Chair, Suresh S. Ramalingam, MD, FACP, FASCO, Arjun Balar, MD, Yelena Janjigian, MD, and Kurt A. Schalper, MD, PhD, prepared useful Practice Aids pertaining to PD-L1 expression as a cancer immunotherapy biomarker for this CME/MOC/CC activity titled “Revisiting PD-L1 as an Immunotherapy Biomarker Across the Cancer Spectrum: Current and Emerging Standards of Testing, Scoring, and Assay Interpretation.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/3t8iyRk. CME/MOC/CC credit will be available until May 10, 2022.

1. Essential Concepts of Immuno-Oncology
Checkpoint Inhibitors and Biomarkers
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CYY40
Tumor Microenvironment
Lymphoid Tissue
Immune checkpoint inhibitors modulate T-lymphocyte responses
against cancer by blocking negative regulation of immune responses
PD-1 pathway inhibits
signaling downstream of TCR
•
TCR triggered by antigen
presented by tumor cell
• Negative regulatory receptor
PD-1 expressed and PD-L1
reactively expressed
• PD-L1 binds to PD-1
T cell inactivated
T cell inactivated
T cell activated
T cell activated
Anti–PD-1 or anti–PD-L1
monoclonal antibodies
block the interaction and
negative regulation
Anti–CTLA-4 monoclonal
antibodies block negative
regulation by CTLA-4
CTLA-4 is a negative regulator
of costimulation required for
activation of an
antitumor T cell in a lymph
node upon recognition of
tumor antigen
What Are
Immune
Checkpoints?1
PD-1/PD-L1
Checkpoint
Inhibition
CTLA-4
Checkpoint
Inhibition
FDA-Approved Therapies
FDA-Approved Therapies
Without
Immunotherapy
With
Immunotherapy
MHC
Antigen
TCR
PD-1
PD-L1
Anti–
PD-L1
Anti–
PD-1
Tumor
cell
Tumor escape
Inactivation
of T Cell
Activation
of T Cell
Elimination of
tumor cells
Without
Immunotherapy
With
Immunotherapy
MHC CD80/86
CTLA-4
Anti–
CTLA-4
antibody
APC
Antigen
TCR
Inactivation
of T Cell
Activation
of T Cell
Tumor escape Elimination of
tumor cells
STOP
STOP
GO
GO
GO
Tumor escape
Tumor escape
Tumor attack
Tumor attack
Anti–PD-1: Nivolumab
Pembrolizumab
Cemiplimab-rwlc
Anti–CTLA-4: Ipilimumab
Anti–PD-L1: Atezolizumab
Avelumab
Durvalumab
•
Proteins on T cells or cancer cells that need to be activated/inactivated to start/stop
an immune response, eg, PD-1, PD-L1, CTLA-4
•
Serve as “brakes” that help keep immune responses in check; can prevent T-cell response
against cancer cells
•
Can be blocked by immune checkpoint inhibitors (the “brakes” on the immune system are
released and T cells are able to attack and kill cancer cells)

2. Essential Concepts of Immuno-Oncology
Checkpoint Inhibitors and Biomarkers
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CYY40
1. Adapted from: Ribas A, Wolchock JD. Science. 2018;359:1350-1355. 2. Mayeux R. NeuroRx. 2004;1:182-188. 3. Naylor S. Expert Rev Mol Diagn. 2003;3:525-529.
What Are
Biomarkers?1-3
• PD-L1: a ligand for the immune checkpoint
receptor PD-1
•
PD-L1 expression can be measured by IHC
and detected on tumor and immune cells
PD-L1
expression
FDA-approved pan-cancer biomarker
used as either a companion or
complementary diagnostic for multiple
checkpoint inhibitors in different settings
PD-L1
PD-L2
PD-1
T cell
Tumor cell
• MSI-H/dMMR status are indicators of
genomic instability
–
MSI-H: change in number of nucleotide
repeats in DNA sequences  different
number of repeats than in inherited DNA
–
dMMR: loss of function in the MMR
pathway, a key DNA-repair system
MSI/MMR
FDA-approved pan-cancer biomarker for
pembrolizumab, and in mCRC, for nivolumab
and nivolumab + ipilimumab
•
TMB = collective no. of somatic mutations
within the tumor’s genome; TMB levels
vary in different tumors
•
Measured as total number of mutations or
mutations per megabase
•
Thresholds for high vs low TMB still in flux;
depend on assay + histology
TMB
•
FDA-approved biomarker for
pembrolizumab for patients with
unresectable or metastatic TMB-high
(≥10 mut/Mb) solid tumors that have
progressed on prior treatment
COMPANION
Test result is required for
prescription of the drug
•
Specified on drug label
•
Typically used when the test is
among inclusion criteria for the trial
(there are some exceptions)
COMPLEMENTARY
Testresultispredictive,butnot
requiredforprescriptionofthedrug
•
Nice to have, but do not need to have
•
Mostly used when the assay is
integrated into the trial, but not used
among inclusion criteria
Predictive
Diagnostic
Categories
•
Biomarkers are defined as “biological characteristics that can be objectively measured
and evaluated as an indicator of normal biological processes, pathogenic processes,
or pharmacological responses to a therapeutic intervention”
•
Biomarkers can be used to support the optimal clinical use (and development) of
anticancer immunotherapies