786P - Fibroblast growth factor receptor 3 (FGFR3) mutant muscle invasive bladder cancers (MIBC) are associated with low immune infiltrates

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Urothelial Cancers
Cancer Immunology and Immunotherapy
Presenter Elaine Kilgour
Citation Annals of Oncology (2016) 27 (6): 266-295. 10.1093/annonc/mdw373
Authors E. Kilgour1, H. Angell2, N.R. Smith3, M. Ahdesmaki2, J.C. Barrett4, E.A. Harrington2, C. Hurst5, M.A. Knowles5
  • 1Oncology Translational Science, AstraZeneca, SK10 4TG - Macclesfield/GB
  • 2Oncology Translational Science, AstraZeneca, Cambridge/GB
  • 3Oncology Translational Science, AstraZeneca, Macclesfield/GB
  • 4Oncology Translational Science, AstraZeneca, Boston/US
  • 5Institute Of Cancer And Pathology, University of Leeds, Leeds/GB

Abstract

Background

Activating FGFR3 mutations occur in about 15% MIBC and 70% non-MIBC (NMIBC), raising the potential for FGFR inhibitors as a therapy option. Clinical trials of anti-programmed cell death protein 1 (PD1) and anti-PD1 ligand (PD-L1) agents have shown benefit in advanced bladder cancer patients and provided evidence for PD-L1 as a predictive marker. We have assessed the association of FGFR3 mutations with FGFR3 expression, PD-L1 and T-cell infiltrates in MIBC samples.

Methods

FGFR3, PD-L1 and CD8 (cytotoxic T-cell marker) expression were assessed by immunohistochemistry (IHC) and FGFR3 mutations by SNaPshot analysis in a cohort of 60 MIBC. FGFR3/FGFR1 expression were also assessed in a cohort of 40 MIBC, 30 NMIBC and 18 normal urothelium (NU) tissues.

Results

FGFR3 expression (H-score >20) was observed in 20% (8/40) of MIBC compared to 60% (23/39) of NMIBC while 94% (17/18) NU were negative. In contrast, FGFR1 expression was low and did not differ between MIBC, NMIBC and NU. FGFR3 mutations were detected in 16% MIBC (10/60) and an association was observed with FGFR3 expression (p 25% cells positive) was 12% (7/59) and immune cell (IC) positivity was 32% (19/59) and FGFR3 mutant samples all displayed low TC PD-L1 (≤5% cells expressing PD-L1) and low CD8 ( 5% cells PDL1 positive) and CD8 from 5-1453 cells/mm2 (23% with > 250 cells/mm2 positive). Consistent with these observations, analysis of the Cancer Genome Atlas MIBC data-set showed FGFR3 mutant/fusion bladder cancers cluster into a low immune subtype.

Conclusions

FGFR3 mutation is associated with increased FGFR3 expression and low PD-L1 and cytotoxic T-cell infiltrates, suggesting these tumours may respond differently to anti-PD1/PD-L1 therapy and supporting investigation of FGFR3 inhibitors as a therapeutic option. Clinical studies with FGFR inhibitors in bladder cancer are ongoing, including assessment of AZD4547 in monotherapy and combination with the anti-PD-L1 agent durvalumab (NCT02546661).

Clinical trial identification

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

E. Kilgour, H. Angell, N.R. Smith, M. Ahdesmaki, J.C. Barrett, E.A. Harrington: Employee of AstraZeneca and holds stock in AstraZeneca. All other authors have declared no conflicts of interest.