Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer.

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.

European urology. 2019 Jul 01 [Epub ahead of print]

Li Wang, Yixuan Gong, Abdel Saci, Peter M Szabo, Alberto Martini, Andrea Necchi, Arlene Siefker-Radtke, Sumanta Pal, Elizabeth R Plimack, John P Sfakianos, Nina Bhardwaj, Amir Horowitz, Adam M Farkas, David Mulholland, Bruce S Fischer, William K Oh, Padmanee Sharma, Jun Zhu, Matthew D Galsky

Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Sema4, a Mount Sinai Venture, Stamford, CT, USA; Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA., Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA., Bristol-Myers Squibb, Princeton, NJ, USA., Department of Urology; Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA., Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Sema4, a Mount Sinai Venture, Stamford, CT, USA; Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA. Electronic address: ., Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA. Electronic address: .

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