In a Chinese phase III trial (RC48-C016) reported at the recent ESMO Congress and in The New England Journal of Medicine, Sheng et al found that the combination of the HER2-directed antibody-drug conjugate disitamab vedotin and the PD-1 inhibitor toripalimab-tpzi improved progression-free survival and overall survival vs platinum-based chemotherapy in patients with previously untreated, HER2-expressing, advanced or metastatic urothelial cancer.
Study Details
In the open-label multicenter trial, 484 patients with HER2-expressing disease (immunohistochemical score of 1+, 2+, or 3+) were randomly assigned to receive disitamab vedotin at 2.0 mg/kg and toripalimab at 3 mg/kg once every 2 weeks (n = 243) or chemotherapy (n = 241) consisting of gemcitabine at 1,000 mg/m2 on days 1 and 8 plus either cisplatin at 70 mg/m2 or carboplatin at an AUC of 4.5 on day 1 of 3-week cycles. Treatment continued until disease progression or unacceptable toxicity. The dual primary endpoints were progression-free survival on blinded independent review and overall survival.
Key Findings
Median progression-free survival was 13.1 months (95% confidence interval [CI] = 11.1–16.7 months) in the disitamab vedotin/toripalimab group vs 6.5 months (95% CI = 5.7–7.4 months) in the chemotherapy group (stratified hazard ratio [HR] = 0.36, 95% CI = 0.28–0.46, P < .001). The rate at 12 months was 54.5% vs 16.2%.
Subsequent anticancer therapy was received by 31.7% of the disitamab vedotin/toripalimab group vs 67.2% of the chemotherapy group.
In an interim analysis of overall survival, median overall survival was 31.5 months (95% CI = 21.7 months to not reached) with disitamab vedotin plus toripalimab vs 16.9 months (95% CI = 14.6–21.7 months) with chemotherapy (stratified HR = 0.54, 95% CI = 0.41– 0.73, P < .001). The rate at 12 months was 79.5% vs 62.5%. Objective response rates were 76.1% with disitamab vedotin plus toripalimab vs 50.2% with chemotherapy.
Grade 3 or higher treatment-related adverse events occurred in 55.1% of patients receiving disitamab vedotin plus toripalimab vs 86.9% of those who received chemotherapy. The most common were increased γ-glutamyltransferase (7.4%), decreased neutrophils (5.8%), and hypokalemia (5.8%) with disitamab vedotin plus toripalimab and decreased neutrophils (61.7%), decreased white blood cells (47.7%), and decreased platelets (45.9%) with chemotherapy. Serious treatment-related adverse events occurred in 28.4% vs 40.5% of patients. Treatment-related adverse events led to discontinuation of any treatment in 12.3% vs 10.4%. Treatment-related adverse events led to death in three patients (1.2%) given disitamab vedotin plus toripalimab (from acute respiratory failure, interstitial lung disease, and pneumonia in one each) and in three patients (1.4%) given chemotherapy (from both decreased platelet count and anemia in two patients and cardiac arrest in one).
The investigators concluded: “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.”
Xinan Sheng, MD, of Peking University Cancer Hospital and Institute, Beijing, and Aiping Zhou, MD, of the National Clinical Research Center for Cancer and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, are two of the corresponding authors for The New England Journal of Medicine article.
Disclosure: The study was funded by RemeGen and others. For full disclosures of all study authors, visit nejm.org.
