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Ref Type Journal Article
PMID (31272788)
Authors Wang L, Gong Y, Saci A, Szabo PM, Martini A, Necchi A, Siefker-Radtke A, Pal S, Plimack ER, Sfakianos JP, Bhardwaj N, Horowitz A, Farkas AM, Mulholland D, Fischer BS, Oh WK, Sharma P, Zhu J, Galsky MD
Title Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer.
Journal European urology
Vol
Issue
Date 2019 Jul 01
URL
Abstract Text Prior studies have demonstrated that fibroblast receptor 3 (FGFR3)-mutant urothelial cancers (UCs) are associated with decreased T-cell infiltration. As FGFR3 mutations are enriched in luminal-like UC and luminal-like UC has been shown to be relatively less responsive to PD-1/PD-L1 inhibition (checkpoint inhibition [CPI]), these data have led to the speculation that FGFR3 mutations may be causally related to poor T-cell infiltration and that UC patients harboring FGFR3 mutations may be suboptimal candidates for CPI. Using data derived from two clinical trials exploring CPI in metastatic UC, we demonstrate no statistically significant difference in response rates in patients with FGFR3-mutant versus wild-type UC. We present hypothesis-generating data, suggesting that similar response rates may be explained by a "balancing out" of previously identified independent positive and negative predictors of CPI sensitivity; that is, compared with FGFR3 wild-type UC, FGFR3-mutant UC is associated with a similar tumor mutational burden, lower T-cell infiltration, but also lower stromal/transforming growth factor beta (TGF-β) signals. Based on our findings, FGFR3 mutation status is not a biomarker of resistance to CPI. Indeed, the single-agent activity of both FGFR3 inhibitors and CPI in FGFR3-mutant UC, and potential non-cross resistance provide a strong pragmatic rationale for combination approaches. PATIENT SUMMARY: In this report, we examined the impact of a mutated gene found in a subset of urothelial cancers on response to treatment with immunotherapy. We found that patients with tumors harboring mutations in the gene FGFR3 respond to immunotherapy similarly to patients without such mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 mutant transitional cell carcinoma no benefit Atezolizumab Phase II Actionable In a Phase II trial (IMVigor 210, CheckMate 275), Tecentriq (atezolizumab) (n=119) treatment resulted in similar response rate (24% vs 21%, p=0.8) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). 31272788
FGFR3 mutant transitional cell carcinoma no benefit Nivolumab Phase II Actionable In a Phase II trial (CheckMate 275), Opdivo (nivolumab) (n=270) treatment resulted in similar response rate (20% vs 21%, p=0.2) in patients with FGFR3 mutant or wild-type metastatic transitional cell carcinoma (PMID: 31272788). 31272788