FGFR Genomic Alterations and Response to Erdafitinib - Expert Commentary
The study cohort consisted of 1,421 patients, among whom 27.5% exhibited FGFR2/3 alterations that were predictive of response to erdafitinib. Specifically, oncogenic FGFR3 alterations were present in 39% of patients with non-muscle invasive bladder cancer (NMIBC), 14% of patients with muscle-invasive bladder cancer (MIBC), 43% of patients with clinically localized upper tract tumors, and 26% of patients with distant metastases. The presence of oncogenic FGFR3 alterations was significantly associated with the following variables: younger age (p =0.03), female sex (p = 0.0002), and less history of tobacco use (p = 0.005). Co-occurring oncogenic alterations were common in the PI3K signaling pathway and cell cycle regulatory genes. To investigate potential differences in the genetic makeup of primary versus metastatic tumor sites, the researchers compared these sites in 27 patients and noted discordance among 26%.
13% of patients with metastatic urothelial carcinoma received immune checkpoint therapy, with no significant difference in survival outcomes between patients with or without FGFR3 alterations. The objective response rate (ORR) to erdafitinib was 40%, while it was 35% among patients who had previously received immune checkpoint therapy. Median progression-free survival (PFS) and overall survival (OS) on erdafitinib were 2.8 months (95% CI, 2.6-5.4) and 6.6 months (95% CI, 4.6-17.3), respectively. Serial cell-free DNA measurements in a subset of 27 patients treated with erdafitinib revealed that those who exhibited decreased variant allele frequency (VAF) of FGFR3 hotspot mutations over time had better responses.
These findings highlight the wide variation in FGFR3 alterations in urothelial carcinoma, which may not be detected in primary tumor tissue and can change over time. This could explain heterogeneity in responses to FGFR inhibitor treatment among many patients. Importantly, liquid biopsies may be valuable in detecting acquired genetic changes that may result in acquired resistance to targeted therapy.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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