PURPOSE To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. METHODS EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4–expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti–PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. RESULTS Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti–PD-(L)1 treatment, liver metastases, or upper-tract disease. CONCLUSION Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

中文翻译：

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EV-101：单药 Enfortumab Vedotin 在 Nectin-4 阳性实体瘤（包括转移性尿路上皮癌）患者中的 I 期研究

目的 评估 enfortumab vedotin (EV) 的安全性/耐受性和抗肿瘤活性，EV 是一种新型研究性抗体-药物偶联物，可将微管破坏剂单甲基 auristatin E 递送至表达 Nectin-4 的细胞。方法 EV-101 是一项 I 期剂量递增/扩展研究，纳入了表达 Nectin-4 的实体瘤（例如，转移性尿路上皮癌 [mUC]）的患者，这些患者在 ≥ 1 次先前的化疗方案和/或程序性死亡 1 受体上取得进展/ 程序性死亡配体-1 [PD-(L)1] 抑制剂，包括一组先前接受过抗 PD-(L)1 治疗的 mUC 患者。患者在每 28 天周期的第 1、8 和 15 天接受递增剂量的 EV 至 1.25 mg/kg。主要目标是评估安全性/耐受性和药代动力学；抗肿瘤活性是次要目标。结果 入组的 mUC 患者 (n = 155) 接受了大量预处理，其中 96% 的患者既往接受过基于铂的化疗，29% 的患者接受过 ≥ 3 线的既往治疗。未确定 EV 的最大耐受剂量；然而，推荐的 II 期剂量被确定为 1.25 mg/kg。皮疹、周围神经病变、疲劳、脱发和恶心是最常见的治疗相关不良事件 (TRAE)；最常见的 TRAE 严重程度为 1-2 级。在接受 EV 1.25 mg/kg 单药治疗的 112 名 mUC 患者中，研究者评估确认的客观缓解率 (ORR) 为 43%，缓解持续时间为 7.4 个月。中位总生存期（OS）为12.3个月，1年OS率为51.8%。在 ≥ 75 岁接受或未接受抗 PD-(L)1 治疗的患者中观察到相似的 ORR 和估计的中位 OS，肝转移或上消化道疾病。结论 单药 EV 通常耐受性良好，并在 mUC 患者中提供具有临床意义和持久的反应；生存数据令人鼓舞。一项关键的 II 期和一项验证性 III 期研究正在进行中。