Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era
Robert Anders, MD, PhD, Julie R. Brahmer, MD, MSc, and Christopher D. Gocke, MD, prepared useful Practice Aids pertaining to immunotherapy and biomarker testing for this CME/MOC/CC activity titled "Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era." For the full presentation, monograph, complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/2L7zlSy. CME/MOC/CC credit will be available until May 2, 2020.
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Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era
1. FDA-APPROVED IMMUNE CHECKPOINT INHIBITORS AND
PREDICTIVE BIOMARKERS IN CURRENT CLINICAL USE
PD-L1 and MSI/MMR Testing to Guide Treatment Decisions in Practice
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for
Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
PRACTICE AID
CANCER IMMUNOTHERAPY: HOW IMMUNE CHECKPOINT INHIBITORS WORK AND WHICH AGENTS ARE APPROVED1
Immune checkpoint inhibitors modulate T-lymphocyte responses against cancer by blocking negative regulation of immune responses
CTLA-4 is a negative regulator
of costimulation that is required
for initial activation of antitumor
T cell in a lymph node upon
recognition of tumor antigen
Activated T cells recognize cognate
antigen presented by cancer cells
à TCR triggered à negative
regulatory receptor PD-1 expressed
à IFN-γ produced à reactive
expression of PD-L1 à antitumor
T-cell responses turned off
This negative interaction
can be blocked by
anti–PD-1 or anti–PD-L1
antibody therapies
Activation of CTLA-4
can be blocked with
anti–CTLA-4
antibody therapies
Approved anti–CTLA-4
antibody therapy:
Anti–PD-1:
Nivolumab
Pembrolizumab
Cemiplimab-rwlc
Anti–PD-L1:
Atezolizumab
Avelumab
Durvalumab
Approved
anti–PD-1 and
anti–PD-L1
antibody
therapies:
Ipilimumab
Cancer Types Currently Being Treated With Immune Checkpoint Inhibitors or Combinations (≥1 approved indication)
Non–small cell lung
Small cell lung
Head and neck
Kidney
Bladder
Cervical
Melanoma
Merkel cell
Cutaneous squamous cell
Liver
Gastric
Colorectal
Breast (triple negative)
Hodgkin lymphoma
Primary mediastinal large
B-cell lymphoma
More to come!
Lymph node
Tumor
microenvironment
Antigen-
presenting
cell
CTLA-4 inhibitor
IFNγ and
other cytokines
Activated
effector
T cell
PD-1
inhibitor
B7
CD28
PD-L1
PD-1
MHC-I Antigen
PD-L1inhibitor
Tumor cell
MHC-II
CTLA-4
TCR
TCR
Exhausted
effector T cell
Naive
T cell
Treg
cell
2. FDA-APPROVED IMMUNE CHECKPOINT INHIBITORS AND
PREDICTIVE BIOMARKERS IN CURRENT CLINICAL USE
PD-L1 and MSI/MMR Testing to Guide Treatment Decisions in Practice
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for
Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
PRACTICE AID
PREDICTIVE TESTING: UNDERSTANDING THE DIFFERENCES BETWEEN COMPANION AND COMPLEMENTARY DIAGNOSTICS
Specified on drug label
Typically used when the
test is among inclusion
criteria for the trial (there
are some exceptions)
Test result is required for
prescription of the drug
Companion Complementary
Test result is predictive, but not
required for prescription of the drug
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:
Companion
vs
Complementary
PD-L1 Expression Testing
PD-L1 is a ligand for the immune checkpoint receptor PD-1 expressed on the surface of cytotoxic T cells
PD-L1 expression can be measured by IHC and detected on tumor and immune cells
Optimal (IHC)
Recent acquisition/current disease biopsy or resection
Abundant tissue (area >25 mm2
, volume >1 mm3
)
Abundant tumor cells (>50% of nucleated cells)
Proper fixation (12-24+ h in 10% NBF for cores)
Fresh section from FFPE block (<3-5 days)
Staining using a validated/approved assay
Minimum (PD-L1)
Within 36 months before treatment, any sample type
Any tissue area (eg, >1-2 mm2
)
>100 viable tumor cells (22C3 and 28-8 pharmDx)
Conventional fixation
Sections obtained up to 2-3 months before staining
Locally available and validated PD-L1 assay
IMMUNO-ONCOLOGY BIOMARKERS: APPROVED PREDICTORS OF BENEFIT FROM CANCER IMMUNOTHERAPIES
ü
X
3. FDA-APPROVED IMMUNE CHECKPOINT INHIBITORS AND
PREDICTIVE BIOMARKERS IN CURRENT CLINICAL USE
PD-L1 and MSI/MMR Testing to Guide Treatment Decisions in Practice
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for
Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
PRACTICE AID
IMMUNO-ONCOLOGY BIOMARKERS: APPROVED PREDICTORS OF BENEFIT FROM CANCER IMMUNOTHERAPIES (Cont’d)
Immune Checkpoint Inhibitors and Associated PD-L1 Assays
Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab
Target PD-1 PD-1 PD-L1 PD-L1 PD-L1
Antibody clone/
epitope
28-8 extracellular 22C3 extracellular SP142 cytoplasmic
SP263
cytoplasmic
73-10
cytoplasmic
IVD class III
diagnostic
partner
Dako Dako Ventana Ventana Dako
Scoring
Tumor cells
1%, 5%, 10%
TPS 1%, TPS 50%,
CPS 10, CPS 1 10%/50%,
Tumor/immune cells
5%, 1%
Tumor cells
25%
Tumor cells
1%, 50%,
80%
Diagnostics
Complementary
(NSCLC, melanoma);
PD-L1 IHC 28-8
pharmDx test
Companion (NSCLC,
bladder, gastric, cervical);
PD-L1 IHC 22C3
pharmDx test
Companion
(bladder, TNBC)
and complementary;
Ventana PD-L1
(SP142) assay
Complementary
(bladder);
Ventana PD-L1
(SP263) assay
Unknown
Setting Second line First line or second line
First line or
second line
Second line Second line
Bolding of text relates to companion diagnostic designation.
4. This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
CPS: combined positive score; CTLA-4: cytotoxic T-lymphocyte–associated antigen 4; dMMR: deficient mismatch repair; IHC: immunohistochemistry; IVD: in vitro diagnostic; FFPE: formalin fixed paraffin embedded; mCRC: metastatic colorectal cancer; MMR: mismatch repair;
MSI: microsatellite instability; MSI-H: microsatellite instability high; NBF: neutral buffered formalin; NGS: next-generation sequencing; PCR: polymerase chain reaction; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; TCR: T-cell receptor;
TNBC: triple-negative breast cancer; TPS: tumor proportion score.
1. Adapted from: Ribas A, Wolchock JD. Science. 2018;359:1350-1355.
FDA-APPROVED IMMUNE CHECKPOINT INHIBITORS AND
PREDICTIVE BIOMARKERS IN CURRENT CLINICAL USE
PD-L1 and MSI/MMR Testing to Guide Treatment Decisions in Practice
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications for
Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
PRACTICE AID
IMMUNO-ONCOLOGY BIOMARKERS: APPROVED PREDICTORS OF BENEFIT FROM CANCER IMMUNOTHERAPIES (Cont’d)
MSI/MMR Testing
Microsatellite instability high or deficient mismatch repair (MSI-H/dMMR) status; indicators of genomic instability
- MSI-H: Change in number of nucleotide repeats in DNA sequences à different number of repeats than in inherited DNA
- dMMR: Loss of function in the MMR pathway, a key DNA repair system
FDA-approved pan-cancer biomarker for pembrolizumab, and in mCRC, for nivolumab and nivolumab + ipilimumab
Testing Methods for Determining MSI-H or dMMR Status
Immunohistochemistry PCR + Capillary Electrophoresis
NGS: Numerous assays being developed
5. TUMOR MUTATIONAL BURDEN AS AN
EMERGING IMMUNO-ONCOLOGY BIOMARKER
Rationale, Testing, and Harmonization
PRACTICE AID
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications
for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
Mutations
Neoantigens
Immune
system
recognition of
tumor
TMB: What Is the Underlying Rationale for Using It as an Immuno-Oncology Biomarker?1-10
Abnormal activity in cellular pathways
(eg, DNA damage repair, DNA replication)
and exposure to mutagens (UV light,
tobacco smoke) can ↑ the overall rate
of somatic mutations in tumors
Neoantigens
TCR
Neoantigen
presentation
Tumor cell Killer
T cellDNA
mutations
HLA
TMB represents an emerging IO biomarker
TMB status correlates with outcomes in patients treated with immune checkpoint inhibitors
across many tumors
- TMB levels vary in different types of tumors; lung, skin, and bladder cancer represent
high-TMB tumors, but % of many other cancers has been found to have high TMB also
Often measured/reported as mutations per megabase (mut/Mb)
Thresholds for high vs low TMB are still in flux and depend on assay and histology
(various labs/groups may calculate it differently and include different kinds of mutations)
Complementary to PD-L1 expression—appears to identify a distinct and independent
population of patients
↑ in tumor-specific neoantigens → ↑ in
# of tumor-infiltrating immune cells
Activated & primed CD8+ cytotoxic T cells can recognize
& target neoantigens that are peptide-bound to major
histocompatibility complex class I & presented on tumor
cells → anti-tumor immune response → tumor cell lysis
6. TUMOR MUTATIONAL BURDEN AS AN
EMERGING IMMUNO-ONCOLOGY BIOMARKER
Rationale, Testing, and Harmonization
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
IO: immuno-oncology; MSKCC: Memorial Sloan Kettering Cancer Center; NCI: National Cancer Institute; NGS: next-generation sequencing; TCGA: The Cancer Genome Atlas; TMB: tumor mutational burden;
US FDA: United States Food and Drug Administration; WES: whole exome sequencing.
1. Hellmann MD et al. N Engl J Med. 2018;378:2093-2104. 2. Carbone DP et al. N Engl J Med. 2017:376;2415-2426. 3. Hellmann MD et al. Cancer Cell. 2018;33:843-852.e4. 4. Ramalingam S et al. American Association for
Cancer Research Annual Meeting 2018 (AACR 2018). Abstract CT078. 5. Snyder A et al. N Engl J Med. 2014;371:2189-2199. 6. Rizvi NA et al. Science. 2015;348:124-128. 7. Le DT et al. N Engl J Med. 2015;372:2509-2520.
8. Van Allen EM et al. Science. 2015;350:207-211. 9. Hugo W et al. Cell. 2016;165:35-44. 10. Yarchoan M et al. N Engl J Med. 2017;377:2500-2501. 11. Chan TA et al. Ann Oncol. 2019;30:44-56. 12. https://www.focr.org/tmb.
Accessed April 17, 2019.
Access the activity,“Keeping Up With Advances in Cancer Immunotherapy and Biomarker Testing: Implications
for Pathologists at the Forefront of the Emerging Precision Immuno-Oncology Era,”at PeerView.com/FJP40.
TMB Harmonization Effort: Friends of Cancer Research12
Workflow
Samples
Publicly available
TCGA data
Cells derived
from human tumors
Clinical samples
Analytical validation Clinical validation
Goals
Identify agreement
between TMB calculated using
WES and various targeted panels
used in the clinic
Agree upon creation of a universal
reference standard using WES
Identify agreement between TMB
score from targeted panels and
reference standard
Conduct a retrospective
analysis using patient
outcome data to identify
cutoff values and inform
prospective studies
Step 1: In silico analysis Step 2: Empirical analysis Step 3: Clinical analysis
Timeframe May 2018 Spring 2019 Summer 2019
Participants:
• 7 test developers
• 6 pharmaceutical companies
• US FDA
• NCI
• Academia
Whole Exome Foundation NGS MSKCC NGS
No. of genes ~22,000 324 cancer-related genes 468 cancer-related genes
Coverage ~30 Mb 0.8 Mb 1.22 Mb
Types of mutations
Coding missense
mutations
Coding, missense, and indel
mutations per Mb
Coding missense
mutation per Mb
Germline mutations
Subtracted using
germline DNA
Estimated bioinformatically
and subtracted
Subtracted using
matched blood
TMB definition
Number of somatic,
missense mutations
in the tumor genome
Number of somatic, coding
mutations (synonymous and
nonsynonymous), short indels
per Mb of tumor genome
Number of somatic,
missense mutations per
Mb of tumor genome
Turnaround time At least 4-6 weeks 2 weeks 2 weeks
TMB: Comparison of Select Assays11