El contexto molecular de la sobreexpresión de PD-L1 Esther Conde Gallego, MD, PhD

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1 El contexto molecular de la sobreexpresión de PD-L1 Esther Conde Gallego, MD, PhD Laboratorio de Dianas Terapéuticas Hospital Universitario HM Sanchinarro Madrid, Spain

2 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

3 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

4 PD-1 / PD-L1 Checkpoint pathway Tumor cell / APC MHC PD-L1 PD-1 TCR Patient s T cells T cell B7-1 + Anti-PD-1 T-cell inhibition Tumor cell growth MHC TCR T cells PD-L1 + Anti-PD-L1 PD-1 X B7-1 T-cell activated Granzymes and perforin Tumor cell death Herbst RS, et al. ASCO Abstract 3000

5 Neoantigen signature and tumour microenvironment TC IC The genetic damage that on the one hand leads to oncogenic outgrowth can also be targeted by the immune system to control malignancies. Schumacher TN et al. Cancer Cell 2015 Schumacher TN and Schreiber RD. Science 2015

6 Somatic mutation prevalence (number mutations per megabase) Pilocytic astrocytoma AML ALL Thyroid Kidney chromophobe CLL Medulloblastoma Neuroblastoma Glioma low grade Glioblastoma Prostate Ovary Myeloma Pancreas Breast Kidney papillary Lymphoma B-cell Kidney clear cell Head and neck Liver Cervix Uterus Bladder Colorectum Lung small cell Oesophagus Stomach Lung adeno Lung squamous Melanoma Neoantigens Formation of neoantigens Frequently Regularly Occasionally Schumacher TN and Schreiber RD. Science 2015

7 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

8 PD-L1 expression (IHC) as a predictive biomarker Complementary diagnostic test Companion diagnostic test Kerr K et al. Arch Pathol Lab Med 2016

9 PD-L1 expression (IHC) as a predictive biomarker Different antibodies and platforms Several definitions of PD-L1 positivity Expression on tumour cells (TC) and/or immune cells (IC) Spatiotemporal heterogeneity Sample types

10 PD-L1 expression (IHC) as a predictive biomarker Different antibodies E1L3N 3 SP142 3 SP263 3 Similar results with 3 antibodies (E1L3N, SP142, 28-8) 1 Fair to poor concordance (25% discordance) using E1L3N and SP142 2 Averbuch S et al. A blueprint proposal for companion diagnostic comparability. Working group proposal presented at: FDA-AACR-ASCO PublicWorkshop Complexities in Personalized Medicine: Harmonizing Companion Diagnostics Across a Class of Targeted Therapies; March 24, 2015; Washington, DC. /downloads/medicaldevices/newsevents/workshopsconferences/ucm pdf 1 Sheffield BS et al. Presented at WCLC 2015; ORAL McLaughlin J et al. JAMA Oncol Conde et al. Unpublished data

11 PD-L1 expression (IHC) as a predictive biomarker Expression on tumour cells (TC) and/or immune cells (IC) E1L3N SP142 SP263 Immune cells Tumour cells Conde et al. Unpublished data

12 PD-L1 expression (IHC) as a predictive biomarker Several definitions of PD-L1 positivity *Intensity 0 *Intensity 1+ *Intensity 2+ *Intensity 3+ Sholl LM et al. Arch Pathol Lab Med 2016 *E1L3N

13 PD-L1 expression (IHC) as a predictive biomarker Spatiotemporal heterogeneity Discordant results in 6% of multisampled cases 1 30% of primary vs metastatic sites 1 in 50% of multifocal independent cases 2 Clone E1L3N 3 1 Phillips T et al. Appl Immunohistochem Mol Morphol 2015; 2 Mansfield AS et al. Clin Cancer Res Conde E et al, unpublished data

14 PD-L1 expression (IHC) as a predictive biomarker Sample types Ilie M et al. Ann Oncol 2016

15 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

16 Immunosuppressive tumour phenotypes TILs+ PD-L1+ Type I Type IV TILs- PD-L1- PD-L1- TILs+ Type II Type III PD-L1+ TILs- TILs: tumour-infiltrating lymphocytes Teng MWL et al. Cancer Res 2015

17 Tumour microenvironment (tumour-infiltrating immune cells) H&E * SP142 * McLaughlin J et al. JAMA Oncol 2015 *Conde et al. Unpublished data

18 Assessment of tumour-infiltrating immune cells Salgado R et al. Ann Oncol 2015

19 Tumour-infiltrating immune cells in NSCLC Intense TILs: strong heavy lymphocytic infiltrate; 50% stromal lymphocytes in the tumor bulk (mimics lymph node involvement) Minority of tumors with intense TILs= 9%; higher proportion in SCC (11%) compared to AC (4%) Brambilla E et al. J Clin Oncol 2016

20 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

21 Mutational landscape in NSCLC Mutation burden Neoantigen burden Immunotherapy is particularly effective in highly mutagenized tumors. Rizvi NA et al. Science 2014

22 EGFR mutations in NSCLC EGFR mutation induces PD-L1 expression PD-L1+/ EGFR mutated patients treated with EGFR TKIs tended to have better prognosis 1 High PD-L1 expression was associated with EGFR mutation in advanced 1,2 and surgically resected 3 NSCLC PD-L1+/ EGFR wt patients treated with EGFR TKIs tended to have poor prognosis 2 1 D Incecco A et al. B J Cancer 2014; 2 Tang Y et al. Oncotarget 2015 ; 3 Azuma K et al. Ann Oncol 2014

23 ALK rearrangement in NSCLC PD-L1 expression is induced by EML4-ALK fusion gene High PD-L1 expression was associated with ALK rearrangement in advanced 1 and surgically resected 2 NSCLC 1 D Incecco A et al. B Journal Cancer Ota K et al. Clin Cancer Res 2015

24 Mutational burden in clinical trials with immunotherapy in NSCLC Brahmer J et al. N Engl J Med 2015

25 Mutational burden in clinical trials with immunotherapy in NSCLC Garon EB et al. N Engl J Med 2015

26 Improved overall survival as a result of combination therapy Sharma P and Allison JP. Cell 2015

27 Contents Background PD-L1 expression (IHC) as a predictive biomarker Tumour microenvironment (tumour-infiltrating immune cells) Mutational landscape Conclusions

28 Conclusions PD-L1 expression is a potential predictive biomarker Multiparameter immunoscore: PD-L1 expression + TILs + mutational context EGFR mutations, ALK rearrangements and KRAS/P53 mutations are associated with high PD-L1 protein levels A new challenge for the prioritisation of the sample

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