Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain.
Breast Cancer Res. 2020 Nov 11;22(1):124. doi: 10.1186/s13058-020-01362-y.
Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer.
Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time.
Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased T signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating T in non-progressors.
This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing T cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting.
(www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.
临床前研究表明，免疫检查点抑制剂与抗血管生成药物联合使用可提高乳腺癌的疗效，尤其是序贯使用。我们旨在探索在曲妥珠单抗联合贝伐珠单抗方案中序贯应用抗 PD-L1 药物 durvalumab 联合抗血管生成药物贝伐珠单抗治疗晚期 HER2 阴性乳腺癌的疗效和生物标志物。
患者为进展期 HER2 阴性疾病，在接受单药贝伐珠单抗维持治疗后进展，该治疗方案是在先前的化疗加贝伐珠单抗方案的基础上进行的。治疗方案为每两周静脉注射 durvalumab 联合 bevacizumab（各 10mg/kg）。在第一次 durvalumab 剂量前和每 4 周采集外周血单核细胞（PBMC），并通过流式细胞术进行免疫表型分析。在使用 durvalumab 前采集新鲜的肿瘤活检组织，进行基因表达研究和免疫组织化学染色以评估血管正常化和特征性免疫浸润。如果患者在 4 个月时具有临床获益（SD/PR/CR），则被归类为“非进展者”。主要次要终点为进展者和非进展者 PBMC 中 T 细胞亚群百分比的变化，以及 PFS/OS 时间。
共入组 26 例患者。中位 PFS 和 OS 分别为 3.5 和 11 个月；在激素阳性亚组中观察到 OS 时间延长的趋势（三阴性患者为 19.8 个月，三阴性患者为 7.4 个月；P=0.11）。2 个月和 4 个月时的临床获益率分别为 60%和 44%，激素阳性和三阴性之间无显著差异（P=0.73）。非进展者的肿瘤显示出贝伐珠单抗治疗后的血管正常化特征，而进展者的肿瘤通常表现为异常模式。与进展者相比，非进展者在基线后-贝伐珠单抗-肿瘤的基因表达研究中显示出增加的 T 效应器和 T 记忆特征，以及减少的 T 特征。值得注意的是，durvalumab 治疗前 PBMC 群体的分析与肿瘤样本的发现一致，显示非进展者循环 T 的百分比降低。
本研究报告了在乳腺癌中序贯应用贝伐珠单抗+durvalumab 的结果，在一个接受过多线治疗的患者队列中显示出令人鼓舞的疗效。相关性研究支持抗血管生成治疗产生的免疫预刺激作用的临床前原理，可能通过减少全身和肿瘤组织中的 T 细胞来实现。这种获益的程度应该在随机研究中进行评估。
（www.clinicaltrials.gov）：NCT02802098。于 2020 年 6 月 16 日注册。
