PDL 1 prediccio n de eficacia en inmunoterapia

PD-L 1, prediccio n de eficacia en inmunoterapia Puesta al día: Biomarcadores Federico Rojo

Multidimensional prediction of benefit to immunotherapy blood-based assays multiparametric FACS antigen-specific T-cells 89 Zr-PDL 1 plasma cytokines/ chemokines PET Lymph node multiparametric IHC Blood vessel Tumor PD-L 1 IHC gene expression signatures TCR diversity mutational burden enterotypes 16 S r. RNA NGS nasal swabs/stool Adapted from Yuan et al. J Immunother Cancer 2016. genotypes clinical data

Higher PD-L 1 expression predicts higher objective response for immunotherapy in advanced solid tumors Ayers, M et al. Clin Cancer Res 2018

Promising predictive value of PD-L 1 expression in clinical trials in NSCLC

PD-L 1 expression and efficacy for 2 L+ immune checkpoint inhibitors in m. NSCLC 1225) 174 1. Brahmer, et al. N Engl J Med 2015; 2. Borghaei, et al. N Engl J Med 2015 3. Herbst, et al. Lancet 2015; 4. Journal of Thoracic Oncology Vol. 13 No. 8: 1156 -1170 0. 45 177) 0. 98 334) 0. 87 531) 0. 84 1225) 0. 80

KEYNOTE-024: High PD-L 1 expression (≥ 50%) appears to be predictive of survival in patients treated with pembrolizumab in 1 st-line (1 L) NSCLC Trial overview: phase 3 trial of pembrolizumab monotherapy PD-L 1 measurement: evaluated on tumour cells using Dako 22 C 3 IHC Safety: TRAE incidence was lower with pembrolizumab compared with chemotherapy 100 Pembrolizumab 90 ≥ 50% PD-L 1 expression Chemotherapy 80 62% PFS (%) 70 Median PFS, months 48% 60 50 50% 40 30 15% 20 10 0 0 3 6 9 Time (months) 12 15 18 Pembrolizumab (n=73) 10. 3 Chemotherapy (n=116) 6. 0 HR (95% CI) P value 0. 50 (0. 37– 0. 68) <0. 001

Scoring methods for PD-L 1 expression by immunohistochemistry

Tumour along with immune-cell expression of PD-L 1 appears to be predictive for pembrolizumab in several tumour types • PD-L 1 expression in the tumor microenvironment has been associated with response with PD-1 pathway inhibition • Combined positive score (CPS) is determined by 22 C 3 PD-L 1 IHC assay • CPS is defined as percentage of PD-L 1 positive cells relative to the total number of tumor cells Balar, AV et al. ESMO 2016

PD-L 1 expression in tumor and stroma predicts benefit to pembrolizumab in bladder cancer 1 L pembrolizumab in cisplatin-ineligible unresectable or metastatic urothelial cancer: KEYNOTE-052 Balar, AV et al. ESMO 2016 Vuky, J et al. ASCO 2018

PD-L 1 expression in tumor and stroma predicts benefit to pembrolizumab in bladder cancer 1 L pembrolizumab in cisplatin-ineligible unresectable or metastatic urothelial cancer: KEYNOTE-052 Vuky, J et al. ASCO 2018

PD-L 1 in BC primary and metastases (asynchronous) GEICAM/2009 -03_Convert. HER trial 45 paired biopsies primary and metastases, treated with Radiotherapy, Chemotherapy, Biological agents and endocrine therapy. Albanell, J et al. ASCO 2017

PD-L 1 in BC primary and metastases (asynchronous) Innate Inflammation Notch Pathway Downregulated in Metastases Fibroblasts TGFB response Albanell, J et al. ASCO 2017 Active Fibroblasts GEICAM/2009 -03_Convert. HER trial

PD-L 1 in BC primary and metastases (asynchronous) GEICAM/2009 -03_Convert. HER trial Dynamic Index (DI) = # Changing Patients Total Patients DI = 0. 7 PDL 1 IC can change between primary and metastases. TNBC BC tend to be more dynamic than HR+ BC Albanell, J et al. ASCO 2017

Non-synonimous mutations generate neoantigens in cancer Somatic mutation frequency in human cancers correlate with response to PD-1/-L 1 inhibition Tumours with high TMB… …may have high neoantigen load… …which may increase immunogenicity and T cell reactivity against the tumour NK cell CD 8 Neoantigens MHC I T cell TCR TMB is defined as the number of somatic mutations in the tumour genome • Tumours tend to accumulate mutations in their genome as they grow uncontrollably • Somatic mutations are acquired over time and are distinct from inherited germline mutations in the DNA Schumacher TN, Schreiber RD. Science. 2015; 348(6230): 69 -74. Kim JM, Chen DS. Ann Oncol. 2016; 27(8): 1492 -1504. Liontos M et al. Ann Transl Med. 2016; 4(14): 264. Sharma P, Allison JP. Science. 2015; 348(6230): 56 -61. Giannakis M et al. Cell Rep. 2016; 15(4): 857 -865.

TMB and PD-L 1 expression interaction Check. Mate 227: TMB as Predictive Biomarker for Benefit to Nivolumab+Ipilimumab Therapy in 1 L m. NSCLC Hellmann, MD et al. AACR 2018, NEJM 2018

TMB and PD-L 1 expression interaction in solid tumors Cristescu, R et al Science 2018

TMB is predictive or prognostic? Check. Mate 227 Median OS in patients with TMB ≥ 10 mut/Mb: - combination arm: 23. 03 m - chemotherapy arm: 16. 72 m (HR, 0. 77; 95% CI, 0. 56 -1. 06) Median OS in patients with TMB <10 mut/Mb: - combination arm: 16. 20 m - chemotherapy arm: 12. 42 m (HR, 0. 78; 95% CI, 0. 61 -1. 00).