Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study.

4566 Background: Disitamab vedotin has shown promising data across a spectrum of HER2 expression in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who progressed on chemotherapy. This study was conducted to evaluate the safety and efficacy of disitamab vedotin plus anti-PD-1 antibody in advanced urothelial carcinoma. Methods: This is an open-label, multicenter, phase 1b/2 trial to evaluate the safety and activity of RC48-ADC combined with toripalimab, a humanized immunoglobin G 4 monoclonal antibody against PD-1 in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression assessed by the investigators, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: Forty-one la/mUC patients were enrolled (22 males; median age 66 y [42-76]; 61% treatment-naïve). 54% of patients had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression IHC 2+ or 3+ was in 59% patients, and PD-L1 positive in 32%. No dose-limiting toxicity was observed and the recommended dose was RC48-ADC 2mg/kg plus toripalimab 3mg/kg every two weeks. By the cutoff date of 18 November 2022, the confirmed ORR was 73.2% (95%CI: 57.1, 85.8), including 9.8% CR. The ORR was 76.0% for treatment-naïve patients. In HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, the ORR was 83.3%, 64.3%, and 33.3%, respectively. The ORR was 61.5% and 78.6% in PD-L1 positive and negative subgroups. DCR was 90.2% (95% CI, 76.9–97.3), with a median progression-free survival (PFS) of 9.2 months (95%CI: 5.7-10.3) and 2-year overall survival (OS) rate of 63.2%. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (68.3%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), γ-glutamyl transferase increase (56.1%), hypertriglyceridemia (53.7%), and appetite decrease (51.2%). Grade 3 or greater TRAEs occurred in 43.9% of patients. Twenty-three patients (56.1%) had immune-related AEs (14.6% ≥ G3), including immune-related skin reactions, hyperglycemia, pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with la/mUC and a manageable safety profile. A phase 3 study is currently ongoing to compare the safety and efficacy of this regimen with standard of care. Clinical trial information: NCT04264936 .