同时抑制 TGF-β 和 PD-L1 通路提供了一种潜在的新型治疗方法。 Bintrafusp alfa 是一种首创的双功能融合蛋白，由 TGF-βRII（TGF-β“陷阱”）的胞外结构域与阻断 PD-L1 的人 IgG1 单克隆抗体融合组成，已在晚期 HCC 患者中进行了评估。在这项全球性开放标签 1 期研究 (NCT02517398) 中，患有 PD-L1 未选择的 HCC 且对 ≥1 种索拉非尼治疗失败或不耐受的患者每 2 周接受一次剂量递增的 bintrafusp alfa 1200 mg（n= 38) 或剂量扩展 (n=68) 队列，直至确认进展、不可接受的毒性或试验退出。主要终点是独立审查委员会根据实体瘤反应评估标准 1.1 制定的最佳总体反应 (BOR)。次要终点包括研究者评估的 BOR、安全性和药代动力学。剂量递增组和剂量扩展组的中位随访时间（范围）分别为 41.4 (39.8-44.2) 和 38.6 (33.5-39.7) 个月。客观缓解率 (ORR) 低于为评估 bintrafusp alfa 在两个队列中的疗效而设定的预先设定的 20% ORR 阈值（分别为 10.5% 和 8.8%）。剂量递增队列中的中位总生存期和无进展生存期分别为 13.8 个月和 1.5 个月，剂量扩展队列中的中位总生存期和无进展生存期分别为 13.5 个月和 1.4 个月。各队列中 78.9% 和 64.7% 的患者发生治疗相关不良事件（18.4% 和 25.0% 的患者发生≥3 级）。 Bintrafusp alfa 显示出中等的临床活性和安全性，与之前的 bintrafusp alfa 研究一致晚期 HCC 患者。版权所有 © 2024 美国肝病研究协会。

Simultaneous inhibition of the TGF-β and PD-L1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1, was evaluated in patients with advanced HCC.In this global, open-label, phase 1 study (NCT02517398), patients with PD-L1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n=38) or dose-expansion (n=68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. Primary endpoint was best overall response (BOR) per Response Evaluation Criteria in Solid Tumors 1.1 by independent review committee. Secondary endpoints included investigator-assessed BOR, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate (ORR) was below the prespecified 20% ORR threshold set to evaluate efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients).Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.Copyright © 2024 American Association for the Study of Liver Diseases.