布勒姆塔图格·富韦多汀（BFv，9MW2821），一种新一代靶向Nectin-4的抗体药物偶联物，用于晚期实体瘤患者：一项首次人体、开放标签、多中心、I/II期研究。

Bulumtatug Fuvedotin (BFv, 9MW2821), a next-generation Nectin-4 targeting antibody-drug conjugate, in patients with advanced solid tumors: a first-in-human, open-label, multicenter, phase I/II study.

作者信息

Zhang J, Liu R, Wang S, Feng Z, Yang H, Gao S, Li X, Yao X, Chen J, Gong Z, Li Y, Li X, Wang S, Hu C, Liu J, Zhang M, Yuan F, Shi B, Lou H, Zhao P, Qiu F, Guo H, Hu B, Xu D, Huang H, Zhang X, Feng M, Wang X, Li G, Liu D, Chen X, Wang P

机构信息

Phase I Unit, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

出版信息

Ann Oncol. 2025 Apr 25. doi: 10.1016/j.annonc.2025.04.009.

DOI:10.1016/j.annonc.2025.04.009

PMID:40288679

Abstract

BACKGROUND

A first-in-human study was carried out to assess the safety and preliminary antitumor activity of bulumtatug fuvedotin (BFv; 9MW2821), a next-generation monoclonal antibody-drug conjugate (ADC) that delivers monomethylauristatin E (MMAE) to cells expressing Nectin-4, in patients with advanced solid tumors.

PATIENTS AND METHODS

This was a first-in-human, open-label, multicenter study and included dose escalation, dose expansion and cohort expansion periods. Patients with advanced solid tumors who failed one or more lines of systemic therapy were recruited to receive BFv by intravenous (IV) infusion at doses of 0.33-1.5 mg/kg on days 1, 8 and 15 of each 28-day cycle. Primary objective was assessment of safety and preliminary efficacy. (NCT05216965, CTR20220106).

RESULTS

Between 11 June 2022 and 3 Apr 2024, 274 patients were enrolled, including 51 with urothelial cancer, 62 with cervical cancer, 49 with esophageal cancer, 20 with triple-negative breast cancer and 92 with other solid tumors. In the dose escalation phase, one dose-limiting toxicity was observed in the 1.5 mg/kg group, which was grade 4 neutropenia that lasted >5 days. Maximum tolerated dose of BFv was not reached. However, the recommended phase II dose was identified as 1.25 mg/kg based on a balance of safety and efficacy. The most common grade ≥3 treatment-related adverse events were decreased neutrophil count, decreased white blood cell count, anemia, increased gamma-glutamyl transferase (GGT) with rash, and peripheral sensory neuropathy in the 1.25 mg/kg group. Among 221 patients assessable for efficacy in 1.25 mg/kg group, objective response rates were 54.1%, 32.1%, 14.0% and 50% in urothelial cancer, cervical cancer, esophageal cancer and triple-negative breast cancer, respectively.

CONCLUSIONS

The results suggest that BFv was tolerable and clinically significant in efficacy in various types of solid tumors besides urothelial cancer. Several pivotal trials are currently in progress (NCT06196736, NCT06592326, NCT06692166).

摘要

背景

开展了一项首次人体研究，以评估下一代单克隆抗体药物偶联物（ADC）布伦他妥富沃多汀（BFv；9MW2821）在晚期实体瘤患者中的安全性和初步抗肿瘤活性，该药物可将单甲基澳瑞他汀E（MMAE）递送至表达Nectin-4的细胞。

患者和方法

这是一项首次人体、开放标签、多中心研究，包括剂量爬坡、剂量扩展和队列扩展期。招募了一线或多线全身治疗失败的晚期实体瘤患者，在每28天周期的第1、8和15天通过静脉输注接受剂量为0.33 - 1.5mg/kg的BFv。主要目标是评估安全性和初步疗效。（NCT05216965，CTR20220106）。

结果

在2022年6月11日至2024年4月3日期间，共入组274例患者，其中51例为尿路上皮癌患者，62例为宫颈癌患者，49例为食管癌患者，20例为三阴性乳腺癌患者，92例为其他实体瘤患者。在剂量爬坡阶段，1.5mg/kg组观察到1例剂量限制性毒性，为持续超过5天的4级中性粒细胞减少。未达到BFv的最大耐受剂量。然而，基于安全性和疗效的平衡，确定推荐的II期剂量为1.25mg/kg。在1.25mg/kg组中，最常见的≥3级治疗相关不良事件为中性粒细胞计数减少、白细胞计数减少、贫血、γ-谷氨酰转移酶（GGT）升高伴皮疹以及周围感觉神经病变。在1.25mg/kg组中可评估疗效的221例患者中，尿路上皮癌、宫颈癌、食管癌和三阴性乳腺癌的客观缓解率分别为54.1%、32.1%、14.0%和50%。