位4.1
比4.2个月（风险比：0.80，95%置信区间：0.50～1.26；P=0.33）
客观缓解率相似：27%
比34%（P=0.49）
总生存相似：中位13.4
比12.5个月（风险比：0.87，95%置信区间：0.48～1.59，P=0.65）
全因不良事件发生于全部患者，其中≥3级占65%，包括联合治疗组2例治疗相关死亡，均由免疫性结肠炎所致脓毒症引起，归因于两药。
对
65例
患者存档
原发肿瘤
标本进行PD-L1测定，其中PD-L1阳性肿瘤24例（37%）。分析表明，PD-L1状态、肿瘤浸润淋巴细胞、肿瘤突变数量、基因组变化与无进展生存无显着相关性。
此外，14例艾立布林单药治疗恶化患者改为帕博利珠单抗单药治疗，其中1例患者病情稳定。6例PD-L1阳性患者与5例PD-L1阴性患者相比，中位无进展生存显着较长：2.0比0.9个月（95%置信区间：1.2～2.4、0～1.9）。
因此，该随机对照研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌患者，帕博利珠单抗＋艾立布林与艾立布林单药相比，无进展生存、客观应答率、总生存相似，无论意向治疗人群还是PD-L1阳性人群，故有必要进一步探索治疗失败次数较少患者化疗±免疫检查点抑制剂的获益。
相关链接
三阴性乳腺癌术前新辅助治疗方案比较
帕博利珠单抗＋化疗治疗早期三阴性乳腺癌：III期KEYNOTE-522研究
帕博利珠单抗单药治疗晚期三阴性乳腺癌：II期KEYNOTE-086研究
帕博利珠单抗单药治疗晚期三阴性乳腺癌：IB期KEYNOTE-012研究
帕博利珠单抗＋放疗治疗晚期三阴性乳腺癌：II期研究
帕博利珠单抗＋曲妥珠单抗治疗曲妥珠单抗耐药晚期HER2阳性乳腺癌：IB期和II期PANACEA研究
高风险早期乳腺癌术前化疗＋免疫治疗：I-SPY2研究
乳腺肿瘤高突变发生率与突变决定因素
早期乳腺癌术前与术后化疗的长期结局十项随机研究个体患者数据的荟萃分析
I-SPY 2 TRIAL——乳腺癌治疗取得更快进展
晚期乳腺癌艾立布林＋帕妥珠＋曲妥珠
艾立布林单药治疗乳腺癌肝肺转移结局
艾立布林对晚期乳腺癌的实际疗效
欧洲癌症杂志发表中国乳腺癌研究
JAMA Oncol. Sep 3. Online ahead of print.
Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial.
Tolaney SM, Barroso-Sousa R, Keenan T, Li T, Trippa L, Vaz-Luis I, Wulf G, Spring L, Sinclair NF, Andrews C, Pittenger J, Richardson ET 3rd, Dillon D, Lin NU, Overmoyer B, Partridge AH, Van Allen E, Mittendorf EA, Winer EP, Krop IE.
Dana-Farber Cancer Institute, Boston, Massachusetts; Broad Institute of MIT and Harvard, Boston, Massachusetts; Beth Israel Deaconess Medical Center, Boston, Massachusetts; Massachusetts General Hospital, Boston, Massachusetts; Brigham and Women"s Hospital, Boston, Massachusetts; Dana-Farber/Brigham and Women"s Cancer Center, Boston, Massachusetts; Hospital Sírio-Libanês, Brasília, Brazil; Gustave Roussy, Villejuif, France.
This phase 2 randomized clinical trial compares the efficacy of eribulin plus pembrolizumab vs eribulin alone in hormone receptor-positive, ERBB2-negative metastatic breast cancer.
QUESTION
: Does the addition of pembrolizumab to eribulin improve efficacy compared with eribulin alone in patients with hormone receptor-positive/ERBB2-negative metastatic breast cancer?
FINDINGS
: In this phase 2 randomized clinical trial that included 88 patients, the median progression-free survival was 4.1 months for patients receiving pembrolizumab and eribulin vs 4.2 months for patients receiving eribulin alone.
MEANING
: The results do not support the use of pembrolizumab in combination with eribulin for patients with hormone receptor-positive/ERBB2-negative metastatic breast cancer, independent of programmed cell death ligand 1 status.
IMPORTANCE
: Prior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies.
OBJECTIVE
: To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC.
DESIGN, SETTING, AND PARTICIPANTS
: Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy.
INTERVENTIONS
: Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy.
MAIN OUTCOMES AND MEASURES
: The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations.
RESULTS
: Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS.
CONCLUSIONS AND RELEVANCE
: In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed.
TRIAL REGISTRATION
: NCT03051659
PMID
: 32880602
DOI
: 10.1001/jamaoncol..3524
