Vlachou Evangelia, Johnson Burles Avner, McConkey David, Jing Yuezhou, Matoso Andres, Hahn Noah M, Hoffman-Censits Jean
Department of Urology, The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, United States.
Department of Oncology, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Front Oncol. 2024 Jun 12;14:1377842. doi: 10.3389/fonc.2024.1377842. eCollection 2024.
Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR).
Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model.
Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925).
In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.
恩杂鲁胺（EV）是一种被批准用于晚期尿路上皮癌的抗体药物偶联物，由与靶向nectin-4的人单克隆抗体连接的单甲基澳瑞他汀E有效载荷组成。目前尚无经过验证的可预测或与EV反应相关的生物标志物。皮肤毒性是最常见的与EV相关的毒性之一，通常在早期周期出现。这项对接受EV单药治疗的尿路上皮癌患者的回顾性研究评估了与EV相关的皮肤毒性是否与包括无进展生存期（PFS）、总生存期（OS）和总缓解率（ORR）在内的改善结局相关。
确定在约翰霍普金斯医院接受EV单药治疗的患者，并通过病历审查提取基线特征、治疗和毒性细节。计算单变量Cox风险比（HR），以评估基线患者特征和皮肤毒性对PFS和OS的影响。基于单变量分析和已知风险因素，所有后续分析均针对以下因素进行调整：东部肿瘤协作组（ECOG）体能状态、基线时的内脏转移、性别以及EV剂量和体重，以考虑剂量差异。使用多变量Cox比例HR比较有和无皮肤毒性的患者之间的PFS和OS，将毒性和EV剂量作为时间依赖性变量进行评估。使用泊松回归模型计算调整后的p值，以比较各组之间的ORR和疾病控制率（DCR）。
在分析的78例患者中，42例（53.8%）出现了与EV相关的皮肤毒性，这些毒性在治疗早期出现（从开始使用EV起，中位发生时间为0.5个月）。皮肤毒性与OS显著改善相关[HR，0.48；95%置信区间（CI），0.25，0.9；P = 0.0235]、ORR（68.3%对20.7%，P = 0.0033）和DCR（82.9%对48.3%，P = 0.0122）。皮肤毒性组的中位PFS在数值上更长（6.3对1.
