Disitamab vedotin plus toripalimab in patients with locally advanced or metastatic urothelial carcinoma (RC48-C014): a phase 1b/2 dose-escalation and dose-expansion study.

Abstract

Background: 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 anti-tumor activity. The current study aimed to evaluate the combination of DV and toripalimab in patients with la/mUC.

Patients and methods: This open-label phase 1b/2 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 two weeks. Primary endpoints were safety and the recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results: From August 2020 to December 2021, a total of forty-one patients were enrolled, including six in the dose-escalation phase, and thirty-five in the dose-expansion phase. Sixty-one percent of patients were treatment naïve. 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 cutoff date of March 1, 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 gamma-glutamyltransferase increased (12.2%), asthenia (9.8%), and alanine aminotransferase increased (7.3%). One treatment-related death (due to pneumonitis) was reported.

Conclusions: The combination of DV and toripalimab demonstrated promising response rate and overall survival 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.