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三阴性乳腺癌的雌激素受体、孕激素受体和人类表皮生长因子受体HER2均为阴性,对传统的内分泌治疗和HER2靶向治疗无效,早期患者主要依靠手术和化疗。近年来,免疫检查点抑制剂已被证实对于晚期三阴性乳腺癌有效。免疫检查点是人体平衡免疫功能的两类分子,一类负责激活免疫细胞,另一类负责抑制免疫细胞,后者包括免疫细胞程序性死亡受体PD-1及其配体PD-L1,肿瘤细胞能够利用PD-1和PD-L1让免疫细胞进入自杀程序,避免自己被免疫细胞消灭,而PD-1或PD-L1抑制剂可以恢复免疫细胞抗肿瘤功能。不过,对于高风险早期三阴性乳腺癌,目前仅KEYNOTE-522研究证实PD-1抑制剂帕博利珠单抗术前新辅助治疗+术后辅助治疗有效,可显著改善患者的病理完全缓解率、无事件生存和总生存,其他PD-1或PD-L1抑制剂已告失败。
2025年8月28日,欧洲肿瘤内科学会官方期刊《肿瘤学年鉴》在线发表意大利帕多瓦大学设计并发起的A-BRAVE研究报告,首次对PD-L1抑制剂阿维利尤单抗辅助治疗高风险早期三阴性乳腺癌术后患者的有效性和安全性进行随机比较。
A-BRAVE (NCT02926196): Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab
该国际多中心非盲随机对照三期临床研究于2016年6月至2020年10月从60家意大利医院和7家英国医院入组高风险早期三阴性乳腺癌完成手术和化疗等标准治疗患者466例,按1比1随机分为两组,其中235例每2周静脉输注阿维利尤单抗治疗1年,其余231例观察。高风险分为两类:A类83例(18%)初次手术后任何pT且≥pN2、pT2且pN1、pT3且pN0,B类383例(82%)术前化疗后乳腺和/或淋巴结残留浸润癌。主要终点包括全部患者和B类患者的无癌生存,次要终点包括全部患者的总生存和PD-L1测定患者的无癌生存,事后探索性分析终点包括全部患者的远处无癌生存。通过免疫组织化学和数字病理学对治疗前肿瘤样本PD-L1进行测定。若主要终点有统计学显著差异,则对次要终点进行统计学分析,否则仅进行描述性分析。
结果,中位随访52.1个月,阿维利尤单抗组与观察组相比:
全部患者3年无癌生存率相似:68.3%比63.2%(风险比:0.81,95%置信区间:0.61~1.09,P=0.172)
B类患者3年无癌生存率相似:66.9%比60.7%(风险比:0.80,95%置信区间:0.58~1.10,P=0.170)
全部患者3年总生存率较高:84.8%比76.3%(风险比:0.66,95%置信区间:0.45~0.97)
全部患者3年远处无癌生存较高:75.4%比67.9%(风险比:0.70,95%置信区间:0.50~0.96)
PD-L1阳性与阴性相比,患者3年无癌生存率较高:80.9%比64.2%(风险比:0.45,95%置信区间:0.26~0.78,P=0.003)。
不过,阿维利尤单抗组与观察组相比:
PD-L1阳性患者3年无癌生存率相似:67.5%比60.7%(风险比:1.72(95%置信区间:0.58~5.12)
PD-L1阴性患者3年无癌生存率相似:84.8%比77.1%(风险比:0.76(95%置信区间:0.54~1.08)
PD-L1不能预测阿维利尤单抗无癌生存获益(相互作用检验P=0.155)
因此,该小规模研究短期随访结果表明,对于早期三阴性乳腺癌复发风险较高患者,完成手术和化疗等标准治疗后,阿维利尤单抗辅助治疗1年与观察相比,3年无癌生存并未改善。不过,出乎意料的是,描述性和探索性分析表明,阿维利尤单抗对3年总生存和远处无癌生存产生有利影响,可能减少远处转移和死亡风险,故有必要进一步长期随访并开展大规模研究进行验证,才能确定其对临床实践的潜在影响。PD-L1虽然可以预测患者无癌生存,但是不能预测阿维利尤单抗无癌生存获益。
相关链接
不可思议的乳腺癌患者总生存曲线
Ann Oncol. 2025 Aug 28. IF: 65.4
A-BRAVE trial: a Phase 3 randomized trial with anti-PD-L1 avelumab in high-risk triple-negative early breast cancer patients.
Conte PF, Dieci MV, Bisagni G, Schmid P, Zambelli A, Piacentini F, De Laurentiis M, Favaretto AG, Tamberi S, Bianchi GV, Zamagni C, Cinieri S, Corsi DC, Del Mastro L, Ferro A, Gennari A, Mion M, Musolino A, Nicolé L, Del Bianco P, De Salvo GL, Guarneri V.
University of Padova, Padova, Italy; Veneto Institute of Oncology IOV IRCCS, Padova, Italy; Azienda USL-IRCCS, Reggio Emilia, Italy; ASST Papa Giovanni XXIII, Bergamo, Italy; Bicocca University, Milan, Italy; University Hospital of Modena, Modena, Italy; Azienda Ospedaliero-Universitaria di Modena, Modena, Italy; Istituto Nazionale Tumori Napoli IRCCS "Fondazione Pascale", Napoli, Italy; Azienda ULSS 2 Marca Trevigiana, Treviso, Italy; Santa Maria delle Croci hospital, Ravenna, Italy; Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Perrino Hospital, ASL Brindisi, Brindisi, Italy; Ospedale Isola Tiberina, Gemelli Isola Rome, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy; Università degli Studi di Genova, Genova, Italy; Santa Chiara Hospital, Trento, Italy; Università del Piemonte Orientale, Novara, Italy; AULSS6 Camposampiero, Camposampiero, Italy; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy; University of Bologna, Bologna, Italy; Angelo Hospital, Mestre, Italy; Queen Mary University of London, London, United Kingdom.
HIGHLIGHTS
A-BRAVE is a Phase III study of 1-year avelumab versus observation after standard treatment in high-risk TNBC.
Avelumab as adjuvant therapy versus observation did not improve DFS in high-risk early TNBC patients
OS analysis suggests a potential favorable impact of avelumab versus observation.
PD-L1 status was not predictive for avelumab efficacy.
BACKGROUND: The A-BRAVE trial evaluated the efficacy of avelumab, an anti PD-L1 antibody, as adjuvant treatment for patients with early triple-negative breast cancer (TNBC) at high-risk.
PATIENTS AND METHODS: A-BRAVE is a Phase III study that randomized patients with high-risk early TNBC to 1-year avelumab vs observation, after completion of standard surgery and neoadjuvant/adjuvant chemotherapyHigh-risk was defined as either: 1) >pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (Stratum A); or 2) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (Stratum B). Co-primary endpoints were disease-free survival (DFS) in the intention-to-treat (ITT) and Stratum B populations (). Secondary endpoints were overall survival (OS) and DFS in PD-L1-positive patients. PD-L1 was evaluated in treatment-naive tumor samples by immunohistochemistry (73-10 RUO assay, Agilent Technologies) and digital pathology.
RESULTS: From June 2016 to October 2020, 466 patients were randomized: 383 entered Stratum B (82%) and 83 entered Stratum A (18%). At a median follow of 52.1 months, avelumab did not significantly improve DFS in the ITT population (HR 0.81, 95% CI 0.61-1.09, p=0.172; 3-year DFS estimates were 68.3% for avelumab versus 63.2%), or in Stratum B (HR 0.80, 95% CI 0.58-1.10, p=0.170; 3-year DFS estimates were 66.9% for avelumab versus 60.7%). In a descriptive analysis, avelumab reduced the hazard of OS events: HR 0.66, 95% CI: 0.45-0.97. The 3-year OS estimates for avelumab and control arm were 84.8% (95% CI: 79.5-88.8) and 76.3% (95% CI: 70.1-81.3), respectively. PD-L1 status resulted prognostic but not predictive for avelumab benefit in terms of DFS (test for interaction p=0.155).
CONCLUSIONS: For patients with TNBC at high risk of relapse who complete standard treatment with surgery and neoadjuvant/adjuvant chemotherapy, 1 year of adjuvant avelumab versus observation did not improve DFS. However, a descriptive analysis suggests a potential favorable impact on OS.
ClinicalTrials.gov identifier: NCT02926196
KEYWORDS: Breast cancer, clinical trial, immunotherapy, triple-negative breast cancer, PD-L1
DOI: 10.1016/j.annonc.2025.08.005
(来源:SIBCS)
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