随机、开放标签、二期、生物标志物研究：新辅助皮下曲妥珠单抗在局部晚期、炎症或早期 HER2 阳性乳腺癌患者中的免疫介导作用机制——Immun-HER 试验（GOIRC-01-2016）。
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).
机构信息
Department of Medicine and Surgery, University of Parma, Parma, Italy.
Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.
出版信息
J Immunother Cancer. 2023 Nov 28;11(11):e007667. doi: 10.1136/jitc-2023-007667.
BACKGROUND
It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.
METHODS
In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).
RESULTS
Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms.
CONCLUSIONS
SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.
TRIAL REGISTRATION NUMBER
NCT03144947, and EudraCT number: 2016-000435-41.
背景
通过改变曲妥珠单抗的给药途径，有可能在 HER2 阳性乳腺癌（BC）中诱导免疫调节。
方法
在这项多中心随机 II 期试验中，所有入组的 T2-T4d HER2 阳性 BC 患者均接受 3 个周期的新辅助治疗（NAT），每 3 周（q21）给予氟尿嘧啶、表柔比星和环磷酰胺，随后给予多西他赛/帕妥珠单抗加静脉注射曲妥珠单抗（A 组）或多西他赛/帕妥珠单抗加皮下（SC）曲妥珠单抗（B 组）q21x4 个周期。手术后，每位患者均使用与 NAT 相同的 SC 或静脉制剂接受 q21x14 个周期的曲妥珠单抗治疗。主要终点是在新辅助治疗后残留疾病（RD）中具有高间质肿瘤浸润淋巴细胞（sTILs）的受试者比例。
结果
共有 63 名患者（31 名（A 组）和 32 名（B 组））入组。A 组有 20/31 名患者（64.5%；95%CI 45.4%至 80.1%）和 B 组有 19/32 名患者（59.4%；95%CI 40.1%至 76.3%）获得病理完全缓解。A 组和 B 组的新辅助 RD 中分别有 27%和 46%的 sTILs 高表达。CD8+T 细胞在两个臂的 RD 中均显著增加（p=0.014 和 0.002，分别为 A 组和 B 组），而仅在 B 组观察到 CD4+FoxP3+调节性 T 细胞水平显著下降（p=0.016）。在 B 组入组患者的 RD 中发现 sTILs 上 PD-1 的显著上调（p=0.012），而 A 组的残留肿瘤中程序性死亡配体 1（PD-L1）显著过表达（p=0.02）。在 B 组中，治疗前 sTILs 上 PD-L1 的表达与 sTILs 上 CD3 的表达之间存在很强的负相关（τ：-0.73）。两个臂之间的≥3 级 AE 发生率相似。
结论
SC 曲妥珠单抗诱导了相关的 sTILs 富集，并在接受 NAT 后 HER2 阳性 BC 患者的 RD 中引起了免疫参数的有利变化。应测试新的免疫治疗策略，以实现 SC 特异性的抗肿瘤免疫反应。
试验注册号
NCT03144947 和 EudraCT 编号：2016-000435-41。
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