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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