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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
Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer
Eur Urol. 2019 Nov;76(5) :599-603
PMID: 31272788    PMCID: PMC6801024    URL: https://www.ncbi.nlm.nih.gov/pubmed/31272788
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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-beta) 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.
1873-7560 Wang, Li Gong, Yixuan Saci, Abdel Szabo, Peter M Martini, Alberto Necchi, Andrea Siefker-Radtke, Arlene Pal, Sumanta Plimack, Elizabeth R Sfakianos, John P Bhardwaj, Nina Horowitz, Amir Farkas, Adam M Mulholland, David Fischer, Bruce S Oh, William K Sharma, Padmanee Zhu, Jun Galsky, Matthew D Journal Article Switzerland Eur Urol. 2019 Nov;76(5):599-603. doi: 10.1016/j.eururo.2019.06.025. Epub 2019 Jul 1.