1. NCCN Guidelines: Pathology and Genomics in Endometrial Carcinoma
Universal Testing of Endometrial Carcinomas for MMR Proteins Is Recommended
Provides an opportunity to determine
which patients should receive genetic
testing to identify Lynch syndrome
Informs treatment decisions if
the patient progresses on initial
chemotherapy
Generates valuable information early
in the treatment course as therapies
move into the frontline setting
POLE sequencing
DNA MMR protein
immunohistochemistry
MSI-H Copy number-low Copy number-high
POLE
No POLE hotspot mutation
Expression lost
POLE hotspot mutation
Expression retained
Normal/wild-type pattern Aberrant/mutant pattern
p53 immunohistochemistry
Biomarkers and Biomarker Testing
in Endometrial Cancer1-5
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2. MSI-H and dMMR are considered the same population biologically—both groups of patients can be treated with the same agents
• dMMR/MSI-H refers to a group of patients with mismatch repair deficiency
• MMRp/MSS refers to a group of patients who are mismatch repair proficient
Microsatellite Instability (MSI)
MSI is detected
through
molecular testing
Consensus definition:
MSI is a condition
of genetic
hypermutability
Characterized by the
clustering of mutations
in microsatellites
typically consisting
of repeat length
alterations
The presence of MSI
represents evidence
that MMR is not
functioning normally,
or dMMR
MSI-H provides
the phenotypic
evidence
of dMMR
Mismatch Repair (MMR)
MMR proteins
are detected
by IHC stain
MMR protein
complexes
(MLH1 + PMS2 and
MSH2 + MSH6) detect
and correct mistakes
during DNA replication
Absence or loss
of function of one
of the four MMR
proteins results in
MMR deficiency, or
dMMR
dMMR is the
cause of MSI-high,
or MSI-H
Biomarkers and Biomarker Testing
in Endometrial Cancer1-5
Full abbreviations, accreditation, and disclosure information available at PeerView.com/YTW40
1. Kloor M et al. Trends Cancer. 2016;2:121-133. 2. Luchini C et al. Ann Oncol. 2019; 30:1232-1243. 3. Hause RJ et al. Nat Med. 2016;22:1342-1350. 4. Levine DA. Nature. 2013;497:67. 5. NCCN Clinical Practice Guidelines in Oncology. Uterine Neoplasms. Version 1.2023.
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

3. Managing Immune-Related
Adverse Events1-4
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available at PeerView.com/YTW40
Safety Considerations
for Immunotherapies
1. Monitor closely for potential
irAEs by evaluating blood
work including liver
enzymes, creatinine, and
thyroid function
2. Ask patients about
symptoms such as cough,
shortness of breath, and
diarrhea, which may be
signs of pneumonitis
or colitis
3. Stay in communication
with patients to help
mitigate and treat more
common AEs such as
fatigue, nausea, and anemia
Pancreatitis,
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic meningitis
Thyroiditis, hypothyroidism,
hyperthyroidism
Dry mouth, mucositis
Hypophysitis
Uveitis
Pneumonitis
Thrombocytopenia,
anemia
Hepatitis
Adrenal insufficiency
Nephritis
Vasculitis
Arthralgia
Neuropathy
Rash, vitiligo
Myocarditis
Any organ system can be affected; commonly occurring irAEs are
pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters, ulcers,
vitiligo), gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis,
pancreatitis), and endocrine (thyroiditis, hypophysitis,
adrenal insufficiency)
What Is the Spectrum of Potential irAEs?
• In general, checkpoint inhibitor therapy should be continued
with close monitoring, with the exception of some neurologic,
hematologic, and cardiac toxicities
Minimal or no symptoms; diagnostic changes only
Grade 1
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or
laboratory values revert to grade 1 or lower
• Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or
equivalent) may be administered
Grade 3 toxicities
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or
methylprednisolone IV 1-2 mg/kg/d)
• If symptoms do not improve with 48-72 hours of high-dose
corticosteroids, infliximab may be offered for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to grade 1 or lower,
rechallenging with immunotherapy may be offered; however, caution
is advised, especially in those patients with early-onset irAEs; dose
adjustments are not recommended
Grade 4 toxicities
• In general, permanent discontinuation of checkpoint inhibitor
therapy is warranted, with the exception of endocrinopathies that
have been controlled by hormone replacement
Grade 2
Mild to moderate symptoms
Severe or life-threatening symptoms
Grades 3/4
Most significant irAEs occur in
less than 5% of patients
irAE Grading and Management

4. Managing Immune-Related
Adverse Events1-4
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/YTW40
Consult irAE management guidelines
(eg, ASCO, NCCN, SITC, ESMO)
IO
Pruritus
Pneumonitis
Myocarditis
Adrenal crisis
TKI
Hypertension
Taste changes
Stomatitis
Dyspepsia
Cytopenia
HFSR
Overlapping
Rash
Diarrhea
Hepatitis
Hypothyroid
AMS
IO + TKI Combination Toxicities
Determine which therapy is causing the AE
in order to plan a management strategy
Hold TKI (shorter half-life than checkpoint inhibitor)
In certain cases, use appropriate supportive care
If symptoms resolve in a few days, TKI was likely the cause
Two mechanisms of action result in two sets of AE
profiles that are not mutually exclusive
PRES
Encephalitis
1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Schneider BJ et al. J Clin Oncol. 2021;39:4073-4126. 3. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related
Toxicities. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 4. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.

5. Numerous Immunotherapy Strategies Under Study in
Advanced Endometrial Cancer
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• Immune checkpoint inhibitors work by blocking
T-cell inhibitory signals, thus removing the
brakes on the immune system
• The combination of increased mutational load,
tumor-infiltrating lymphocytes, and PD-1/PD-L1
expression makes endometrial cancer an ideal
target for immunotherapeutic interventions
• Cytotoxic agents have immunomodulatory
effects, providing a rationale for combining
PD-1/PD-L1 inhibitors with chemotherapy
• Chemotherapy may be synergistic in
combination with immunotherapy; its ability to
increase tumor immunogenicity may enhance
tumor-specific T-cell activation when combined
with immune checkpoint blockade
− Immunogenic cell death
− Enhanced presentation of tumor-specific
antigens
− Increased T-cell activation by DC
IO Monotherapy IO + TKI4,5
IO + Chemo6
PD-1/PD-L1 Checkpoint Inhibition
- -
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
• Selected trials in the recurrent setting1
– Phase 2 KEYNOTE-158 (pembrolizumab)2,a
– Phase 1 GARNET (dostarlimab)3,a
– Phase 2 PHAEDRA (durvalumab)
• Selected trials1
– Phase 3 KEYNOTE-775
(pembrolizumab + lenvatanib, in the
recurrent setting)a
– Phase 3 LEAP-001
(pembrolizumab + lenvatanib, in the
frontline setting)
• Selected trials in the frontline setting1
– Phase 3 RUBY (dostarlimab + chemo)
Positive results reported
– Phase 3 NRG-GY018 (pembrolizumab + chemo)
Positive results reported
– Phase 3 AtTEnd (atezolizumab + chemo)
– Phase 3 DUO-E (durvalumab + chemo)
• Angiogenesis and evasion of immune
destruction are hallmarks of cancer, supporting
the rationale for combining VEGFR TKI and
immunotherapies targeting PD‐1/PD-L1
• Targeting TKIs may promote an immune-
permissive tumor environment and enhance
responses to immune checkpoint inhibitors
− Reduction in Treg activity
− Reversal of immunosuppressive effects of
VEGF
− Improved T-cell trafficking and infiltration of
CD8+ into the tumor bed
Anti-VEGF/R Vessel normalization
Depletion
Increasing of infiltration
and activation
Increasing of
infiltration and
activation
Differentiation
iDC
MDSC
Treg
CD8
Tumor cell Normal cell
PD-L1
PD-L1
Inhibition
PD-L1
CD8
CD4
TAM
Anti–PD-1/PD-L1 Immunotherapy alone Immunotherapy + chemotherapy
Immuno-suppressive
tumor microenvironment
Immuno-reactive tumor
microenvironment
CD8+
Tc
PD-L1 sensitivity
CD8+
Tc
Tregs
Tregs
APC, MDSC
APC, MDSC
"Cold tumor" "Hot tumor"
+ + +
+