Research Summary

Disitamab Vedotin Plus Toripalimab Extends Survival in HER2-Expressing Urothelial Cancer

Edited by:
Ashton L. Stahl

Key Highlights

  • Combination therapy significantly prolonged progression-free survival (13.1 vs 6.5 months).
  • Overall survival improved to 31.5 months compared with 16.9 months with chemotherapy.
  • Objective response rate reached 76.1% with the combination versus 50.2% with chemotherapy.
  • Grade ≥ 3 treatment-related adverse events were less frequent with the combination regimen (55.1% vs 86.9%).

A multicenter, randomized phase 3 trial published in The New England Journal of Medicine reports that disitamab vedotin plus toripalimab improved clinical outcomes compared with standard chemotherapy in previously untreated patients with HER2-expressing locally advanced or metastatic urothelial cancer. The findings provide new evidence supporting the combination of HER2-targeted therapy with PD-1 inhibition in this population.

Researchers enrolled 484 adults with centrally confirmed HER2-expressing urothelial carcinoma and assigned participants 1:1 to receive either disitamab vedotin plus toripalimab every 2 weeks or gemcitabine with cisplatin or carboplatin every 3 weeks. Dual primary endpoints included progression-free survival and overall survival, as assessed by blinded independent review. Secondary endpoints included objective response and safety. The prespecified analysis was conducted after a median follow-up of 18.2 months.

Study Findings

Progression-free survival more than doubled in the disitamab vedotin-toripalimab group, reaching a median of 13.1 months versus 6.5 months with chemotherapy (hazard ratio for progression or death, 0.36; 95% CI, 0.28-0.46; P < .001). Overall survival was also significantly prolonged at 31.5 months compared with 16.9 months (hazard ratio for death, 0.54; 95% CI, 0.41-0.73; P < .001).

The objective response rates were higher with the combination therapy (76.1% vs 50.2%), and responses were consistent across prespecified subgroups. The median duration of response was 14.6 months in the combination arm and 5.6 months in the chemotherapy arm.

The safety analyses showed fewer high-grade adverse events with disitamab vedotin plus toripalimab. Grade ≥ 3 events occurred in 55.1% of combination-treated patients compared with 86.9% in the chemotherapy group. Hematologic toxicities were substantially less frequent with the combination, while aminotransferase elevations and peripheral neuropathy were more common but mostly mild.

Clinical Implications

According to the study authors, these findings suggest that disitamab vedotin plus toripalimab provides a clinically meaningful survival advantage over platinum-based chemotherapy in patients with previously untreated HER2-expressing urothelial cancer. The data support a biomarker-informed approach to first-line therapy and highlight the potential role of HER2-targeted antibody-drug conjugates combined with PD-1 blockade.

Expert Commentary

“Our trial showed significantly greater progression-free survival and overall survival with disitamab vedotin plus toripalimab than with chemotherapy in patients with untreated HER2-expressing locally advanced or metastatic urothelial cancer,” the researchers concluded.

Reference

Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. 2025;393(23):2324-2337. doi:10.1056/NEJMoa2511648