双特异性抗体bintrafusp alfa在复发或转移性鼻咽癌患者中的疗效、安全性及相关生物标志物：一项II期临床试验
Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.
作者信息
Chiang Chi Leung, Lam Tai Chung, Li James Chun Bong, Chan Kenneth Sik Kwan, El Helali Aya, Lee Yolanda Yim Ping, Law Laalaa Hiu Ting, Zheng Danyang, Lo Anthony Wing Ip, Kam Ngar Woon, Li Wing Sum, Cheung Alice Ka Wai, Chow James Chung Hang, Chan Sunny Po Chung, Lai Jessica Wing Yu, Lee Sarah Wai Man, Kong Feng-Ming Spring, Ng Wai Tong, Kwong Dora Lai Wan, Lee Anne Wing Mui
机构信息
LKS Faculty of Medicine, Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong and University of Hong Kong-Shenzhen Hospital, China.
LKS Faculty of Medicine, Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, China.
出版信息
Lancet Reg Health West Pac. 2023 Sep 6;40:100898. doi: 10.1016/j.lanwpc.2023.100898. eCollection 2023 Nov.
BACKGROUND
The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients.
METHODS
In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety.
FINDINGS
Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR.
INTERPRETATION
Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning.
FUNDING
The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.
背景
转化生长因子-β（TGF-β）和程序性死亡受体-1配体（PD-L1）通路双重阻断策略此前尚未在铂类难治性复发或转移性鼻咽癌（R/M NPC）患者中进行过试验。本研究旨在评估双特异性抗体bintrafusp alfa在难治性R/M NPC患者中的安全性和疗效。
方法
在这项单臂、单中心的II期临床试验中，纳入了38例经组织学确诊的R/M NPC患者，每2周给予bintrafusp alfa治疗。主要终点是根据实体瘤疗效评价标准1.1版（RECIST v1.1）评估的客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、总生存期（OS）、缓解持续时间（DOR）和安全性。
结果
共纳入38例患者（33例男性；中位年龄54岁）。ORR为23.7%（完全缓解2例；部分缓解7例）。中位DOR为19.2个月，中位PFS为2.3个月，中位OS为17.0个月，1年OS率为63.2%。遗憾的是，25例患者（65.7%）在治疗8周内病情进展，分别根据RECIST v1.1和肿瘤生长率（TGR）比值，有15例患者（39.5%）和8例患者（21.1%）出现超进展性疾病（HPD）。16例患者（42.4%）发生≥3级治疗相关不良事件（TRAEs），最常见的是贫血（9例，23.7%）和继发性恶性肿瘤（4例，10.5%）。TRAEs导致7例患者永久停药。在第8周时血浆TGFβ1水平受到强烈抑制的患者意外地与较差的ORR（9.1%对44.4%，P = 0.046）和HPD的发生相关。PD-L1表达与ORR之间无相关性。
解读
Bintrafusp alfa在R/M NPC中显示出一定活性，但HPD发生率高以及TRAEs导致的高停药率令人担忧。
资助
该项目由雅丽氏何妙龄那打素慈善基金教授席捐赠基金和默克公司资助。
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