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.
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. Research Summary Disitamab Vedotin–Toripalimab in HER2-Expressing Urothelial Cancer
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
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.)
Small testing size, but still with high overall response rate (32%) with progression-free survival of 5.6 months. Now, this is not randomized and is after failure of check point inhibitors. Of note this medication will not be marketed for second line therapy since it did not show overall survival advantage.
Both medications are approved as a single agent in second-filine therapy, and now the combination seems to be promising with manageable toxicity. Overall Response Rate (ORR): 41% I think we need phase 3 data to show superiority over single agent therapy. And now with pembrolizumab used in first-line therapy, this regimen may disappear.
This antibody doublet is essentially the new SOC in met-urothelial cancer. The anti-PD1 and ADC combination is compelling in many ways and the survival outcomes compared to chemo were very significant. This combination is on NCCN, as well.
This is a negative study looking at atezolizumab + chemo vs. chemo alone in metastatic urothelial carcinoma. In the same issue, there is a negative study on atezolizumab vs. chemo alone, as well. It does seem that atezolizumab has limited disease activity versus some comparable agents.
Erdafatinib was compared to chemo in the >=2nd line in patients who had FGFR2/3 mutations, fusions or alterations with metastatic bladder cancer. Survival endpoints were superior in the targeted group with a overall survival of 12 vs. eight months. In my experience, the challenge with this group of targeted agents is tolerability.