Disitamab Vedotin plus Toripalimab in HER2-Expressing Advanced Urothelial Cancer
Mené sur 484 patients atteints d'un cancer urothélial HER2+ et de stade localement avancé ou métastatique (durée médiane de suivi : 18,2 mois), cet essai multicentrique de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité du toripalimab en combinaison avec le disitamab védotin
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.)
New England Journal of Medicine , résumé, 2025