Zhou L, Yang K W, Zhang S, Yan X Q, Li S M, Xu H Y, Li J, Liu Y Q, Tang B X, Chi Z H, Si L, Cui C L, Guo H Q, He Z S, Guo J, Sheng X
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital, Beijing, China.
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center of China, Beijing, China.
Ann Oncol. 2025 Mar;36(3):331-339. doi: 10.1016/j.annonc.2024.12.002. Epub 2024 Dec 9.
Human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates (ADCs) such as disitamab vedotin (DV) and trastuzumab deruxtecan (T-DXd) have emerged as effective treatment options and received regulatory approvals for HER2-expressing locally advanced or metastatic urothelial carcinoma (la/mUC). In addition, ADCs in combination with immunotherapy have demonstrated antitumor activity. The current study aimed to evaluate the combination of DV and toripalimab in patients with la/mUC.
This open-label phase Ib/II study enrolled patients with untreated or chemo-refractory la/mUC. During the dose-escalation phase, DV was administered at escalating doses of 1.5 and 2.0 mg/kg in combination with toripalimab 3.0 mg/kg once every 2 weeks. Primary endpoints were safety and the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
From August 2020 to December 2021, a total of 41 patients were enrolled, including 6 in the dose-escalation phase and 35 in the dose-expansion phase. Sixty-one percent of patients were treatment naive. No dose-limiting toxicity was observed. The RP2D was determined as DV (2.0 mg/kg) plus toripalimab (3.0 mg/kg). By the data cut-off date of 1 March 2024, the confirmed ORR was 73.2%. The median PFS was 9.3 months, and the median OS was 33.1 months. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (65.9%), alanine aminotransferase increased (63.4%), and peripheral sensory neuropathy (63.4%). Grade 3 or higher TRAEs occurred in 51.2% of patients, with the most common being γ-glutamyltransferase increased (12.2%), asthenia (9.8%), and alanine aminotransferase increased (7.3%). One treatment-related death (due to pneumonitis) was reported.
The combination of DV and toripalimab demonstrated promising response rate and OS results with a manageable safety profile in HER2-unselected la/mUC patients. This combination represents a promising first-line option for la/mUC. Randomized phase III study is currently ongoing.
人表皮生长因子受体2（HER2）靶向抗体药物偶联物（ADC），如迪西他单抗维汀（DV）和曲妥珠单抗德鲁替康（T-DXd），已成为有效的治疗选择，并已获得监管部门批准用于治疗HER2表达的局部晚期或转移性尿路上皮癌（la/mUC）。此外，ADC与免疫疗法联合使用已显示出抗肿瘤活性。本研究旨在评估DV与托瑞帕利单抗联合治疗la/mUC患者的疗效。
这项开放标签的Ib/II期研究纳入了未经治疗或化疗难治性la/mUC患者。在剂量爬坡阶段，DV以1.5和2.0mg/kg的递增剂量给药，与托瑞帕利单抗3.0mg/kg联合使用，每2周一次。主要终点是安全性和推荐的II期剂量（RP2D）。次要终点包括客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。
从2020年8月至2021年12月，共纳入41例患者，其中6例在剂量爬坡阶段，35例在剂量扩展阶段。61%的患者为初治患者。未观察到剂量限制性毒性。RP2D确定为DV（2.0mg/kg）加托瑞帕利单抗（3.0mg/kg）。截至2024年3月1日的数据截止日期，确认的ORR为73.2%。中位PFS为9.3个月，中位OS为33.1个月。最常见的治疗相关不良事件（TRAEs）为天冬氨酸转氨酶升高（65.9%）、丙氨酸转氨酶升高（63.4%）和周围感觉神经病变（63.4%）。51.2%的患者发生3级或更高等级的TRAEs，最常见的是γ-谷氨酰转移酶升高（12.2%）、乏力（9.8%）和丙氨酸转氨酶升高（7.3%）。报告了1例与治疗相关的死亡（由于肺炎）。
DV与托瑞帕利单抗联合使用在未选择HER2的la/mUC患者中显示出有前景的缓解率和OS结果，安全性可控。这种联合治疗方案是la/mUC有前景的一线治疗选择。目前正在进行随机III期研究。
