First-line treatment with disitamab vedotin plus toripalimab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to standard platinum-based chemotherapy in patients with HER2-expressing locally advanced or metastatic urothelial carcinoma. 

These findings from the first interim analysis of the phase 3 RC48-C016 trial were presented at the 2025 European Society of Medical Oncology (ESMO) Congress in Berlin, Germany.

Building on earlier phase 1b/2 findings in both untreated and chemotherapy-refractory urothelial carcinoma (Zhou et al, Ann Oncol 2024), this multicenter, open-label study enrolled 484 patients with previously untreated, unresectable locally advanced or metastatic urothelial carcinoma and centrally confirmed HER2 expression (IHC 1+, 2+, or 3+). 

Participants were randomized 1:1 to receive disitamab vedotin plus toripalimab or chemotherapy (gemcitabine with cisplatin or carboplatin). Randomization was stratified by cisplatin eligibility, visceral metastases, and HER2 expression level. The dual primary end points were blinded independent review committee (BIRC)–assessed PFS and OS.

After a median follow-up of 18.2 months, disitamab vedotin plus toripalimab produced a markedly superior PFS compared with chemotherapy: 13.1 vs 6.5 months (hazard ratio [HR], 0.36 (95% confidence interval [CI], 0.28 to 0.46; P <.0001). The benefit extended to OS, with a median OS of 31.5 months for disitamab vedotin plus toripalimab vs 16.9 months for chemotherapy (HR, 0.54; 95% CI, 0.41 to 0.73; P <.0001). These improvements were consistent across all prespecified subgroups, including cisplatin-eligible and -ineligible patients, those with or without visceral metastases, and across HER2 expression levels.

The BIRC-assessed objective response rate (ORR) reached 76.1% with disitamab vedotin plus toripalimab and 50.2% with chemotherapy. In addition, investigator assessments of PFS and tumor response were aligned with the BIRC findings. Median duration of response data were not reported at this interim analysis, but responses appeared durable and sustained across subgroups.

Importantly, the safety profile favored disitamab vedotin plus toripalimab, with grade ≥3 treatment-related adverse events observed in 55.1% of patients vs 86.9% in the chemotherapy arm. No unexpected safety signals emerged, and treatment discontinuations due to toxicity were less frequent in the disitamab vedotin plus toripalimab arm.

The trial investigators concluded that these results establish disitamab vedotin plus toripalimab as a potential new first-line standard of care for patients with HER2-expressing locally advanced or metastatic urothelial carcinoma, offering unprecedented improvements in both PFS and OS with a more tolerable safety profile than platinum-based chemotherapy.

Source:

Guo J, Sheng X, Zeng G, et al. 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 the 2025 ESMO Congress; October 17-21, 2025. Berlin, Germany. LBA7