Background: Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints.
Patients and methods: Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D.
Results: Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration.
Conclusion: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC.
Implications for practice: This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the "cold" tumors to be able to combine current immune-oncology agents.
摘要
背景。免疫检查点抑制剂在众多癌症中具有活性，包括程序性死亡配体 1 (PD‐L1) 阳性、三阴性、转移性乳腺癌 (MBC)。抗体依赖性细胞介导的细胞毒性是曲妥珠单抗的作用机制。我们进行了一项关于度伐单抗联合曲妥珠单抗治疗先前曾接受化疗和抗 HER2 抗体治疗的 HER2 阳性MBC患者的 Ib 期试验，旨在对安全性、疗效和相关终点进行评估。
患者和方法。HER2 阳性MBC患者以标准 3 + 3 设计入组。剂量水平 1 为度伐单抗(第 1 天静脉给药 1 125 mg)和曲妥珠单抗(第 1 天静脉给药 8 mg/kg负荷量，之后的剂量为 6 mg/kg维持量)，每3周为 1 个周期。按照推荐的 II 期研究剂量 (RP2D) 给药的扩展队列在基线时以及在经过第 1 个周期后接受肿瘤活检。主要终点旨在确定 RP2D。
结果。从 2016 年 4 月至 12 月期间，本研究共纳入 15 名患者，其中，14 名患者可进行疗效评估。中位年龄为 54 岁(范围为 40–86 岁)；大多数患者患有内脏疾病 (87%)，既往至少采用 3 线(辅助性和/或转移性)化疗方案 (73%)，包括针对MBC的曲妥珠单抗 (93%)、帕妥珠单抗 (60%) 以及曲妥珠单抗‐emtansine (93%)。在第 1 个周期内，在剂量水平 1 组 (n = 6) 或剂量扩展组 (n = 9) 均未观察到剂量限制性毒性。一名患者出现 ≥3 级的免疫相关不良反应(4 级糖尿病)。未发现实体瘤疗效评价标准 (RECIST) 中的任何缓解，在第 6 周时，14 名患者中有 4 名患者 (29%) 表现出最佳缓解，即疾病稳定(中位持续时间为 2.7 个月)。所有患者在标本组织检查 (7/15) 或前期研究活检 (8/15) 中均出现 <1% PD‐L1 表达。在剂量扩展队列中，可评估的治疗前和治疗中肿瘤活检 (n = 5) 均显示出最小 CD8 细胞浸润。
结论。度伐单抗和曲妥珠单抗的 RP2D 是这两种药物的标准全剂量。在既往曾多次接受治疗的 HER2 阳性 PD‐L1 阴性MBC患者中，未观察到显著的临床活性。
实践意义:这项具有相关终点的 Ib 期试验证明度伐单抗联合曲妥珠单抗治疗既往曾多次接受治疗的 HER2 阳性转移性乳腺癌 (MBC) 患者缺乏活性。在既往曾多次接受治疗的 HER2 阳性程序性死亡配体 1 (PD‐L1) 阴性MBC患者中，有证据表明细胞毒性 T 细胞衰竭，未观察到显著的临床活性。此外，所有患者在肿瘤细胞中均未出现 PD‐L1 表达。这些数据证实了 PD‐L1 作为重要选择标志物的重要性以及对免疫调节细胞的肿瘤微环境进行评估的必要性。了解如何激活“冷”肿瘤还需要进一步开展工作，以便能够联合使用现有的各种免疫肿瘤药物。
Keywords: Durvalumab; HER2 metastatic breast cancer; Immunotherapy; Trastuzumab.
© AlphaMed Press 2019.