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Fibroblast growth factor receptor 3 alterations and response to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer

  • 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

Publication: European Urology, Volume 76, Issue 5, November 2019, Pages 599-603

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.

Commented by Dr. Moschini

In this hypothesis generating analysis, authors evaluate the impact of fibroblast receptor 3 (FGFR3) mutation in urothelial cancers patients on the ability in responding to immunotherapy. Patients with FGFR3 mutations have been believed to response less to immunotherapy compared to patients not affected by this mutation as a consequence of the decreased T cell infiltration. FGFR3 mutations in facts is present in luminal like UC and luminal like UC has been shown to be relatively less responsive to PD1 and PD L1 inhibition. Authors of this study used data from IMVigor 210 cohorts 1 and 2, a phase 2 trial exploring the PD L1 inhibitor atezolizumab in patients with metastatic urothelial carcinoma to assess the association between mFGFR3 and response to check point inhibitor. They found that no statistically significant difference in response rates in patients with FGFR3 mutant versus wild type urothelial cancer was recorded. Based on their findings authors support the hypothesis and FGFR3 mutation status should not be used as a biomarker of resistance of check point inhibition.