Chair, David M. O'Malley, MD, Ana Oaknin, MD, PhD, and Matthew A. Powell, MD, prepared useful Practice Aids pertaining to endometrial cancer for this CME/MOC/AAPA activity titled “Endometrial Cancer Care in the Age of Immunotherapy: Translating Clinical Evidence Into Meaningful Improvements in Patient Outcomes Across the Disease Continuum.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at https://bit.ly/40bmalK. CME/MOC/AAPA credit will be available until July 3, 2024.

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
Generates valuable information early
in the treatment course as therapies
move into the frontline setting
HER2 IHC testing should also
be considered in TP53-aberrant
endometrial carcinoma regardless
of histotyping
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
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UDV40

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/UDV40
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 2.2023.
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

3. Managing Immune-Related
Adverse Events1-7
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/UDV40
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 Events1-7
Full abbreviations, accreditation, and disclosure information
available at PeerView.com/UDV40
Consult irAE management guidelines
(eg, ASCO, NCCN, SITC, ESMO, SGO)
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 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 4. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. 5. Naidoo J
et al. J Immunother Cancer. 2023;11:e006398. 6. Haanen J et al. Ann Oncol. 2022;33:1217-1238. 7. O’Cearbhaill RE et al. Gynecol Oncol. 2022;166:25-35.

5. Numerous Immunotherapy Strategies Under Study in
Advanced Endometrial Cancer
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UDV40
a
FDA-approved regimen.
1. https://clinicaltrials.gov. 2. Keytruda (pembrolizumab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136lbl.pdf. 3. Jemperli (dostarlimab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2023/761174s003s004lbl.pdf. 4. Daly RJ et al. Mol Cancer. 2022;21:189. 5. Ciciola P et al. J Clin Med. 2020;9:675. 6. Bailly C et al. NAR Cancer. 2020;2:zcaa002.
• 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"
+ + +
+

6. Patient-Centered Education: Understanding Treatment
Options for Endometrial Cancer
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UDV40
Patient-centered education and support is key in care for endometrial cancer, as
receiving a cancer diagnosis can be overwhelming for patients and their caregivers.
The printable resource on the following page is designed to help patients
and their caregivers understand endometrial cancer, navigate treatment options,
and find support.
Printable Resource

7. Spotlight on Clinical Trials
Your cancer care team may offer you the option of enrolling in a clinical trial. These studies provide
important information on whether a treatment is safe and effective and give you access to new
strategies that could be better than the options currently used.
Clinical trial enrollment is voluntary. Each trial has specific enrollment criteria, such as
age, type of cancer, stage, and prior treatments. Talk to your patient care team
about whether clinical trial enrollment is right for you.
Where Can You Get More Support?
Reach out to your nurses—nurses are gatekeepers and provide holistic support to patients.
They bring clinical trial expertise to patients and caregivers, help in coordination of care, psychosocial assessments, facilitation of communication across disciplines, guidance for
support service referrals, check-in phone calls, tools to help patients take their medications at the right time, and more.
Online and in-person advocacy organizations for patients and their caregivers provide a variety of services, including support groups, counseling, financial assistance, information on treatments and
clinical trials, opportunities to support and participate in research, and educational workshops. Your cancer care team and the links below are good resources for finding in-person and online support.
 Society of Gynecologic Oncology: https://www.sgo.org/patient-resources/uterine-cancer/
 ECANA: Endometrial Cancer Action Network for African-Americans: https://ecanawomen.org/
 American Cancer Society: https://www.cancer.org/cancer/types/endometrial-cancer.html
What Is the Role of Genetic Testing in Endometrial Cancer?
Genetic mutations can be inherited or they can be acquired (develop on their own)
Information from genetic testing allows your provider to select the most appropriate treatment
option for your specific type of endometrial cancer
Genetic testing results may help you and your doctor understand how your cancer behaves and
how fast it will grow
Results can also provide information on whether the patient's family members may be at risk for
the same or a different cancer
Genetic testing for endometrial cancer is universally recommended for all patients at diagnosis
What Are the Different Treatment Options for Endometrial Cancer?
Chemotherapy
Radiation
Immune checkpoint inhibitors
Tyrosine kinase inhibitors
Determining which treatment is right for you depends on your age
and the type of endometrial cancer you have. Your cancer care team will help
you make a decision that takes into account your goals and preferences.
PARP inhibitors
Combination approaches
Rash
Diarrhea
Underactive thyroid
Dizziness
Nausea or vomiting
Muscle or joint aches
Fatigue
Headache
What Are Some Common Side Effects Associated
With Treatments for Endometrial Cancer?
Treatment for endometrial cancer can result in a number of side effects depending on the
regimen chosen. Talk to your doctor about how your treatment may affect your quality of life.
Understanding Endometrial Cancer:
A Quick Reference for Patients and Caregivers
If you or someone you love has been diagnosed with endometrial cancer,
you may have a lot of questions about treatment options and where you can turn for help.