Fibroblast Growth Factor Receptor 3 Alterations and Response to Immune Checkpoint Inhibition in Metastatic Urothelial Cancer: A Real World Experience

Purpose: We evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance Methods: 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014-2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3 alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients Results: Our findings from this dataset confirm that FGFR3-altered (n=17) and wild type (n=86) bladder cancers are equally responsive to ICB (12 vs 19%, p=0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumors have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response Conclusions: Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumors have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response. RNA sequencing of patients with advanced UC. Sample BACI165 was sequenced twice. >>>Submitter states that raw data are unavailable due to patient privacy concerns<<< Update: [07-12-2023] GSE176307_salmon_tpm_gene.matrix.tsv replaced GSE176307_BACI_tpm_gene.matrix.tsv.