Phase 2 Trial of Enfortumab Vedotin in Patients With Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma in China

IF 2.9 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2024-11-12 DOI:10.1002/cam4.70368

Siming Li, Yanxia Shi, Haiying Dong, Hongqian Guo, Yu Xie, Zhongquan Sun, Xiaoping Zhang, Eric Kim, Jun Zhang, Yue Li, Chenming Xu, Haishan Kadeerbai, Sue Lee, Seema Gorla, Jun Guo, Xinan Sheng

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Abstract

Background

Enfortumab vedotin, a fully human monoclonal antibody–drug conjugate (ADC) directed to Nectin-4, prolonged overall survival (OS) versus standard chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma (mUC) previously receiving a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor and platinum-based chemotherapy in the pivotal, phase 3 EV-301 clinical trial, supporting global approvals of enfortumab vedotin monotherapy. This bridging study was the first to evaluate enfortumab vedotin monotherapy in previously treated Chinese patients with locally advanced or mUC.

Methods

EV-203 was a multicenter, open-label, phase 2 study (NCT04995419) assessing efficacy, safety/tolerability, pharmacokinetics (PK), and immunogenicity of enfortumab vedotin in 40 Chinese patients (PK analysis set, n = 13) with previously treated locally advanced or mUC. Patients received enfortumab vedotin 1.25 mg/kg (Days 1, 8, and 15). Primary endpoints included confirmed objective response rate (ORR) by the independent review committee (IRC) and PK parameters of ADC, total antibody (TAb), and free monomethyl auristatin E (MMAE). Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; immunogenicity; and safety/tolerability.

Results

As of May 13, 2022, the median follow-up was 6.5 months. Confirmed ORR was 37.5% (n/N = 15/40; 95% CI: 22.7%–54.2%) by IRC and 42.5% (n/N = 17/40; 95% CI: 27.0%–59.1%) by investigator assessment. By IRC, DCR was 72.5% (n = 29), median DOR was not reached, and median PFS was 4.7 months. Median OS was not reached. Endpoints assessed by investigators were consistent with IRC assessments. Two patients discontinued treatment for treatment-related adverse events. No new safety signals were identified. ADC, TAb, and free MMAE were characterized in Chinese patients and consistent with previously characterized populations. The incidence of positive antitherapeutic antibodies postbaseline was 0%.

Conclusion

Enfortumab vedotin demonstrated meaningful clinical activity with a manageable safety profile in Chinese patients with previously treated locally advanced or mUC.

Trial Registration

ClinicalTrials.gov identifier: NCT04995419

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中国恩福单抗维多汀治疗既往接受过治疗的局部晚期或转移性尿路上皮癌患者的 2 期试验。

研究背景Enfortumab vedotin是一种针对Nectin-4的全人源单克隆抗体-药物共轭物（ADC），与标准化疗相比，在关键的3期EV-301临床试验中，它延长了既往接受过程序性细胞死亡蛋白1/配体1（PD-1/L1）抑制剂和铂类化疗的局部晚期或转移性尿路上皮癌（mUC）患者的总生存期（OS），为enfortumab vedotin单药治疗获得全球批准提供了支持。这项桥接研究首次评估了恩福单抗韦多汀在既往接受过治疗的中国局部晚期或mUC患者中的单药治疗效果：EV-203是一项多中心、开放标签的2期研究（NCT04995419），评估了恩福鲁单抗维多汀在40例既往接受过局部晚期或mUC治疗的中国患者（PK分析组，n = 13）中的疗效、安全性/耐受性、药代动力学（PK）和免疫原性。患者接受1.25 mg/kg 恩福单抗维多汀治疗（第1、8和15天）。主要终点包括独立审查委员会（IRC）确认的客观反应率（ORR），以及ADC、总抗体（TAb）和游离一甲基乌司他丁E（MMAE）的PK参数。次要终点包括研究者评估的确证 ORR；研究者/独立审查委员会评估的应答持续时间（DOR）、疾病控制率（DCR）和无进展生存期（PFS）；OS；免疫原性；以及安全性/耐受性：截至 2022 年 5 月 13 日，中位随访时间为 6.5 个月。经IRC确认的ORR为37.5%（n/N = 15/40；95% CI：22.7%-54.2%），经研究者评估的ORR为42.5%（n/N = 17/40；95% CI：27.0%-59.1%）。经 IRC 评估，DCR 为 72.5%（n = 29），中位 DOR 未达标，中位 PFS 为 4.7 个月。未达到中位OS。研究者评估的终点与 IRC 评估一致。两名患者因治疗相关不良事件而中断治疗。未发现新的安全性信号。中国患者的 ADC、TAb 和游离 MMAE 的特征与之前的人群特征一致。基线后抗治疗抗体阳性发生率为0%：结论：恩福妥单抗维多汀在既往接受过局部晚期或mUC治疗的中国患者中显示出有意义的临床活性和可控的安全性：试验注册：ClinicalTrials.gov identifier：NCT04995419。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.