Sequential Response to FGFR3 Inhibition With Subsequent Exceptional Response to Atezolizumab in a Patient With FGFR3-TACC3 Fusion–Positive Metastatic Urothelial Carcinoma

Recent work has pointed to alterations in fibroblast growth factor receptors (FGFRs) as potential drivers of colder metastatic urothelial carcinoma (mUC) microenvironments.1,2 FGFRs mediate cell proliferation, migration, differentiation, and survival.3 Activating genomic alterations in FGFR3 are frequent in bladder cancer.4-6 In the muscle-invasive bladder cancer data set of The Cancer Genome Atlas, FGFR3 alterations were found to be enriched in the luminal papillary subtype.7 Clinical benefit from immune checkpoint inhibitors (ICIs) has been a major advance for many cancer types in recent years, including mUC, leading to US Food and Drug Administration approval.5 Although durable clinical benefit is seen in multiple cancer types, objective response rates in mUC are only 15% to 24%.8 Mechanisms contributing to ICI resistance and low response rates are poorly understood. A phase II trial comparing the association between The Cancer Genome Atlas mRNA subtypes and response to atezolizumab, an anti–programmed cell death ligand 1 (PD-L1) monoclonal immunoglobulin G1 antibody, showed that the luminal cluster (enriched for FGFR genomic alteration) was associated with lower expression levels of CD8+ genes and lower response rates (10%).1 Another study has shown that higher FGFR3 expression and FGFR3 pathway mutations are strongly associated with immune exclusion in bladder cancer.9 This association was also found in patients with bladder tumors harboring FGFR3-TACC3 fusions.2 These observations suggest that patients harboring FGFR3 alterations are relatively poor candidates for ICI therapy. Herein, we report a patient with metastatic bladder cancer harboring an FGFR3-TACC3 fusion and exhibiting an exceptional response to sequential FGFR3 inhibition and anti–PD-L1 blockade. We speculate that treatment of this patient with an FGFR3 inhibitor may have led to tumor microenvironment changes that enhanced the ICI response.