1. Asociación entre el ARNm de PD1 y la respuesta a tratamiento con anti-PD1 en monoterapia en múltiples tipos de cánceres
Tomás Pascual*, Laia Paré*, Elia Seguí*, Adela Rodríguez, Oscar Reig, Joan Maurel, Javier García-Corbacho, Cristina Teixidó, Ana Arance y Aleix Prat

2. Disclosure Information
Employment:
Consultant or Advisory Role: AP: Pfizer, Lilly, Novartis, Roche, Nanostring Technologies, Oncolytics Biotech
Stock Ownership:
Research Funding: AP: Novartis, Roche, Nanostring Technologies
Speaking:
Grant support:
Other:

3. Background
Anti-PD1 antibody drugs such as nivolumab or pembrolizumab have demonstrated unprecedented clinical efficacy in more than 15 cancer types.
The overall response rate (ORR) achieved by these drugs across 22 cancer-types varies and ranges from 0% to 50%
Patients responding to these therapies usually gain a large survival benefit from these drugs, leading to impressive outcomes
Thus, selecting patients most likely to respond to anti-PD1 monotherapy is necessary

4. Non progressive disease
Background
Recent studies support the role of PD-L1 expression by immunohistochemistry (IHC) as a potential biomarker in NSCLC
We previously reported that the expression of immune-related genes, including PD1, is associated with anti-PD1 monotherapy efficacy in 65 patients with advanced solid tumors
Progression disease
Non progressive disease
Prat, Navarro et al. Cancer Research. 2017

5. Hypothesis We hypothesized that PD1 mRNA in tumor samples:
Explain the ORR differences observed across different cancer-types following anti-PD1 monotherapy
Provides superior predictive information with respect to other biomarkers

6. Methods Cohort#1 (from TCGA): Cohort#2 (in-house)
RNAseq data from 10,462 samples representing 36 cancer-types.
18 immune-related gene signatures and 547 immune-related genes, including PD1, and TMB were explored.
Correlations between each gene/signature and ORRs reported in the literature were calculated.
Cohort#2 (in-house)
FFPE-based PD1 mRNA data from 773 samples representing 17 cancer-types using the nCounter platform.
Cohort#3 (in-house and GEM)
FFPE-based PD1 mRNA data from an independent dataset of 117 patients with advanced solid tumors treated with anti-PD1 monotherapy (nivolumab or pembrolizumab).

7. PD1 and immune-related gene expression in TCGA
PD1 highly correlated with a group of 30 genes, including CD3 and CD8A, which were found significantly enriched in biological processes such as CD8 T-cell activation.
TCGA DATASET
36 tumor types
10,462 tumor samples
15,557 genes (RNAseq)
Tumor Mutational Burden
Acute Myeloid Leukemia
Diffuse Large B-cell Lymphoma
151 Breast Cancer w/o subtype
12 Esophageal Carcinoma  w/o subtype
Expression of PD1 mRNA across 34 cancer-types in TCGA.
15,010 non-immune genes
34 tumor types
10,078 tumor samples
547 immune genes (RNAseq)
18 immune GES (Including TIS and 2 clusters)
Tumor Mutational Burden

8. Immune-related gene expression and reported anti-PD1 efficacys
Immune Gene and GES Proportion Cutoff (Percentile).
90th
PD1
0.86
CD8A
IL12RB1
0.84
CCL5
0.83
80th
PD1
0.91
KLRK1
0.85
Cytotoxic cell
CD(A
70th
LTA
0.82
PD1
0.81
KLRK1
0.78
Cytotoxic cell
60th
PD1
0.82
LTA
0.77
CD8A
0.75
ICAM1
Mean
ICAM
0.78
LTA
0.77
PD1
0.76
CTSW
0.71
PUBMED
PHASE I-III TRIALS
ANTI-PD1 MONOTHERAPY
16 cancer-types
Correlation between the % of PD1-high and the reported ORR
Overall Response Rate
Proportion GES/Gene high
16 cancer-types
TCGA 566 Genes/GES mRNA

9. Implementing PD1 expression in the clinical setting
Expression of PD1 mRNA across 17 cancer-types in 773 FFPE samples.
773 In-house Dataset
PD1 mRNA FFPE
Nanostring Platform
17 cancer-types
Proportion PD1-high
Correlation of 80th Top Percentile PD1 mRNA expressers in TCGA vs in−house
Proportion PD1-high
17 cancer-types
TCGA PD1 mRNA

10. Direct association between PD1 expression and anti-PD1 efficacy
155 patients with advanced cancer treated with anti-PD1 monotherapy
117 FFPE tumor tissues obtained before anti-PD1 treatment
Nanostring
Patform

11. Conclusions PD1 expression correlates with high CD8 T-cell activation
Cancer-types known to be anti-PD1 sensitive have higher PD1 expression than cancer-types known to be more anti-PD1 resistant
The proportion of PD1-high tumors within each cancer-type ranges from 0 to 84%
These proportions of PD1-high disease are strongly associated with the anti-PD1 sensitivity reported in the literature across cancer-types
PD1 mRNA can be clinically implemented in FFPE tumor tissue and is found directly associated with anti-PD1 sensitivity regardless of the type of cancer

12. Acknowledgements
We thank all the patients and family members for participating in the study
BECA 40 ANIVERSARIO FSEOM – PARA PROYECTOS DE INVESTIGACIÓN EN INMUNO-ONCOLOGÍA