Join Dr. Bhavana Pothuri, gynecologic oncologist at NYU Langone Medical Center, as she breaks down the different types of uterine cancer treatments available to patients based on their particular diagnosis. Learn about new research and treatment updates, options for when cancer recurs, side effects, and more.

1. THE EVOLVING ENDOMETRIAL CANCER
LANDSCAPE
Bhavana Pothuri, MD, MS
Professor, Dept of Ob/Gyn and Medicine, NYU Grossman School of Medicine
Medical Director, Clinical Trials Office (CTO)
Director, Gynecologic Oncology Clinical Trials
Laura & Isaac Perlmutter Cancer Center, NCI Designated Comprehensive
Cancer Center
Associate Clinical Trial Advisor, GOG Partners
Director of Diversity and Health Equity for Clinical Trials, GOG Foundation

2. Disclosures
• Research support: AstraZeneca, Clovis Oncology, Tesaro/GSK, ImmunoGen,
Roche/Genentech, SeaGen, Merck, Mersana, Celsion/Imunon, Karyopharm,
Sutro, Imab, Toray
• Advisory board: Clovis oncology, Tesaro/GSK Inc, Lily AstraZeneca, Merck,
Eisai, Mersana, Sutro, SeaGen, Imvax, GOG Foundation

3. • Background
• Molecular classification and new staging
• Current Standard Treatments
• Recent advances in treatment
• Future frontline treatment /Ongoing trials
• Recurrent Em ca Treatments
Frontline Endometrial Cancer Treatment

4. Endometrial Cancer 2023
66,200 new cases* 13,030 deaths*
Siegel et al. Cancer Statistics 2023
Cancer Facts & Figures 2023. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-
figures/2023/2023-cancer-facts-and-figures.pdf. Accessed January 31, 2023.
Population of interest
~2/3 of these will have
early stage and low
grade disease with
excellent prognosis
~ 1/3 will have high
grade or advanced
stage/metastatic
disease
Increasing
Incidence
Increasing
Mortality
Anticipated to
surpass ovarian
cancer mortality in
the coming years

5. Endometrial Cancer
Year Cases Deaths
1987 35,000 2,900
2008 52,630 8,590
2017 61,380 10,920
% Increase 75% 276%
NCI. https://seer.cancer.gov/statfacts/html/corp.html.
Published April 2021. Accessed June 3, 2021. Clarke MA et
al. J Clin Oncol. 2019;37(22):1895-1908.

6. Trends in uterine and ovarian
cancer mortality rates by race
and ethnicity, US 1990–2019.
All racesand ethnicities Uterus/ovary rate ratio
non-Hispanic White non-Hispanic Black
non-Hispanic API Hispanic
Giaquinto Obstet & Gynecol Feb 2022

7. New York Times. June 17, 2022
• Mortality rates for endometrial cancer are
now similar to ovarian cancer
– This change comes from declining rates for
ovarian cancer and increasing rates for
endometrial cancer (2% annually 2008-2018)
• The burden for Black women has
increased disproportionately
• Reflects a significant racial disparity in
cancer care
• Racial disparities cannot be completely
explained by differences in histology and
stage alone

8. Why is Diversity Important?

9. Generalizability of clinical trials
Gross, Annette S et al. “Clinical trial diversity: An opportunity for improved insight into the determinants of variability in drug response.” British
journal of clinical pharmacology vol. 88,6 (2022): 2700-2717. doi:10.1111/bcp.15242

10. Minority Accrual in Clinical Trials in the US
• Study populations vary by institution and cancer type, but patients from
minority racial/ethnic backgrounds are consistently underrepresented
–Black patients represent 15% of people with cancer but only 4-6% of
trial participants
–Hispanic patients represent 13% of people with cancer but only 3-6%
of trial participants
• Less than 33% of cancer trials report race/ethnicity data so
underrepresentation is likely more extreme
• Phase 1 trials particularly do not represent the population with the
greatest medical need
Unger et al J Natl Cancer, 2019
Duma et al. J Oncol Practice 2018

11. Why we need inclusive participation in clinical trials
• Reflect racial/ethnic diversity of the
population expected to use the
medicine
• Understand potential differences in
efficacy and safety
• Help mitigate racial/ethnic disparities in
health outcomes
• Promote equity and justice.
ASCO: “Access to clinical trials is a critical component of high quality cancer care”

12. Barriers to Achieving DEI in Clinical Trials
• Access to trials
• Diversity of
research staff
• Restrictive
eligibility criteria
• Numerous visits
• Limited info
• Financial
barriers
• Distrust
• Language
• Bias
• Limited time,
personnel to
search for trials
Clinician
Barriers
Patient
Barriers
Institutio
n
Barriers
Trial
Barriers

13. ASCO and ACCC Joint Research Statement
• Outlines 6 key
recommendations to increase
racial and ethnic diversity in
cancer clinical trials
• Recommendations apply to
trial sponsors, investigators,
organizational leadership,
clinical and research teams
Oyer et. Al. J Clin Oncol. 2022

15. Molecular Classification/ New FIGO Staging

16. Type I Type II
Precursor:
estrogen related
Yes No
Frequency 80% 20%
Histology Endometrioid CCC, serous,
mucinous
Prognosis Good Bad
Endometrial Cancer was thought to be a simple disease
1983 The Bokhman’s dualistic model

17. Molecular Classification of Endometrial Cancer: From 2 to 4 Groups
The Cancer Genome Atlas Research Network. Nature. 2013;494(7438):506.
POLEmut dMMR/MSI-H CNL p53abn
POLE mutations are
ultra-mutated, 100-
500 mutations/Mb
MSI high group with
10-20mut/Mb,
CN high: 2-3
mutations/Mb, high
grade
CN Low: 2-3
mutations/Mb,
endometrioid, G1

18. Prognostic Significance of Subgroups Confirmed
in Studies
PFS
Months
Log-rank P = 0.02
0
0
20
20
40
60
80
100
40 60 80 100 120
TCGA1
n=373
POLEmut dMMR/MSI-H Copy-number low/MSS/p53 wt/NSMP Copy-number high/p53abn
DSS
P < 0.001
0
0.0
2
0.2
0.4
0.6
0.8
1.0
4 6 8 10 12
PORTEC-22
n=317
dMMR, mismatch repair deficient; DSS, disease-specific survival; IHC, immunohistochemistry; MMR, mismatch repair; NSMP, no specific molecular profile; PFS, progression-free
survivall; TGCA, Cancer Genome Atlas Research Network; wt, wild type.
1. Cancer Genome Atlas Research Network, et al. Nature. 2013;497:67-73 2.. Wortman BG, et al. Br J Cancer. 2018;119:1067–1074.
 POLEmut
tumors have
significantly
better survival,
whereas
p53mut
(copy-number
high) tumors
have the
poorest
outcomes

19. TransPORTEC Initiative: PORTEC-3 Trial Confirmed Prognostic
Significance In High Risk Patients
25
50
75
100
1 2 3 4 5
0
Recurrence-free
survival
(%)
Time since random assignment (years)
P log-rank <0.001
No at risk:
P53abn 93 72 57 49 44 32
POLEmut 51 50 50 49 48 37
dMMR 137 124 112 102 96 74
NSMP 129 122 113 105 94 69
25
50
75
100
1 2 3 4 5
0
Recurrence-free
survival
(%)
Time since random assignment (years)
P log-rank <0.001
No at risk:
P53abn 93 87 71 61 52 37
POLEmut 51 51 50 49 48 37
dMMR 137 136 128 115 108 85
NSMP 129 125 122 118 110 85
RFS According to Molecular Subgroup OS According to Molecular Subgroup
León-Castillo A et al. J Clin Oncol. 2020;38:3388–3397.
POLEmut dMMR/MSI-H Copy-number low/MSS/p53 wt/NSMP Copy-number high/p53abn

20. PORTEC-3
21
Predictive role
21
xx
Leon-Castillo et al, JCO 2020
Great benefit
from CT
No added
benefit from CT
No benefit from
CT
No statistically
significant
benefit from CT

21. NCCN Guidelines® (V2.2023) Biomarker Testing
Recommendations for Endometrial Carcinoma
• 4 clinically significant molecular subgroups
identified with different clinical prognoses:
—POLE mutations
—MSI-H
—Copy-number low
—Copy-number high
22
NCCN Guidelines. Version 2.2023-April 28, 2023. Uterine Neoplasms.
DNA MMR protein
IHC POLE
POLE hotspot mutation
No POLE hotspot
mutation
POLE sequencing
MSI-H
Expression lost
Expression retained
p53 immunohistochemistry
Copy-number low
Copy-number
high
Normal/wild-type
pattern
Aberrant/mutant
pattern

22. 23
Identification of patients who may be more
sensitive to different treatment options
Estimate PFS and OS according to
molecular class
Prognostic
factor
Predictive
factor
Identification of patients who may harbour
genes’ mutations (Lynch syndrome)
Genetic
screening
More objective attribution to a specific
risk class
Risk
Assessment
Clinical implications of Molecular Testing
Molecular classification’s roles

23. FIGO EC Staging Updates (2023)
24
1. Léon-Castillo A. Int J Gynecol Cancer. 2023;33:333-342. 2. Olawaiye A. SGO 2023. Abstract 212. 3. Concin N, et al. Int J Gynecol
Cancer. 2021;31(1):12-39. 4. Oaknin A, et al. Ann Oncol. 2022;33(9):860-877.
 The 2021 ESGO/ESTRO/ESP guidelines and
the 2022 ESMO clinical practice guidelines have
integrated the molecular subgroups with
traditional clinicopathological features into a
novel risk stratification system to assess relative
risk of recurrence, with subsequent impact on
adjuvant treatment decisions1
“The authorities that collect staging information
in the US, including the NCDB, collect in the TNM
system… The [published] FIGO endometrial
cancer staging will not be adopted until the TNM
is ready... We are probably 1½ to 2 years [out]
before the staging is adopted in the US.”
– Dr. Alexander Olawaiye, SGO 20232

24. Updated FIGO EC Recommendations (2023)
25
Berek JS, et al. Int J Gynaecol Obstet. 2023;162(2):383-394.
 Data and analyses from the molecular
and histological classifications performed
and published in the recently developed
ESGO/ESTRO/ESP guidelines were used
as a template for adding the new
subclassifications to the proposed
molecular and histological staging system
 Complete molecular classification
(POLEmut, MMRd, NSMP, p53abn) is
encouraged in all endometrial carcinomas
and as potential influencing factors of
adjuvant or systemic treatment decisions
— If the molecular subtype is known, this is
recorded in the FIGO stage by the
addition of “m” for molecular classification,
and a subscript indicating the specific
molecular subtype
— When molecular classification reveals
p53abn or POLEmut status in Stages I
and II, this results in upstaging or
downstaging of the disease (IICmp53abn or
IAmPOLEmut)
Prognosis Definition
Good
prognosis
Pathogenic POLE mutation (POLEmut)
Intermediate
prognosis
Mismatch repair deficiency
(dMMR)/microsatellite instability (MSI)
dMMR/MSI and no specific molecular profile
(NSMP)
Poor
prognosis
p53 abnormal (p53abn)
Stage designation
Molecular findings in patients with early
endometrial cancer (Stages I and II after
surgical staging)
Stage IAm-POLEmut
POLEmut endometrial carcinoma, confined to the
the uterine corpus or with cervical extension,
regardless of the degree of LVSI or histological type
Stage IICm-p53abn
p53abn endometrial carcinoma confined to the
uterine corpus with any myometrial invasion, with
with or without cervical invasion and regardless of
of the degree of LVSI or histologic type

25. Frontline Therapy

26. GOG 209
Established carboplatin and paclitaxel as the chemotherapy backbone for patients with advanced
stage or recurrent disease

27. CT TAP
ORR (%) 52 52
PFS
(mos)*
13.2 13.9
OS (mos) 20.4 22
* PFS includes both radiologically apparent
and non-apparent disease
Carboplatin and Paclitaxel established as
Standard of Care for 1L EC
GOG209: Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall
Survival and Adverse Event Analysis of a Phase III, Randomized, Noninferiority, Open-
Label Trial
Miller et al. JCO 2020

28. Phase 3 Clinical Trial Data With 1L IO:
Study Designs
30
1. Eskander RN, et al. SGO 2023. Abstract 264. 2. Eskander RN, et al. N Engl J Med. 2023. doi:10.1056/NEJMoa2302312
3. Mirza MR, et al. SGO 2023. Abstract 265. 4. Mirza MR, et al. N Engl J Med. 2023. doi: 10.1056/NEJMoa2216334.
GOG-3031/RUBY Part 13,4
NRG-GY0181,2
Key Eligible Patients
 Histologically/cytologically proven advanced or recurrent EC
 Stage III/IV disease or first recurrent EC with low potential for cure
by
Rt or Sx alone or in combination
— Carcinosarcoma, clear cell, serous, or mixed histology
permitted
 Naive to systemic therapy or systemic anticancer therapy and
recurrence/PD ≥6 months after completing treatment
 ECOG PS 0-1
Stratification
Factors
 MMR/MSI status
 Prior pelvic RT
 Disease status
Primary Endpoints
 PFS by INV
 OS
Secondary Endpoints
 PFS by BICR, PFS2, ORR,
DOR, DCR , HRQoL/PRO,
safety
Dostarlimab IV 500 mg
Carboplatin AUC 5 mg/mL/min
Paclitaxel 175 mg/m2
q3w for 6 cycles
Placebo
Carboplatin AUC 5 mg/mL/min
Paclitaxel 175 mg/m2 q3w for
6 cycles
Placebo IV
q6w up to
3 years
Dostarlimab IV
1000 mg
q6w up to
3 years
Randomization
1:1
Key Eligibility Criteria
 Measurable stage III/IVA or measurable/nonmeasurable stage IVB
or recurrent EC
 No prior Chemo except prior adjuvant Chemo if completed
≥12 months before study
 ECOG PS 0-1 or 2
Pembrolizumab 200 mg IV q3w
Paclitaxel 175 mg/m2 IV q3w
Carboplatin AUC 5 IV q3w
for 6 cycles
Placebo IV q3w
Paclitaxel 175 mg/m2 IV q3w
Carboplatin AUC 5 IV q3w
for 6 cycles
Placebo IV q6w
for up to
14 additional cycles
Pembrolizumab
400 mg IV q6w
for up to
14 additional cycles
Randomization
1:1
Stratification Factors
 MMR/MSI status
 ECOG PS (0-1 vs 2)
 Prior adjuvant
Chemo
Primary Endpoints
 PFS per RECIST v1.1
by investigator in
MMRp and dMMR
populations
Secondary Endpoints
 Safety, ORR/DOR,
OS (MMRp and
dMMR), QOL (MMRp)

29. Dostarlimab +
CP
Placebo + CP
Most Recent Clinical Trial Data With 1L IO: PFS in dMMR
31
aMedian follow-up time was 12 months. PFS in dMMR population was a primary endpoint of the study bMedian follow-up time was 24.79 months. PFS in dMMR/MSI-H population was a primary endpoint of the
study.
1. Eskander RN, et al. SGO 2023. Abstract 264. 2. Eskander RN, et al. N Engl J Med. 2023. doi:10.1056/NEJMoa2302312
3. Mirza MR, et al. SGO 2023. Abstract 265. 4. Mirza MR, et al. N Engl J Med. 2023. doi: 10.1056/NEJMoa2216334.
NRG-GY018: PFS in dMMR Population1,2,a GOG-3031/RUBY Part 1: PFS in dMMR/MSI-H
Population3,4,b
Events,
n/N
Median
(95% CI), mo
HR
stratified;
95% CI
Pembrolizumab
+ CP
26/112
NR
(30.6-NR) 0.30
(0.19-0.48)
P<0.00001
Placebo + CP 59/113
7.6
(6.4-9.9)
Events,
n/N
Median
(95% CI), mo
HR stratified;
95% CI
Dostarlimab + CP 19/53
NE
(11.8-NE) 0.28
(0.16-0.50)
P<0.001
Placebo + CP 47/65
7.7
(5.6-9.7)
 12-mo PFS rate: 74% vs 38%
 24-mo PFS rate: NE
 12-mo PFS rate: 63.5% vs 24.4%
 24-mo PFS rate: 61.4% vs 15.7%

30. Moving Efforts to the Frontline: Immunotherapy vs.
Chemotherapy
ENGOT-en13
DOMENICA
GOG 3064
KN-C93
ENGOT-en9
LEAP-001

31. Dostarlimab + CP
Placebo + CP
Most Recent Clinical Trial Data With 1L IO: PFS MMRp
33
.
aMedian follow-up time was 7.9 months. PFS in MMRp/MSS population was a primary endpoint of the study. bPFS maturity was 65.4%. PFS in MMRp/MSS population was a prespecified subgroup analysis.
1. Eskander RN, et al. SGO 2023. Abstract 264. 2. Eskander RN, et al. N Engl J Med. 2023. doi:10.1056/NEJMoa2302312
3. Mirza MR, et al. SGO 2023. Abstract 265. 4. Mirza MR, et al. N Engl J Med. 2023. doi: 10.1056/NEJMoa2216334.
GOG-3031/RUBY Part 1: PFS in MMRp/MSS
Population3,4,b
Events,
n/N
Median
(95% CI), mo
HR
stratified;
95% CI
Pembrolizumab
+ CP
89/290
13.1
(10.5-18.8) 0.54
(0.41-0.71)
P<0.00001
Placebo + CP 133/292
8.7
(8.4-10.7)
Events,
n/N
Median
(95% CI), mo
HR stratified;
95% CI
Dostarlimab + CP 116/192
9.9
(9.0-13.3) 0.76
(0.59-0.98)
Placebo + CP 130/184
7.9
(7.6-9.8)
NRG-GY018: PFS in MMRp Population1,2,a
 12-mo PFS rate:
NE
 24-mo PFS rate:
NE
 12-mo PFS rate:
43.5% vs 30.6%
 24-mo PFS rate:
28.4% vs 18.8%

32. Moving IO & PARPi to Front Line Metastatic:
Completed Phase 3 Trials
GOG 3031 Ruby Part 2:
NCT03981796
PRIMARY ENDPOINT
BICR assessed PFS per RECIST v1.1: 1) All Patients 2) MSI-
H
Stratification:
MSI/MMR Status), WPRT, Disease Status (Primary Stage III,
Stage IV, First Recurrent)
GOG 3041: DUO-E
NCT04269200

33. DUO-E: PFS
Control
(N=192)
Durva
(N=192)
Durva+Ola
(N=191)
Events, n (%) 148 (77.1) 124 (64.6) 108 (56.5)
Median PFS (95% CI),*
months
9.7 (9.2–10.1) 9.9 (9.4–12.5) 15.0 (12.4–18.0)
HR (95% CI) vs Control† 0.77 (0.60–0.97) 0.57 (0.44–0.73)
HR (95% CI) vs Durva† 0.76 (0.59–0.99)
PFS: pMMR (80% of population)
Durva+Ola
Durva
Control
PFS,
%
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Months since randomisation
12 months
59.4%
44.4%
40.8%
18 months
42.0%
31.3%
20.0%
Westin S. ESMO 2023.
Control
(N=241)
Durva
(N=238)
Durva+Ola
(N=239)
Events, n (%) 173 (71.8) 139 (58.4) 126 (52.7)
Median PFS (95% CI),* months 9.6 (9.0–9.9) 10.2 (9.7–14.7) 15.1 (12.6–20.7)
HR (95% CI) vs Control† 0.71 (0.57–0.89);
P=0.003
0.55 (0.43–0.69);
P<0.0001
HR (95% CI) vs Durva† 0.78 (0.61–0.99)
Overall data maturity 61.0%
PFS: ITT (primary endpoint)

34. Future Maintenance Therapies

35. Selenixor: XPO1 Inhibition -Exportin 1 (XPO1) is the
major nuclear export protein for
Tumor suppressor proteins
(TSPs, e.g., p53, IkB, and
FOXO)
-Inhibition of XPO1 impacts
tumor by reactivating multiple
TSPs by preventing nuclear
export and Inhibits oncoprotein
translation
-Selinexor is an oral selective
XPO1 inhibitor

36. Non-IO regimens in the 1L ENGOT-EN5/GOG-3055/SIENDO

37. GOG 3055: SIENDO Selinexor (SINE) as Switch Maintenance
Median PFS:
Selinexor (n=174) 5.7 mo (95% CI 3.8 – 9.2)
Placebo (n=89) 3.8 mo (95% CI 3.68-7.39)
Audited HR =0.705 (95% CI 0.499-0.996;p=0.024)
PFS: ITT
PFS: TP53 wt (Prespecified, exp
endpoint)
Median PFS:
Selinexor (n=67) 13.7 mo (95% CI 9.2-NR)
Placebo (n=36) 3.7 mo (95% CI 1.87-12.88)
Audited HR =0.375 (95% CI 0.229-0.670; p=00003)
Confidential – For Internal Use Only. Not for Promotion. Embargoed Data

38. SIENDO: Long-term PFS, TP53
Pre-specified subgroups

39. PFS in TP53wt subgroup based on MSI/MSS status
41
P53wt / MSS P53wt / MSI
TP53wt / MSS TP53wt / MSI
• These results suggest improvement in PFS was seen regardless of MSI/MSS status with selinexor
maintenance treatment in the TP53wt subgroup
EC, endometrial cancer; HR, hazard ratio; mo, months; MSI, microsatellite instability; MSS, microsatellite stable; PFS, progression-free survival; wt, wild-type.
• Selinexor 13.1 mo
• Placebo 3.7 mo
• HR 0.53 (0.18-1.56)
• P value = 0.12
• Selinexor 27.4 mo
• Placebo 4.9 mo
• HR 0.36 (0.17-0.75)
• P value = 0.002

40. Selinexor
60mg QW
until PD
Placebo
until PD
Primary Endpoint:
• PFS assessed by
Investigator
(BICR as a sensitivity
analysis)
Secondary Endpoint:
• OS
• Safety
n = 220 PFS (HR 0.7)
Key Eligibilities
• Known p53wt EC by central NGS
• Primary stage IV or recurrent EC
• Received at least 12 weeks of
taxane-platinum chemotherapy
(1st or 2nd line)
Stratified by:
• Primary stage IV vs
recurrent
• PR vs CR
• Prior CPI (yes/no)
PR/CR
Per RECIST
v1.1
R
1:
1
ENGOT-EN20/GOG3083/XPORT-EC-042 Randomized, blinded Phase 3 international study
of oral Selinexor once weekly versus placebo for maintenance therapy in patients with
p53wt endometrial carcinoma responding to front line chemotherapy) NCT05611931
Primary Objective: To evaluate the efficacy of selinexor compared to placebo as
maintenance therapy in patients with p53wt advanced or recurrent endometrial cancer
GOG/ENGOT Trial
GOG PI: Coleman

41. 43
Strictly Confidential
MDM2 is a Key Negative Regulator of p53
• Abbreviations: MDM2, murine double minute 2; p53, tumor suppressor protein 53.
MDM2 modulates p53 activity by
Directly inhibiting p53 transcriptional activity
Transporting p53 out of the nucleus
Ubiquitinating and tagging p53 for proteasomal degradation
1
2
3
MDM2 upregulation or overexpression within malignant cells
can drive cancer-cell proliferation
MDM2 inhibitors (Navtemadlin) can restore normal p53
tumor-suppressor function leading to cell death (apoptosis)
MDM2 is a promising target for anti-cancer drug development
2
1
3
Normal cell
DNA p53
Nucleus
p53
degradation
MDM2
Cytosol
© 2022 Kartos Therapeutics, Inc.
Cancer cells
DNA
p53
Nucleus
p53
degradation
MDM2
overexpression
Cytosol
© 2022 Kartos Therapeutics, Inc.

42. 44
Strictly Confidential
ARM
A/B
Navtemadlin Phase 3
Dose
7D ON, 21D OFF
(n=130)
ARM
C/D
Placebo
7D ON, 21D OFF
(n=65)
Randomized
2:1
(Double
Blind)
GOG 3089: A Two-Part, Randomized Phase 2/3 Maintenance
Study of Navtemadlin in Subjects With TP53WT in Advanced
or Recurrent Endometrial Cancer Who Responded After
Chemotherapy NCT05797831
• 1 Cycle: 28 days
• Abbreviations: BIRC, blinded independent radiographical committee; CR, complete remission; D, day; DCR, disease control rate (CR + PR + stable disease); Inv, investigator assessed; NGS, next-generation sequencing;
ORR, objective response rate (per RECIST v1.1); OS, overall survival; PFS, progression free survival; PK, pharmacokinetics; PR, partial response; TFST, time to first subsequent treatment.
PRIMARY ENDPOINTS KEY SECONDARY ENDPOINTS EXPLORATORY OBJECTIVES
Part 1: To determine the navtemadlin Phase 3 Dose • To evaluate the ORR, DCR, PFS and OS
• To determine the PK profile of navtemadlin
Part 1 and Part 2:
• To evaluate efficacy and safety of navtemadlin
relative to select PD markers
• To monitor the PK of navtemadlin (Part 2 only)
Part 2: To compare PFS (BIRC) between
navtemadlin and placebo
• To compare the ORR, DCR, PFS, TFST and OS
between navtemadlin and placebo
ENROLLMENT PART 1: PHASE 2, N=63 PART 2: PHASE 3, N=195
ARM
1
Navtemadlin 180 mg
QD
7D ON, 21D OFF
(n=21)
ARM
2
Navtemadlin 240 mg
QD
7D ON, 21D OFF
(n=21)
ARM
3 Observational Control
28D
(n=21)
Randomized
1:1:1
(Open
Label)
Women with TP53WT
advanced or recurrent
endometrial cancer who have a
PR/CR after completion of up to 6
cycles of platinum-based
chemotherapy

43. Recurrent Disease

44. Current treatment algorithm for recurrent endometrial cancer
MSI/dMMR testing
TMB testing
MSI-H/dMMR
High TMB
Pembrolizumab
or Dostarlimab
MSS/pMMR
Low TMB
Pembrolizumab
and Lenvatanib

45. Response to single agent IO in dMMR or MSI-high endometrial
Single Agent IO in “biomarker” Selected Endometrial Cancer
Populations (dMMR)
Marabelle A, et al. J Clin Oncol, 2019
Antill PSK et al. J Clin Oncol 2019
Oaknin A et al. SGO virtual meeting 2020
Konstantinopoulos PA et al. J Clin Oncol 2019
Study & Drug Patient Population Outcome
Keynote 158: Pembrolizumab (N=49) Advanced stage or metastatic
dMMR endometrial cancer
ORR: 57.1%
PHAEDRA trial: Durvalumab (N=35
dMMR)
Advanced stage or metastatic
endometrial cancer
ORR in dMMR: 43%
GARNET study: Dostarlimab (N=70) Previously treated, recurrent
advanced stage endometrial cancer
ORR in dMMR: 45%
Ph II Avelumab study (N= 15 dMMR) Advanced stage or metastatic
endometrial cancer
ORR: 26.7%

46. Dostarlimab (Garnet A1): Anti-tumor Activity in dMMR/MSI-H
48
dMMR/MSI-H
EC
N=143
MMRp/MSS EC
N=156
Median follow-up time, months 27.6 33.0
ORR, % (95% CI; n/N)
Complete response, n (%)
Partial response, n (%)
Stable disease, n (%)
Progressive disease, n (%)
Not evaluable, n (%)
45.5% (37.1–
54.0; 65/143)
23 (16.1%)
42 (29.4%)
21 (14.7%)
51 (35.7%)
6 (4.2%)
15.4% (10.1–22.0;
24/156)
4 (2.6%)
20 (12.8%)
29 (18.6%)
88 (56.4%)
15 (9.6%)
Median time from cycle 1 day 1
to best overall response, mo
Complete response
Partial response
2.79
2.69
2.81
2.79
Disease control rate, % (95%
CI; n/N)
60.1% (51.6–
68.2; 86/143)
34.0% (26.6–42.0;
53/156)
Response ongoing, n (%) 54 (83.1%) 9 (37.5%)
Median duration of response
(range), months
NR (1.18+ to
47.21+)
19.4 (2.8 to 47.18+)
Probability of maintaining
response, %
6 months
12 months
24 months
96.8
93.3
83.7
82.6
60.3
44.2
10
−10
−30
−50
−70
−90
Patients
−110
30
50
70
90
110
130
Percent
change
CR
PR
SD
PD
NE
MMR-unk/MSI-H
Ongoing
dMMR/MSI-H EC
Oaknin, Asco 2022
FDA Approval April 2021
Dostarlimab was granted accelerated approval for
adult patients with dMMR-recurrent or advanced
endometrial cancer; FDA Regular Approval Feb 9,
2023
FDA Approval August 2021
Approved for adult patients with dMMR recurrent
or advanced solid tumors.

47. Pembrolizumab (KEYNOTE-158): Antitumor Activity in Patients With MSI-
H/dMMR Advanced EC
aPatients who received ≥1 dose of pembrolizumab and had been enrolled ≥26 weeks before data cutoff. bPatients with baseline assessment evaluated by the central radiology assessment but no postbaseline assessment on the data cutoff
date including missing, discontinuing, or death before the postbaseline scan.
Data cut off data: October 5, 2020.
dMMR, mismatch repair deficient; EC, endometrial cancer; MSI-H, microsatellite instability-high; NR, not reached; ORR, objective response rate; OS, overall survival;
PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.
1. O’Malley D, et al. Ann Oncol. 2021;32(suppl_5):S725-S772.. 2. Mirza M. Presented at The 22nd European Congress on Gynaecological Oncology. October 23–25. Prague, Czech Republic.
49
Confirmed Objective Response
per RECIST v1.1 by BIRC1
MSI-H/dMMR EC,
N=79a
(Cohorts D + K)
ORR, % (95% CI) 48 (37-60)a
Best objective response, n (%)
Complete response 11(14)
Partial response 27 (34)
Stable disease 14 (18)
Progressive disease 23 (29)
Not evaluable 1 (1)
Not assessedb 3 (4)
Time to response, median
(range), mo
2.3 (1.3-10.6)
• Median DOR not reached: at 36 months, 68% of patients were
• still in response
• Median PFS: 13.1 months
• Median OS: Not reached
Percentage change from baseline in target
lesion size2
100
80
60
40
20
0
-20
-40
-60
-80
-100
20% tumour
increase
30% tumour
reduction
FDA Approval May 2017
First FDA approval based on a biomarker regardless of tumor type
Regular approval March 2022, Endometrial ca, MSI-H/dMMR
progression following prior systemic therapy

48. Response to single agent IO in pMMR or MSI-stable endometrial cancer has been modest
Single Agent IO in “non-biomarker” Selected Endometrial
Cancer Populations
Ott PA et al. J Clin Oncol 2017
Antill PSK et al. J Clin Oncol 2019
Oaknin A et al. Gynecol Oncol 2019
Konstantinopoulos PA et al. J Clin Oncol 2019
PD-L1 positive endometrial cancer is not approved indication of Pembrolizumab in China, Taiwan, Korea, Singapore, Philippines, and HK
Study & Drug Patient Population Outcome
Keynote 28: Pembrolizumab (N=24) Advanced stage or metastatic PD-
L1 + endometrial cancer
ORR: 13%
PHAEDRA trial: Durvalumab (N=36
pMMR)
Advanced stage or metastatic
endometrial cancer
ORR in pMMR: 3%
GARNET study: Dostarlimab
(N=94)
Previously treated, recurrent
advanced stage endometrial
cancer
ORR in pMMR: 13%
Ph II Avelumab study (N= 16
pMMR)
Advanced stage or metastatic
endometrial cancer
ORR: 6.25%
** = updated data in the pMMR cohort has not been presented

49. 51
Combinatorial IO approach: Lenvatinib + Pembrolizumab
Keynote 775 (NCT03517449)
Pembrolizumab 200 mg IV q 3 weeks plus
lenvatinib 20 mg PO once daily (QD) during
each 21-day cycle for up to 35 cycles.
EITHER: Doxorubicin 60 mg/m2 IV q 3 weeks
(max cumulative dose of 500 mg/m2) OR
Paclitaxel 80 mg/m2 administered by IV on a
28-day cycle: 3 weeks receiving paclitaxel
once a week and 1 week not receiving
paclitaxel.
Primary endpoints:
1) Progression-free Survival (PFS) by RECIST 1.1 by BICR
2) Overall Survival (OS).
Secondary endpoints: ORR, DOR, TTF, AEs, PK, PROs
• Advanced, recurrent or
metastatic endometrial
• Progressive disease 1-2 prior
platinum regimens
• Measurable disease per
RECIST 1.1
• Available archival tumor tissue
• Performance status of 0 to1
• Adequate organ function
N = 770
175 Sites as of Jan 12, 2018
R
1:1
Stratification:
1. MMR status (pMMR or dMMR)
2. ECOG performance status (0 or 1)
3. Geographic region (Region 1 [Western Europe, North America, Australia] or Region 2 [rest of world])
4. Prior history of pelvic radiation (yes or no)

50. Pembrolizumab + Lenvatinib (KEYNOTE-775): Clinically Meaningful
Improvement Over Physician’s Choice Therapy in MMRp Patients1
aNo progressive disease reported at the last disease assessment. bData cut date: October 26, 2020.
CI, confidence interval; CR, complete response; DOR, duration of response; MMRp, mismatch repair proficient; len, lenvatinib; NE, not evaluated; ORR, objective response rate; OS, overall survival; PD, progressive disease; PC, physician’s
choice; pembro, pembrolizumab; PFS, progression free survival; PR, partial response; SD, stable disease.
1. Makker V, et al. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual. 2. Colombo N, et al. Ann Oncol. 2021;32(suppl_5):S725-S772.
52
MMRp All-comers
Efficacy n=346 n=351 n=411 n=416
Median PFS
(95% CI),months
6.6
(5.6-7.4)
3.8
(3.6-5.0)
7.2
(5.7-7.6)
3.8
(3.6-4.2)
Median OS (95%
CI), months
17.4
(14.2-19.9)
12.0
(10.8-13.3)
18.3
(15.2-20.5)
11.4
(10.5-12.9)
ORR, %
(95% CI)
30.3
(25.5-35.5)
15.1
(11.5-19.3)
31.9
(27.4-36.6)
14.7
(11.4-18.4)
CR, % 5.2 2.6 6.6 2.6
PR, % 25.1 12.5 25.3 12.0
SD, % 48.6 39.6 47.0 40.1
PD, % 15.6 30.8 14.8 29.6
NE/ assessed,
%
0.6/4.9 2.0/12.5 1.2/5.1 1.9/13.7
Median DOR
(range), months
9.2
(1.6a-23.7a)
5.7
(0.0a-24.2a)
14.4
(1.6a-24.2a)
5.7
(0.0a-24.2a)
Pembro + len
Physician’s choice
Time in Months
0 3 6 9 12 15 18 21 24 27
20
10
0
30
40
50
60
70
80
90
100
Progression-free
Survival
(%)
HR 0.60 (95% CI 0.50-0.72)
P <0.0001
Pembro + len
MMRp
Median PFS (95% CI)
6.6 mo (5.6, 7.4)
3.8 mo (3.6, 5.0)
No. at risk
346
351
264
177
165
83
112
37
60
15
39
8
30
3
12
1
5
1
0
0
Physician’s choice
• Post hoc analyses of efficacy by tumor histology, prior therapy, and
progression-free interval demonstrated pembrolizumab + lenvatinib
maintained PFS and OS benefit compared with physician’s choice2,b

51. Combinatorial IO approach: Lenvatinib + Pembrolizumab
Keynote 775 (NCT03517449) Overall Survival Benefit
.
1. Makker V, et al. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual. 2. Colombo N, et al. Ann Oncol. 2021;32(suppl_5):S725-S772.
• FDA Accelerated Approval:
Sept 2019 advanced, MMRp
endometrial cancer
• FDA Regular approval July
2021: Advanced MMRp
endometrial cancer
progressed following prior
systemic therapy

52. Future therapies: the role of non-IO regimens in Endometrial Cancer
• XPO inhibitors
• HER-2 targeted therapies
• ADC’s
• Hormonal Therapy
Confidential – For Internal Use Only. Not for Promotion. Embargoed Data

53. HER-2 Pathway
TGCA analysis of HER2 mutation, deletion, and amplification across the 12 most
common disease sites
Diver EJ et al. Oncologist. 2015;20(9):1058-1068.

54. Targeting HER2 in UPSC with Paclitaxel and Carboplatin
Fader AN et al. JCO 2018
Randomized phase 2 trial: chemo vs chemo/trastuzumab
PFS – advanced disease
• Advanced (41 pts) or recurrence
(17 pts) serous EC
• IHC 3+ or 2+ with FISH positive
• All pts: mPFS from 8 to 12.6 mos
(HR 0.58; 90% CI 0.34-0.99)
• Primary treatment stage III-IV:
mPFS from 9.3 to 17.9 mos
• mOS from 25.4 vs NR (HR 0.49;
p=0.31)
• Recurrent disease:
mPFS from 6 to 9.2 mos
mOS – no benefit in the recurrent
population
PFS – ITT

55. • Median OS of 24.4 (control) versus 29.6 (experimental) months (P = 0.046, HR = 0.58, 90% CI 0.34—0.99;
Fig. 1).
• This benefit was particularly striking in stage III–IV patients, who had OS medians of 25.4 months (control) versus
not reached (experimental, P = 0.041, HR = 0.49, 90% CI 0.25–0.97).
57
Incorporation of anti-HER-2 treatment: Trastuzumab with
Chemotherapy (Updated Survival Analysis)
Nickles-Fader Clin Cancer Research 2020
Recurrent Disease
Advanced Stage Disease
ITT Population

56. Courtesy of Dr. B. Erickson
Chemo-naïve, non-recurrent, stage I-IVB,
HER2 positive endometrial serous carcinoma or
carcinosarcoma
Randomization 1:1:1
Stratification
 Stage I-II v. III-IV
 Histology (serous vs carcinosarcoma)
 Plan for vaginal brachytherapy (yes vs no)
Arm 1:
Paclitaxel/Carboplatin
every 3 weeks x 6 cycles
Arm 2:
Paclitaxel/Carboplatin/Trastuzumab
and hyaluronidase-oysk
(HERCEPTIN HYLECTA) every 3
weeks x 6 cycles
Maintenance HERCEPTIN
HYLECTA every 3 week for up to 1
year
Arm 3:
Paclitaxel/Carboplatin/Pertuzumab
, Trastuzumab, and hyaluronidase-
zzsf (PHESGO) q 3 weeks x 6
cycles
Maintenance PHESGO every 3
weeks for up to 1 year
INTERVAL TOXICITYASSESSMENT
INTERIM FUTILITYANALYSIS
Convert to phase 3 if active arm(s)
NRG-GY026
Study Schema

57. Recurrent Disease

58. Checkpoint Combinations in Endometrial Cancer
1Lheureux S, Matei DE, Konstantinopoulos PA, et al. Journal for ImmunoTherapy of Cancer 2022;10:e004233.
2M. Mckean, E.E. Dumbrava, O. Hamid, et al ESMO 2023
-
- -

59. GOG-3038/POD1UM-204
An Umbrella Study of INCMGA00012 Alone and in Combination With Other Therapies in Participants With Advanced or
Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-Based Chemotherapy (PI: Brian Slomovitz, MD)
NCT04463771

60. p53 mutation and WEE1 inhibition: Opportunity for Synthetic Lethality
• Molecular aberrations found in uterine serous = loss
and dysregulation of G1/S checkpoint
– TP53 mutations - 90%+
– CCNE1 amplification ~25%
• Loss of G1/S checkpoint
– Increases replication stress
– Increases dependence on G2/M checkpoint
• WEE1 regulates the G2/M checkpoint
M
G1
S
G2 Mitosis
Growth
DNA
synthesis
Growth
G1/S
TP53
S
phase
ATR
CHK1
G2/M
WEE1

61. Wee-1 Inhibitors in Endometrial Cancer
-
- -
Trial Name Phase
Publicatio
n/Present
ation
Number of
patients
Median
Duration of
Response
Overall
Response
Rate
Median
Progression-
Free Survival
A phase II study of the
WEE1 inhibitor
adavosertib in recurrent
uterine serous carcinoma
II
ASCO
2022
72 9.0 months 29.4% -
ADAGIO: A phase IIb
international study of the
Wee1 inhibitor adavosertib
in women with recurrent or
persistent uterine serous
carcinoma
IIb JCO 2023 167 - 24.2% 5.3 months
ZN-c3 Phase 1
Monotherapy Expansion
Cohort in Patients with
Advanced/Recurrent
Uterine Serous Carcinoma
I
AACR
2022
43 - 27.3% 9.9 months

62. TETON / GOG-3065 / ZN-c3-004 (version 3)
Evaluating Azenosertib in Uterine Serous Carcinoma
Endpoints (ICR)
Cohort 2 (N=60)ii
Azenosertib 400 mg QD 5:2
ClinicalTrials.gov NCT04814108
Cohort 1 (N=30)ii
Azenosertib 400 mg QD 5:2
ORR
DOR
All Comers Enrollment
All Comers Enrollment
Key Eligibility: Recurrent or persistent USC; ≥1 prior platinum-based chemotherapy regimen; Prior HER-2 directed
therapy for known HER2+; Prior anti-PD(L)1i; Measurable disease per RECIST; ECOG PS 0-1
i Except for sites outside the US where aPD1 is not available, or for subjects ineligible for aPD(L)1
iiResponse-evaluable subjects
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance score; RECIST, response evaluation criteria in solid tumors; ORR, objective response rate; DOR, Duration of Response

63. ADC’s in Endometrial Cancer
Luveltamab Tazevibulin (STRO-OO2): Early Evidence Of Anti-
tumor Activity in FolRα Expressing EC: Phase 1 Dose expansion
Pothuri B, Naumann W, Martin L, et al ESMO 2023
Trastuzumab Deruxtecan: Td-XD Efficacy by HER2 Expression
PFS
NCCN Guidelines1.2024 9/20/23
F. Meric-Bernstam, V. Makker, A. Oaknin, et al ESMO 2023

64. GOG-3095/MK-2870 in Post Platinum and Post
Immunotherapy Endometrial Cancer
ClinicalTrials.gov ID NCT06132958

65. Hormonal therapy
-Megesterol acetate approved in
1971
-RR of 14-33% and PFS 2.5 – 3.2
months
J Clin Oncol 1996;14:357-61; J Clin Oncol 1999;17:1736-44; Gyn Oncol 2000;78:212-6; J Clin Oncol
2001;19:364-7; Gyn Oncol 2004;92:4-9; Gyn Oncol 2004;92:10-14; Gyn Oncol 2011;120:185-8

66. Hormonal Therapy
– .
MacKay HJ, 2020 ASCO Educational Book; Ethier et al Gynecologic Oncology 2017; Meenakshi Singh et al. Gynecologic Oncology 2007; Mirza et al. ESMO 2020 ; Slomovitz et al, Gyn Oncol 2022
ENGOT-EN3/NSGO-PALEO
Option for 1st line or ≥2nd line:
•1st line ORR = 21.6%
•2nd line ORR = 18.5%
•Median PFS = 2.8mths
•Median OS = 10.2 months
•↑ORR ER+ (26.5%)/ PgR+ (35.5%) disease
•↓ORR in ER− (9.2%) or PgR− (12.1%)
tumors.
•↓ORR older age and high grade.
Prior-
chemo
PFS
(mths)
Chemo-
naïve
PFS
(mths)
Letrozole/
everolimus
4 28
MA/
tamoxifen
3 5
GOG 3007

67. Summary
• Patients with dMMR tumors have unprecedented responses to immunotherapy and
should be the standard of care in the frontline
• Patients with pMMR tumors do have improved outcomes with immunotherapy;
however, improved treatment options in the frontline remain an unmet need and
should be further explored (PARP, non-IO, etc)
• Lenvatinib/pembrolizumab remains standard after chemotherapy in patients with
MMR proficient em ca
• The role of IO after IO needs to be investigated as limited efficacy data to date
• Non-IO treatment options including HER2 directed therapies, ADC’s and hormonal
combinations are needed to providebetter treatment options
• Enrollment into clinical trials is crucial to continue to evolve the standard of care
• Diversity in clinical trials is critical to ensure new medicines work in the population
expected to use the medicine

68. Thank you!
bpothuri@gog.org
bhavana.pothuri@nyulangone.org
@bpothuri