Disitamab Vedotin plus Toripalimab in HER2-Expressing Advanced Urothelial Cancer

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate monotherapy has shown preliminary clinical efficacy in patients with chemotherapy-refractory HER2-positive locally advanced or metastatic urothelial cancer. Previous data showed promising antitumor activity and safety of HER2-specific disitamab vedotin as monotherapy and when combined with programmed cell death protein 1 (PD-1)-directed immunotherapy in this cancer. METHODS: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with previously untreated HER2-expressing (immunohistochemical score of 1+, 2+, or 3+) locally advanced or metastatic urothelial cancer in a 1:1 ratio to receive either disitamab vedotin plus PD-1-specific toripalimab every 2 weeks or chemotherapy (gemcitabine plus cisplatin or carboplatin) every 3 weeks. The dual primary end points were progression-free survival (assessed by blinded independent review) and overall survival. Secondary end points included objective response and safety. Here we report the prespecified progression-free survival analysis and interim overall survival analysis. RESULTS: A total of 484 patients underwent randomization. The median follow-up was 18.2 months. Progression-free survival was significantly longer in the disitamab vedotin-toripalimab group than in the chemotherapy group (median, 13.1 vs. 6.5 months; hazard ratio for progression or death, 0.36; 95% confidence interval [CI], 0.28 to 0.46; P<0.001). Overall survival was also significantly longer in the disitamab vedotin-toripalimab group than in the chemotherapy group (median, 31.5 vs. 16.9 months; hazard ratio for death, 0.54; 95% CI, 0.41 to 0.73; P<0.001). The percentage of patients with an objective response was 76.1% (95% CI, 70.3 to 81.3) in the disitamab vedotin-toripalimab group and 50.2% (95% CI, 43.7 to 56.7) in the chemotherapy group. The safety profile of disitamab vedotin plus toripalimab was more favorable than that of chemotherapy; grade 3 or higher treatment-related adverse events occurred in 55.1% of patients who received disitamab vedotin plus toripalimab and 86.9% of those who received chemotherapy. CONCLUSIONS: Disitamab vedotin-toripalimab led to a significantly greater improvement in outcomes than chemotherapy among patients with untreated HER2-expressing locally advanced or metastatic urothelial cancer. (Funded by RemeGen and others; RC48-C016 ClinicalTrials.gov number, NCT05302284; ChinaDrugTrials.org.cn number, CTR20220348.).