Second-line single-agent chemotherapies or immune checkpoint inhibitors have provided suboptimal response rates and survival benefits in patients with locally advanced and unresectable or metastatic urothelial carcinoma. Certain types of urothelial carcinomas, such as the luminal I subtype, have higher percentages of mutations in the genes encoding fibroblast growth factor receptor (FGFR), associated with immune response; such alterations are relatively common in urothelial carcinoma in general, decreasing sensitivity to immune interventions. Erdafitinib is a potent tyrosine kinase inhibitor of FGFR1-4, and has shown anti-tumor activity in preclinical models and a phase I study involving patients with FGFR mutations. The objective of this uncontrolled, multicenter open-label phase II study was to assess the response of erdafitinib in patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Ninety-nine patients with a history of disease progression during or after at least one course of first-line chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy were enrolled. They were initially randomly assigned to receive 28-day cycles of either intermittent or continuous regimens. Based on a planned interim analysis, further enrollment to the intermittent regimen group was stopped. Researchers found that 40% (95% CI 31% to 50%) had a confirmed response (3% complete, 37% partial); response rates were similar regardless of previous chemotherapy, number of previous treatment courses, or baseline characteristics. Of those who underwent previous immunotherapy, 59% of patients had a confirmed response. Median progression-free survival was 5.5 months, and overall survival duration was 13.8 months. Treatment-related adverse events of grade III or higher were noted in 46% of patients, with 13% of patients discontinuing therapy. No treatment-related deaths were reported. This study therefore shows that among patients with locally advanced and unresectable or metastatic urothelial carcinomas with FGFR alterations, objective partial or complete response was achieved in more than 40% of previously treated patients with erdaftinib therapy, though therapy was associated with significant toxicity and associated medication discontinuation.
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