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Molecularly Targeted Therapy in Advanced Urothelial Cancer
The standard initial treatment for metastatic urothelial cancer has long been platinum-based chemotherapy, but only a small subset of patients achieve durable long-term disease control. While the EV-302 trial demonstrating clear superiority of enfortumab vedotin plus pembrolizumab over chemotherapy will likely change up-front management, second- and later-line therapy options will remain a critical unmet need.
Mutations in the gene encoding fibroblast growth factor receptor (FGFR) are observed in approximately 20% of advanced or metastatic urothelial cancers. Erdafitinib is a selective pan-FGFR tyrosine kinase inhibitor that is FDA approved for advanced urothelial cancer. In this pharmaceutical-sponsored, multinational, randomized phase 3 trial, investigators compared erdafitinib versus investigator's choice of docetaxel or vinflunine (approved in Europe) in patients with metastatic urothelial cancer with FGFR3/2 alterations (mutations or fusions) who had progression after one or two prior treatments that included an immune checkpoint inhibitor.
Of 8733 patients screened for molecular eligibility, 266 were randomized. The median age was 66 years in the erdafitinib group and 69 in the chemotherapy cohort. Most patients were male and 74% had visceral metastases; 66% of patients in the erdafitinib and 75% in the chemotherapy group had received two prior lines of therapy.
At a median follow-up of 15.9 months, overall survival — the primary endpoint — was significantly longer in the erdafitinib group than the chemotherapy group (median, 12.1 vs. 7.8 months; hazard ratio for death, 0.64; P=0.005). The objective response rates also favored erdafitinib (45.6% vs. 11.6%). Grade 3 or 4 treatment-related adverse events occurred in approximately 46% of patients in each group.
These results validate erdafitinib as a management option for patients with metastatic urothelial cancer with the appropriate mutations following disease progression on chemotherapy and immune checkpoint inhibition. Erdafitinib's utility is complicated by the need for tissue-based next-generation sequencing, which is not broadly performed in metastatic urothelial cancer, and its toxicity profile.
Loriot Y et al.
Title: Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma.
Source: N Engl J Med 2023 Oct 21; [e-pub]. (Abstract/FREE Full Text)