一期臨床研究KEYNOTE-28結果表明，T淋巴細胞程序性死亡蛋白PD-1抑制劑帕博利珠單抗（可瑞達，俗稱K藥）單藥僅對難治型激素受體陽性HER2陰性且程序性死亡蛋白配體PD-L1陽性晚期乳腺癌安全有效。二期臨床研究I-SPY2結果發(fā)現，帕博利珠單抗＋術前新輔助化療可顯著提高激素受體陽性HER2陰性或三陰性早期乳腺癌的病理完全緩解率。此外，三期臨床研究EMBRACE證實，艾立布林單藥與其他治療方案相比，可顯著延長難治型晚期乳腺癌患者的總生存。不過，艾立布林＋帕博利珠單抗對難治型激素受體陽性HER2陰性晚期乳腺癌的效果尚不明確。
2020年9月3日，《美國醫(yī)學會雜志》腫瘤學分冊在線發(fā)表美國哈佛大學達納法伯癌癥研究所、麻省理工學院布羅德研究所、貝絲以色列女執(zhí)事醫(yī)療中心、麻省總醫(yī)院、布萊根醫(yī)院和波士頓婦女醫(yī)院、達納法伯布萊根婦女癌癥中心、巴西敘利亞黎巴嫩醫(yī)院、法國古斯塔夫魯西研究所的研究報告，對艾立布林±帕博利珠單抗治療難治型激素受體陽性HER2陰性晚期乳腺癌的有效性和安全性進行了比較。
NCT03051659: A Randomized Phase II Study Of Eribulin Mesylate With Or Without Pembrolizumab For Metastatic Hormone Receptor Positive Breast Cancer
該多中心非盲隨機對照二期臨床研究于2017年4月6日～2018年8月28日從哈佛大學三家教學醫(yī)院（麻省總醫(yī)院癌癥中心、貝絲以色列女執(zhí)事醫(yī)療中心、達納法伯布萊根婦女癌癥中心）入組至少二線內分泌治療失敗、最多二線化療失敗的激素受體陽性HER2陰性晚期乳腺癌患者88例（年齡30～76歲，中位57歲；既往化療中位一線、最多二線失敗，既往內分泌治療中位二線、最多五線失?。┌?∶1的比例隨機分為兩組各44例，分別給予艾立布林＋帕博利珠單抗或艾立布林單藥。對于病情惡化的艾立布林單藥治療患者，可給予帕博利珠單抗單藥治療。主要終點為無進展生存，次要終點為客觀緩解率和總生存。探索分析無進展生存、PD-L1狀態(tài)、腫瘤浸潤淋巴細胞、腫瘤突變數量、基因組變化的相關性。
結果，中位隨訪10.5個月（95%置信區(qū)間：0.4～22.8），艾立布林＋帕博利珠單抗與艾立布林單藥治療相比：
無進展生存相似：中位4.1比4.2個月（風險比：0.80，95%置信區(qū)間：0.50～1.26；P=0.33）
客觀緩解率相似：27%比34%（P=0.49）
總生存相似：中位13.4比12.5個月（風險比：0.87，95%置信區(qū)間：0.48～1.59，P=0.65）
全因不良事件發(fā)生于全部患者，其中≥3級占65%，包括聯合治療組2例治療相關死亡，均由免疫性結腸炎所致膿毒癥引起，歸因于兩藥。
對65例患者存檔原發(fā)腫瘤標本進行PD-L1測定，其中PD-L1陽性腫瘤24例（37%）。分析表明，PD-L1狀態(tài)、腫瘤浸潤淋巴細胞、腫瘤突變數量、基因組變化與無進展生存無顯著相關性。
此外，14例艾立布林單藥治療惡化患者改為帕博利珠單抗單藥治療，其中1例患者病情穩(wěn)定。6例PD-L1陽性患者與5例PD-L1陰性患者相比，中位無進展生存顯著較長：2.0比0.9個月（95%置信區(qū)間：1.2～2.4、0～1.9）。
因此，該隨機對照研究結果表明，對于激素受體陽性HER2陰性晚期乳腺癌患者，帕博利珠單抗＋艾立布林與艾立布林單藥相比，無進展生存、客觀應答率、總生存相似，無論意向治療人群還是PD-L1陽性人群，故有必要進一步探索治療失敗次數較少患者化療±免疫檢查點抑制劑的獲益。
相關鏈接
JAMA Oncol. 2020 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.2020.3524
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