1.
Shifting to Personalized Approaches: The Role of Molecular Profiling Predictive Biomarkers
Genetic profiling enables personalized
approaches to endometrial cancer care.
Not all cancers act the same. In fact, different
types of cancer have their own natural histories
and respond differently to various medications.
Traditional histologic classifications
of high- or low-grade endometrioid or
serous carcinomas are shifting based
on molecular profiling.
Molecular profiling allows for personalized
treatment selection because it identifies
genetic/biologic characteristics about patients'
endometrial cancer, which guides
decision-making and treatment selection.
 High grade
 Low grade
• The cancer immunotherapy
landscape is rapidly
expanding
• The benefit of immune
checkpoint inhibitors, both
as single agents and in
combination approaches,
is seen across different
tumor types and treatment
settings
• Predictive biomarkers can
guide clinical decisions
regarding the use
of immunotherapies
• MSI/MMR and TMB are
immunotherapy
biomarkers across many
cancers
Biomarkers and Biomarker Testing
in Endometrial Cancer1-4
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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 Cancer1-4
Full abbreviations, accreditation, and disclosure information available at PeerView.com/GEP40
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.

3.
Managing Immune-Related
Adverse Events1-4
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available at PeerView.com/GEP40
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 Managment

4.
1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. 3. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related
Toxicities. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 4. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.
5. Makker V et al. Oncologist. 2021;26:e1599-e1608. 6. How JA et al. Gynecol Oncol. 2021;162:24-31.
Managing Immune-Related
Adverse Events5,6
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available at PeerView.com/GEP40
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

5.
Numerous Strategies Under Study in
Advanced Endometrial Cancer
Full abbreviations, accreditation, and disclosure information available at PeerView.com/GEP40
1. https://clinicaltrials.gov. 2. Daly RJ et al. Mol Cancer. 2022;21:189. 3. Bailly C et al. NAR Cancer. 2020;2(1): zcaa002. 4. Vergote IB et al. ESMO 2022. 5. Makker V et al. ASCO 2022. Abstract 5511. 6. Fung HY and Chook YM. Semin Cancer Biol. 2014;27:52-61.
7. Tai YT et al. Leukemia. 2014;28:155-165.
• 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
• Exportin 1 (XPO1) is the major nuclear
export protein for6
– Tumor suppressor proteins (TSPs), eg, p53,
lkB, PTEN, FOXO1
• Inhibition of XPO1 results in6
– Increase in nuclear levels and activation of TSPs
– Reduction of oncoprotein levels
• Selinexor is an oral selective XPO1 inhibitor
– Preclinical data shows reactivation of
multiple TSPs (including p53 wild-type) by
preventing nuclear export7
IO Monotherapy Combinations XPO1 Inhibition4,5
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 trials1
– Phase 2 KEYNOTE-158 (pembrolizumab)
– Phase 1 GARNET (dostarlimab)
– Phase 2 PHAEDRA (durvalumab)
• Selected trials1
– Phase 3 KEYNOTE-775
(pembrolizumab + lenvatanib)
– Phase 3 LEAP-001
(pembrolizumab + lenvatanib)
• Selected trials1
– Phase 2 SIGN
– Phase 3 SIENDO
– Phase 3 XPORT-EC
• 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
Cell membrane
Nuclear envelope
Nuclear pore complex
Cytoplasm
Nucleus
Selinexor
Tumor Suppressor Proteins
P53
pRb
P21
IkB
BRCA1
FOXO3a
Oncoprotein mRNA
eF4E
c-Myc
Bcl-6
Bcl-2
Cyclin D1
Pim1
MDM2
Glucocorticoid
Receptor
XPO1
IO + TKI2
IO + Chemo3
• 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
• Selected trials1
– Phase 3 NRG-GY018
(pembrolizumab + chemo)
– Phase 3 AtTEnd (atezolizumab + chemo)
– Phase 3 RUBY (dostarlimab + chemo)
– Phase 3 DUO-E (durvalumab + chemo)