Disitamab vedotin plus toripalimab significantly extends survival vs chemotherapy in la/mUC

The combination of disitamab vedotin (DV) plus toripalimab (T; Loqtorzi) nearly doubled progression-free survival (PFS) and overall survival (OS) vs chemotherapy in patients with HER2-expressing locally advanced/metastatic urothelial carcinoma (la/mUC), according to data from the phase 3 RC48-C016 trial (NCT05302284).¹

The findings, which represent a potential new standard of care in this patient population, were met by rounds of applause during a Presidential Symposium at the 2025 European Society for Medical Oncology (ESMO) Congress.

“The phase 3 RC48-C016 study demonstrated for the first time superiority of an anti-HER2 antibody drug conjugate plus an anti-PD1 inhibitor in a biomarker-selected patient population with la/mUC,” explained presenting author Jun Guo, MD, of Peking University during the presentation.

In total, the study included 484 patients who were randomly assigned to receive DV plus T (n = 243) or to gemcitabine plus cisplatin/carboplatin for a maximum of 6 cycles (n = 241). Patients were eligible for enrollment if they had no prior systemic treatment for unresectable la/mUC; measurable disease per RECIST v1.1; central lab-confirmed HER2 expression per immunohistochemistry 1+, 2+, or 3+; and an ECOG performance score of 0 or 1.

Baseline characteristics were well-balanced between both arms. Notably, 45.7% of patients in the DV plus T arm and 50.6% of patients in the chemotherapy arm had upper tract urothelial carcinoma. The dual primary end points were PFS per blinded independent central review (BIRC) and OS.

Overall, the combination of DV plus T significantly extended PFS and OS vs chemotherapy.

Specifically, the median PFS was 13.1 months (95% CI, 11.1 to 16.7) in the DV plus T arm vs 6.5 months (95% CI, 5.7 to 7.4) in the chemotherapy arm, translating to a 64% reduction in the risk of disease progression or death (HR, 0.36; 95% CI, 0.28 to 0.46; P < .0001). The PFS benefit was consistent across all pre-specified subgroups.
Further, the combination led to a statistically significant and clinically meaningful 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.41 to 0.73; P < .0001). At a median follow-up of 18.2 months, the median OS was 31.5 months (95% CI, 21.7 to NE) in the DV plus T arm compared with 16.9 months (95% CI, 14.6 to 21.7) in the chemotherapy arm. Like PFS, the OS benefit was consistent across all pre-specified subgroups.

Treatment with DV plus T also led to significant tumor response. Overall, the objective response rate (ORR) per BIRC was 76.1% in the DV plus T arm vs 50.2% in the chemotherapy arm (RD, 26%; 95% CI, 17.6 to 34.1). ORR per the investigators was 71.6% vs 49.8%, respectively (RD, 21.9%; 95% CI, 13.3 to 30.2). The median duration of response was 14.6 months (95% CI, 11.3 to 18.7) in the DV plus T arm compared with 5.6 months (95% CI, 5.3 to 5.8) in the chemotherapy arm.

Notably, 64.7% of patients in the chemotherapy arm received at least 1 subsequent systemic anticancer therapy, of whom 40.2% received an anti-HER2 containing therapy. In the DV plus T arm, 27.2% of patients received at least 1 subsequent systemic anticancer therapy, of whom 2.1% received an anti-HER2 containing therapy.

Safety data also favored the DV plus T arm. Specifically, the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was 55.1% in the DV plus T arm vs 86.9% in the chemotherapy arm. The most common TRAEs in the combination arm were increased aspartate aminotransferase (49.4%), increase alanine aminotransferase (43.6%), and anemia (41.6%).

Based on these findings, Guo concluded, “Disitamab vedotin plus toripalimab offers a valuable new treatment option and represents a potential new standard of care for the first-line treatment of patients with HER2-expressing la/mUC.”

REFERENCE

1. Disitamab vedotin (DV) plus toripalimab (T) versus chemotherapy (C) in first-line (1L) locally advanced or metastatic urothelial carcinoma (la/mUC) with HER2-expression. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA7. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA7.html.pdf