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Efficacy of FGFR Inhibitor Derazantinib in Metastatic Urothelial Carcinoma - Expert Commentary

There have been significant advancements in treatment options for patients with metastatic urothelial carcinoma (mUC) in recent years, including immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and fibroblast growth factor receptor (FGFR) inhibitors. FGFR alterations are present in 15-20% of patients with mUC and inhibitors, such as erdafitinib, derazantinib, and atezolizumab have therefore been approved for use in patients harboring selected alterations. The aim of this study was to analyze findings from a phase 1b/2 clinical trial (FIDES-02) in which patients with mUC and FGFR alterations were treated with derazantinib alone or in combination with atezolizumab.

The study cohort consisted of 95 patients who initially received at least one dose of derazantinib or atezolizumab. All patients discontinued derazantinib due to disease progression (76.8%), adverse events (AEs, 7.4%), or death (4.2%). All patients discontinued atezolizumab due to disease progression. There were no dose-limiting toxicities for the combination treatment of derazantinib and atezolizumab. The combined objective response rate (ORR) in patients receiving derazantinib monotherapy was 8.2% (95% CI, 2.3 – 19.6). The disease control rate (DCR) was 30.6% (95% CI, 18.3 – 45.4). Median duration of response (DOR) was 6.9 months. Median progression-free survival (PFS) was 2.1 months (95% CI, 2.0 – 2.1) and median overall survival (OS) was 6.6 months (95% CI, 4.4 – 8.2). Across treatment groups, most patients had at least one treatment-emergent AE (TEAE, 90.5%) and 70.5% had at least one TEAE of Grade 3 or higher. In patients receiving derazantinib alone, common TEAEs that Grade 3 or higher included anemia, nausea, fatigue, and increased blood transaminases. TEAEs typically observed with other FGFR inhibitors included hyperphosphatemia (14.3%), retinal events (16.3%), nail toxicities (4.1%), and stomatitis (4.1%). In patients receiving derazantinib monotherapy, serious TEAEs were present in 51.0% of patients, and TEAEs leading to death occurred in 18.4% of patients.

The efficacy of derazantinib was modest and was far lower than previously reported outcomes for other FGFR inhibitors. Future studies defining pathways that lead to bypass of FGFR3 signaling and thus short response durations or primary resistance in UC warrant further investigation.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

  1. Necchi A, Ramlau R, Falcón González A, et al. Derazantinib alone and with atezolizumab in metastatic urothelial carcinoma with activating FGFR aberrations. JNCI Cancer Spectr. Published online April 16, 2024. doi:10.1093/jncics/pkae030

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