Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC.

IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Hepatology Pub Date : 2025-01-01 Epub Date: 2024-08-13 DOI:10.1097/HEP.0000000000001054
Ho Yeong Lim, Jeong Heo, Julio A Peguero, Baek-Yeol Ryoo, Thomas Decaens, Fabrice Barlesi, Markus H Moehler, Genevieve Jehl, S Peter Eggleton, Marcis Bajars, James L Gulley
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Abstract

Background and aims: Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 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 programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC.

Approach and results: In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1-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. The primary endpoint was the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Secondary endpoints included investigator-assessed best overall response, 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 was below the prespecified 20% objective response rate threshold set to evaluate the 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).

Conclusions: Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.

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bintrafusp alfa 在两个晚期肝细胞癌 1 期扩增队列中的疗效和安全性。
背景和目的: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单克隆抗体融合而成:在这项全球性、开放标签的1期研究(NCT02517398)中,PD-L1未被选择的HCC患者在接受索拉非尼治疗≥1个疗程失败或不耐受后,在剂量递增(38例)或剂量扩大(68例)队列中接受宾特法昔单抗1200毫克,每2周1次,直至确诊病情进展、出现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《实体瘤反应评价标准 1.1》确定的最佳总体反应(BOR)。次要终点包括研究者评估的最佳总反应、安全性和药代动力学。剂量递增组和剂量扩大组的中位随访时间(范围)分别为41.4(39.8-44.2)个月和38.6(33.5-39.7)个月。两个队列的客观反应率(ORR)均低于为评估宾特法昔单抗疗效而预先设定的20%的ORR阈值(分别为10.5%和8.8%)。剂量递增队列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,剂量扩大队列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。78.9%和64.7%的患者在各自队列中发生了与治疗相关的不良事件(18.4%和25.0%的患者≥3级):Bintrafusp alfa在晚期HCC患者中显示出适度的临床活性和安全性,与之前的bintrafusp alfa研究结果一致。
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来源期刊
Hepatology
Hepatology 医学-胃肠肝病学
CiteScore
27.50
自引率
3.70%
发文量
609
审稿时长
1 months
期刊介绍: HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.
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Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Controversies regarding albumin therapy in cirrhosis. A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma. FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1. Alternatives to animal testing to assess MASH drugs and hepatotoxicity.
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