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Biomarkers: PDL1 and beyond PDL1Boon Cher Goh

Department of Hrmatology-Oncology, National University

Cancer Institute, Singapore

Cancer Science Institute of Singapore

Disclosure slide

• Research funding

– MSD, Bayer Healthcare, Genentech

• Consultancy

– MSD, Bayer Healthcare, Otsuka pharmaceuticals, AstraZeneca

• Biomarkers for immune checkpoint inhibitors (ICI)

• PDL1 as a biomarker for ICI

• Tumour IHC based biomarkers

• Genomics based biomarkers

• Evolving biomarkers

Biomarkers and their usefulness

• Assessment of a physiological or pathological state

• Predictive vs prognostic biomarkers

• Continuous variable vs ordinal variable biomarkers

• Proof of mechanism biomarkers vs proof of concept biomarkers

• Validated vs non validated biomarkers

• Assay performance – precision and accuracy

• NPV and PPV

Tumour neoantigens

HLA presentation

Poor vasculature

Immune checkpoints

Pro and anti immune signaling molecules

Tumour hypoxia

Inhibitory cytokines

Immune suppressive cells

PDL1 expression as a biomarker (IHC)

PDL1 amplification is common in Hodgkins Disease

Rare in solid tumours (0.7%)

May not correlate with protein expression

PDL1 as a biomarker

PDL1 expression by immunohistochemistry correlates with response to antiPD1 treatment

RR increase with PDL1 expression

Keynote 189 - NSCLC

PD1 is highly expressed in exhausted T cells

PDL1 expression in the host immune cells may also contribute to inhibition of T cell response

J Clin Oncol 2016;34:3838

Challenges with PDL1 IHC assays• Continuous variable with arbitrary cutoffs

• Multiple antibodies not cross validated

• Inter-observer variation

• Time dependence of PDL1 expression not accounted for

• Non expressors may respond to ICI; cannot be used to exclude patients

• Tumour cells and immune cells expressing PDL1

RNA based methods eg PCR, RNAscope

being evaluated

JTO 2017;17(2):208

Challenges with PDL1 as a biomarker for ICI

• High proportion of PDL1 positive patients do not respond

• PDL1 negative patients may respond – therefore cannot be used to exclude patients for ICI

treatment

• Does not take into account all the complexities of the tumour – immune response

• Does not work well with all tumour types eg melanoma

Tumor immunophenotypesCan IHC provide an assay for identifying immune

phenotypes?

Tumeh et al. Nature 2014;515:568

Melanoma patients who respond to ICI enriched

with CD8+ T cells, PD1 and PDL1 expression at

tumour margin and invasive margin

Immune infiltrate increases in responding

patients after treatment

IFNg is a key cytokine expressed

by activated T cells

That mediates antitumor immunity

Tumor mutational burden as a biomarker

Yarchoan. NEJM 2017;377;25

TMB as a biomarker of ICI response

• TMB is defined as the total number of nonsynonymous mutations per

coding area of a tumor genome

• Whole exome sequencing

• Targeted comprehensive genomic profiling (eg Foundation One assay)

• Plasma cell free DNA sequencing

• Challenges of harmonization between gene panels

• Somatic mutations need filtering of germline polymorphisms

• Assay considerations, bioinformatics,

• cut off of “high TMB”

Genome Med. 2017 Apr 19; 9(1):34

NEJM 2018;378(22):2093

Checkmate 227 study

NSCLC first line study PDL1<1% randomized to Nivo/ipi:nivo/chemo:chemo

FoundationOne CDX assay to assess TMB

TMB>10mut/MB: Nivo/ipi PFS 7.2m vs chemo 5.3m HR 0.58

ORR: 45.3% vs 26.9%

dMMR and MSI as biomarker of ICI therapy

• MSI tumours harbour thousands of mutations

• defective DNA mismatch repair (dMMR) system

• biallelic inactivation of one of the four genes coding for

the proteins involved in this mechanism

• Detected by a molecular test analysing few polyA DNA

microsatellites that, due to their monomorphic

composition, are highly prone to misalignments during

DNA replication

NEJM 2915;372:2509

Nature Med 2019;25:1715

phcgbc@nus.edu.sg