Carcinoma Urotelial: La Célula Inflamatoria Clave en la Inmunoterapia Fernando López-Ríos

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1 Carcinoma Urotelial: La Célula Inflamatoria Clave en la Inmunoterapia Fernando López-Ríos Laboratorio de Dianas Terapéuticas Hospital Universitario HM Sanchinarro Madrid, Spain

2 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

3 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

4 Background Gibney GT et al. Lancet Oncology 2016

5 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

6 PD-L1 Expression (IHC) as a Predictive Biomarker Suboptimal negative predictive value? Different antibodies and platforms Expression on tumour cells and/or immune cells Harmonization studies Several definitions of PD-L1 positivity Spatiotemporal heterogeneity Biological Continuum

7 PD-L1 Expression (IHC) as a Predictive Biomarker Suboptimal Negative Predictive value? Sharma P J et al. Lancet Oncol 2016

8 PD-L1 Expression (IHC) as a Predictive Biomarker Different Antibodies and Platforms Kerr K et al. Arch Pathol Lab Med 2016 Algunos fármacos en uso experimental no autorizado

9 Tumour cells PD-L1 Expression (IHC) as a Predictive Biomarker Expression on Tumour Cells (TC) and/or Immune Cells (IC) 22C SP263 SP142 Caminoa A and Conde E, unpublished data

10 PD-L1 Expression (IHC) as a Predictive Biomarker Expression on Tumour Cells (TC) and/or Immune Cells (IC) SP142* Immune cells Fehrenbacher L et al. Lancet 2016 *Caminoa A,Conde E et al. unpublished data

11 PD-L1 Expression (IHC) as a Predictive Biomarker Harmonization Studies Scores in tumor cells (TCs) were similar for 22C3, 28-8, and SP263; lower for SP142. SP142 stained immune cells (ICs) more intensely. Higher agreement when assessing TCs than when assessing ICs. Inter-observer and inter-laboratory concordance more challenging than inter-clone agreement. Hirsch FR et al. J Thorac Oncol 2016 Scheel AH T et al. Mod Pathol 2016 Ratcliffe et al. Clin Cancer Res 2017

12 PD-L1 Expression (IHC) as a Predictive Biomarker Several Definitions of PD-L1 Positivity Modified from Sholl LM et al. Arch Pathol Lab Med 2016 Algunos fármacos en uso experimental no autorizado

13 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

14 Tumour Microenvironment Tumor microenvironment types based on TILs and PD-L1 TILs+ PD-L1+ Type I Type IV PD-L1- TILs+ TILs- PD-L1- Type II Type III PD-L1+ TILs- EGFR mutant NSCLC ALK rearranged NSCLC TILs: Tumour-Infiltrating Lymphocytes Teng MWL et al. Cancer Res 2015

15 Ock C-Y et al. Clin Cancer Res 2016 Tumour Microenvironment

16 Rosenberg JE et al. Lancet Oncol 2016 Tumour Microenvironment

17 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

18 Mutational or Neoantigen Burden Mutation burden Neoantigen burden High mutation rates increase the probability that tumors display neoantigens. Immunotherapy is particularly effective in highly mutagenized tumors. Rizvi NA et al. Science 2015

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20 Mutational or Neoantigen Burden Rosenberg JE et al. Lancet Oncol 2016

21 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen burden Selective genomic burden Conclusions

22 Rosenberg JE et al. Lancet Oncol 2016 Selective Genomic Burden

23 Farina MS et al. Drugs 2017 Selective Genomic Burden

24 Contents Background Immunotherapy biomarkers PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational or neoantigen load Selective genomic burden Conclusions

25 Conclusions Combination of methodologies in some (all?) cases Multiparameter score: PD-L1+TILs+molecular properties PD-L1 IHC issues: Negative predictive value Pre-analytical issues Interoberver and interlaboratory agreement

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