双功能融合蛋白靶向 TGF-β和 PD-L1 的 Bintrafusp alfa 治疗头颈部鳞状细胞癌的 I 期队列研究结果。
Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort.
机构信息
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, The Republic of Korea
Department of Medical Oncology, Hôpital Saint-André, University of Bordeaux-CHU, Bordeaux, France.
出版信息
J Immunother Cancer. 2020 Jul;8(2). doi: 10.1136/jitc-2020-000664.
BACKGROUND
We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).
METHODS
In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety.
RESULTS
As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 34%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths.
CONCLUSIONS
Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors.
TRIAL REGISTRATION NUMBER
NCT02517398.
背景
我们报告了 bintrafusp alfa 的临床活性和安全性，bintrafusp alfa 是一种首创的双功能融合蛋白，由转化生长因子β（TGF-β）RII 受体的细胞外结构域（TGF-β“陷阱”）与阻断程序性死亡配体 1（PD-L1）的人 IgG1 单克隆抗体融合而成，用于治疗经过大量预处理的头颈部鳞状细胞癌（SCCHN）患者。
方法
在这项 I 期剂量扩展队列研究中，患有无法治愈的晚期 SCCHN 患者，这些患者在复发/转移性疾病中铂类治疗后进展/复发，或在局部晚期疾病中铂类治疗后 <6 个月，接受 bintrafusp alfa 1200mg 静脉输注，每 2 周一次。主要终点是根据独立审查委员会（IRC）确认的最佳总缓解（BOR；实体瘤反应评估标准（RECIST）1.1）；其他终点包括研究者评估的 BOR 和安全性。
结果
截至 2018 年 8 月 24 日，32 名患者接受了 bintrafusp alfa 治疗（中位随访 86.4 周；范围 2-97）。根据 IRC，确认的客观缓解率（ORR）为 13%（95%CI4%-29%；4 例部分缓解（PR））；4 例患者疾病稳定（SD）（疾病控制率 34%；95%CI12%-43%）。根据研究者评估，有 5 例 PR（ORR，16%），包括 2 例患者在初始疾病进展后出现延迟 PR（总临床缓解率 22%）。在 PD-L1 阳性（12%）、PD-L1 阴性（17%；73-10 抗体用于免疫组化）、人乳头瘤病毒（HPV）阳性（33%）和 HPV 阴性肿瘤（5%）患者中观察到缓解（ORR）。11 名患者（34%）报告了 3 级治疗相关不良事件（TRAEs），无 4 级 TRAEs 或治疗相关死亡。
结论
bintrafusp alfa 在 PD-L1 表达亚组和 HPV 阳性肿瘤中显示出临床活性，并且在经过大量预处理的晚期 SCCHN 患者中具有可管理的安全性。与 PD-L1 抑制剂的历史数据相比，HPV 阳性肿瘤的活性更有利，并且正在一项正在进行的 HPV 相关肿瘤研究中进一步研究。
试验注册编号
NCT02517398。
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