Navigating Recent Advances in Endometrial Carcinoma Treatment: Expert Guidance to Unleash the Power of Immunotherapy and Other Emerging Therapeutic Regimens

Co-Chairs Mansoor Raza Mirza, MD, and Ana Oaknin, MD, PhD, discuss endometrial cancer in this CME/MOC/NCPD/AAPA/IPCE activity titled “Navigating Recent Advances in Endometrial Carcinoma Treatment: Expert Guidance to Unleash the Power of Immunotherapy and Other Emerging Therapeutic Regimens.” For the full presentation and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3WMnfln. CME/MOC/NCPD/AAPA/IPCE credit will be available until June 27, 2025.

1. Navigating Recent Advances
in Endometrial Carcinoma Treatment
Expert Guidance to Unleash the Power
of Immunotherapy and Other Emerging
Therapeutic Regimens

Mansoor Raza Mirza, MD Ana Oaknin, MD, PhD
Rigshospitalet, Copenhagen Head of Gynaecological Cancer Program
University Hospital Medical Oncology Department
Copenhagen, Denmark Vall d'Hebron University Hospital

Vall d'Hebron Institute of Oncology (VHIO)

Barcelona, Spain

Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.

> 2000-2024, PeerView

2. Our Goals for Today

Augment your knowledge of the evidence supporting modern
immunotherapy approaches for patients with endometrial cancer

Share tips on integrating the latest options into personalized care
plans, taking into consideration guideline recommendations, biomarker

status, and available clinical trials

Equip you with skills to confidently create proactive and collaborative
strategies to mitigate and manage adverse events

Copyright © 2000-2024, Peerview

3. How Common Is Endometrial Cancer?!

: Cases by Stage
Q Across all cancer types in the Unknown,
United States, uterine cancer represents ge
3.4% of new cases 2.2% of deaths na
ES
Estimates for 2022 —
67,880 new cases 13,250 deaths =

5-Year Relative Survival by Stage
100 ) 94.8

63 years

median age at diagnosis

7
+ 69.

189

Localized Regional — Distant Unknown

1. Mtps:/seer cancer govistaactsMtmucor him PeerView.com

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4. Shifting the Paradigm:
Personalizing Treatment With Molecular Profiling!

+ 5%-10% of endometrial cancers

POLE (ultramutated) + High mutation burden leads to

100 POLE: ultramutated, n
better immune response,

x Copy-number low 100-500 mutations/Mb cessive mutations lead to
= (endometrioid) inability to proliferate
So
2 + 20%-30% of endometrial cancers
5 MSI (hypermutated) Ce ae + Heredita

ry (Lynch syndrome) or
® © 10-20 mutations/Mb bres
8
E Copy-number high + Most common endometrial cancer
£ 40 (serous like) CN low/NSMPITP53 + Low-grade tumors
S WTIMSS: J
3 o + Estrogen/progesterone positive
3 re + PTEN, PIK3CA, ARID1A, and
5 2 A KRAS mutations
9
à Log-rank P = .02 3
E) lia Fe en + Often serous or mixed histology

0 20 40 60 80 100 120 high grade = + Poorest prognosis
Time, mo
1. The Cancer Genome Atas Research Neburk Nature. 2013:497:9773, PeerView.com
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5. Guidelines: Principles of Molecular Analysis

Pathology and Genomics in Endometrial Carcinoma! Endometrial Carcinoma
(histological subtype independent)?

POLE sequencing
No POLE hotspot mutation POLE hotspot mutation ne PM
or
POLE Status athogenic non-pathogenic
DNA MMR protein
immunohistochemistry

Expression retained MMR status dMMR MMRp

POLE

aa gal 53 immunohistochemist
lost 153 immunohistochemistry pe a
Normalwidtype pattem | Aberrantmutant pattern v Ñ =
Integrated EC, EC. EC, EC
amr CN low! CN high . A A à
pay ee au diagnosis POLEmut dMMR NSMP pSämut
NECN Lo Esmo |
1. NCCN Cinia Practice Guidelines in Oncology. Uterine Neoplasms. Version 22024. mps nm cen orpprotessonl/tysician, iveco pt ñ
2, Oaknin A, ESMO Guidlines Committe. Ann Oncol 2022:38:860-877, PeerView.com

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6. MMR Incidence in Endometrial Cancer’?

Endometrial cancer can be classified as
+ MMRp/MSS (70%-75%)
+ dMMRIMSI-H (25%-30%)

MSI-H Cancers, %

UCECCOAD STAD READ KIRC OV PRAD LUADHNSC LIHC LUSC BLCA GBM LGG BRCA KIRP SKCMTHCA

); PRAD (n = 483): LUAD (n = 480); HNSC (n = 506); LINC (n = 338)

IT); COAD (n = 294) STAD (n = 278): READ (n = 96): KIRG (n = 279) OV
7) SKCM (n = 288), THCA (n= 484). a
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443), BLCA (n= 253), GBM (n = 262); LOG (n = 513), BRCA (n = 288); KIRP.
1-Hause RJ et al, Nat Med, 2016.22:1342-1350.

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7. MMR and MSI?

MMR Protein (IHC Test) MSI (Molecular Test)

+ MMR protein complexes (MLH1 + PMS2 and + Consensus definition: MSI is a condition of
MSH2 + MSH6) detect and correct mistakes genetic hypermutability
during DNA replication + MS is characterized by mutation clustering

+ Absencelloss of function in one of the four MMR: in microsatellites typically consisting of repeat
proteins results in dMMR length alterations

phenotypic evidence that MMR is not
functioning normally (AMMR)

MSI-H provides phenotypic evidence of dMMR;
thus, MSI-H and dMMR are considered biologically the same population
+ dMMRIMSI-H refers to patients with mismatch repair deficiency
+ MMRP/MSS refers to patients with mismatch repair proficiency

1.Kioor Metal. Trends Cancer 2016:121-133, 2. Luchini Get al. Ann Oncol 2019;30:1232-1243 PeerView.com

The presence of MSI represents
dMMR is the cause of MSI-H

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8. Immune Checkpoint Inhibitors Block
T-Cell Inhibitory Signals

PD-1/PD-L1 Checkpoint Inhibition

Tumor Microenvironmel

o Without with
O) Immunotherapy | Immunotherepy
an
S
2
3
E Antigen
w
© Actiyalion
o Kiel ofT Cell
= I

Tumor escape Elimination of

tumor cells

PeerView.com/RZJ827

+ Immune checkpoint inhibitors work by

blocking T-cell inhibitory signals—removing
the brake on the immune system

+ The cancer immunotherapy landscape is
rapidly expanding; benefit of immune
checkpoint blockers is seen across different
tumor types and treatment settings (as
single agents and combinations)

+ Predictive biomarkers can guide
clinical decisions regarding the use
of immunotherapies

Improved responses occur with
checkpoint inhibitors in dMMR/MSI-H tumors,

whereas chemotherapy and targeted agents
may have lower responses

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9. Personalized Treatment Plans in the Second-Line Setting

Until recently, the backbone of 1L treatment
was mostly carboplatin and paclitaxel

In this scenario, immunotherapy emerged as a
game changer in the management of endometrial carcinoma

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10. Single-Agent Immunotherapy Approaches

Monotherapy immune checkpoint inhibition is an effective strategy for biomarker-selected patients
with advanced or recurrent endometrial cancer who have progressed on chemotherapy

Phase 2 KEYNOTE-158 Phase 1 GARNET
Pembrolizumab* Dostarlimab?

FDA Approval Pembrolizumab Single-Agent Indication

20172: 2023” Tissue-agnostic approval for the treatment of unresectable or metastatic MSI-H

2 or dMMR solid tumors that have progressed following prior treatment
20202 Tissue-agnostic approval for TMB-H tumors following progression on prior treatment
2022» Advanced endometrial carcinoma that is dMMR following progression on prior treatment

FDA Approval Dostarlimab Single-Agent Indication

2021: 2023” Recurrent or advanced endometrial cancer that is dMMR following
a progression or prior treatment
20217 Tissue-agnostic approval for dMMR recurrent or advanced solid tumors

that have progressed on or following prior treatment

A Accelerated FDA approval. > Full FDA approval
1 Keytrda (pembrotzumab) Preseting Information. Nps vw accessdat da govisrugsatsa_doce/abel/2023!1255148136 pa. m
2. Jemperi (ostarimab) Presenbing information, Nips vw accessdata da govidrugsatia_docs/abel2023/781174s003S00AIb1 pa PeerView.com

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11. Phase 2 KEYNOTE-158: Pembrolizumab Monotherapy
for Advanced Endometrial Cancer‘?

Key Inclusion Criteria For 35 cycles

+ Aged 218 years (approximately 2 y)
+ MSI-H/dMMR advanced endometrial cancer Panbrolisumab or until disease
= Cohort D: endometrial cancer, regardless of MSI EN progression,
status and excluding sarcomas and = x intolerable toxicity,
mesenchymal tumors investigator decision,

— Cohort K: any MSI-H/dMMR advanced solid
tumor except colorectal

Progression on or intolerance to 21 line of

standard treatment for unresectable and/or

metastatic disease

Measurable disease per RECIST v1.1

ECOG PS Oor1

Provision of a tumor sample for biomarker

assessment

or patient withdrawal

+ Primary endpoint: ORR per RECIST v1.1
by ICR

+ Secondary endpoints: DOR and PFS
per RECIST v1.1 by ICR, OS, safety

1. pci. govieZshowNCTO2628087. 2. Keytuda (pembrolzumab)Prescrbing Information ñ
ips ur accessdata Ka govidrogsatida_docs/abel/2023/12551481360 paf. PeerView.com

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12. KEYNOTE-158: Improved Responses With Pembrolizumab
in dMMR Endometrial Cancer’

dMMR EC A

Variable (N =94) Best Percentage Change From Baseline
Median follow-up, mo 54.5 100 In Target lesion Se?
ORR, % 50 80

CR, % 16 x 60

PR, % 34 Es

SD, % 18 320

PD, % 28 Lo
mDOR, mo 63.2 Lo
Estimated DOR at 4 y, % 66 & 40
mPFS, mo 13.1 In
Estimated PFS at 4 y, % 37 e =
mOS, mo 65.4
Estimated OS at 4 y, % 59 100

Mates Ona. Jin Orca 2002007527622 OM) OM ll ESMO 2022. Abstract 46 PeerView.com

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13. Phase 1 GARNET: Dostarlimab Monotherapy
in Multiple Tumor Types’

Part 1: Part 2A: Part 2B:
Dose finding Fixed-dose safety run-in Expansion cohorts

A1: dMMR/MSI-H EC

E: NSCLC

F: Nonendometrial
dMMRIMSI-H basket

G: PROC

- Primary endpoints:
ORR, DOR

Key Inclusion Criteria
+ Patients with recurrent or advanced EC that progressed on
or after treatment with a platinum-containing regimen
dMMR status by IHC testing

Patients must have received <2 lines of treatment for
recurrent or advanced disease

Dostarlimab 500 mg IV
then 1,000 mg Q

1. tps cinicatials.gouct/shou/NCTO2715284. ñ
2. Jemperi (ostarimab) Presenbing information, tps vw accessdata da goviérugsada_docs/abel2023/76 174500380041 pt. PeerView.com
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14. PeerView.com/RZJ827

GARNET: Dostarlimab Showed Durable Antitumor Activity
in dMMR Endometrial Cancer!

MMR SMMRIMSIH
dMMRIMSI-H EC dMMR
n=141 13 CRT dnote mg
=

Median follow-up, mo 276 27.6 =
‘ORR, n, % 64,454 65,455
(95% ch (97.0540) (81.1540)
Best confirmed response,

CR 22156) 23(16.1)

PR 42(29.8) 42294)

so 21019) 21(147)

PO 51 (96.2) 51 (3.7) A

NE 565 6(42) H
DCR, n (x) 85 (60.3) 86 (60.1)
MOOR (95% CI), mo NR (B8.9-NR) NR (38.9-NR) union
Duration 212 mo, n (%) 51 (797) 52 (60.0) Pe
Duration 224 mo, n (%) 28 (43.8) 29 (44.6) on
Probability of maintaining response (95% CI) am

At12 mo 93.1 (827-974) _ 93.3 (63.0-97.4) oa Mw mw ww wm wm Ww wa ie te Wo a A

ALZA mo 83.4(703.910) 837708912) ln un

1. Oaknin À et al. Gin Cancer Res, 2023;20:4564-4574, PeerView.com

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15. ICI Monotherapy Resulted in Low Response Rates in
Patients With Recurrent MMRp EC

Trial KEYNOTE-028* NCT01375842? GARNE NCT02912572* IAEDRA'

Treatment Pembrolizumab Atezolizumab Dostarlimab Avelumab Durvalumab

Phase 1b ta 12 2 2

cohort ieralyadvancader lee menace Recent Rema
metastatic PD-L1+ EC MMRp EC

Patients, n a is 156 16 35

(in efficacy analysis) (5 PD-L1 high)

mPFS 1.8 mo 1.4 mo 2.7 mo 1.9 mo =
mos NR 9.6 mo 16.9 mo 6.6 mo _

"fine 3 responders, 1 had POLE-mutated disease: the 1 MSI-H patient had progressive disease as best response, > Of he 2 responders, 1 had MSH disease,
1. ON PA etal. J Cin Oncol 2017:352535-2541, 2 Fleming GF et a, ASCO 2017. Abstract 5585. 3. Oaknin A et al ASCO 2022. Abstract 8500 na
4 Konstaninopouls PA etal. Gin Oncol 2019.37 2786-2794. 5, An Yet al. ASCO 2019. Abstract 5501 PeerView.com

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16. Phase 3 KEYNOTE-775:
Lenvatinib Plus Pembrolizumab!

Treat until progression
or unacceptable toxicity
Lenvatinib
20 mg PO QD +
pembrolizumab*

/ Q3W

Key Inclusion Criteria
+ Advanced, metastatic, or

recurrent endometrial
EEx vs dMMR) and further

$ stratification within MMRp by:
Ae ao — Region (Europe, US, Canada,
One por pltourcbassd Australia, New Zealand, and
een Israel vs rest of the world)
a - ECOG PS (vs 1)
Tissue available for = Prior history of pelvic paclitaxel
MMR testing radiation (yes vs no) 80 mg/m? IV Q

k on/1 wk off)
(n= 416)

Stratification Factors
MMR status (MMRp

+ Primary endpoints: PFS by BICR, OS
+ Secondary endpoints: ORR, HRQOL, pharmacokinetics, safety
+ Key exploratory endpoint: DOR

{patents may have rev up o plo latrum-based CT repens one vas gen ne nessa! aan eaten seg Maina of 36 dose.
Maximum cumulative dose of 00 A
{Mater Vela N Engl) Med. 2022200 47-448. PeerView.com

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17. KEYNOTE-775: Continued Benefit With Additional
Follow-Up in the MMRp Population’22

Median PFS (95% Cl) Median OS (95% Cl)

_ Lenvatinib + pembrolizumab: 6.7 mo (5.6-7.4) anes Lenvatinib + pembrolizumab: 18.0 mo (14.9-20.5)

Chemotherapy: 3.8 mo (3.6-5.0) # 00 Chemotherapy: 12.2 mo (11.0-14.1)

le HR for progression or death = 0.60 (95% Cl, 0.50-0.72) $ HR for death = 0.70 (95% Cl, 0.58-0.83)
- © 2
ip i:
28 «0 fo
33 La Lenvatinib +
Es Ep pembrolizumab
dE PN AE

2 pembrolizumab 52»

a en Chemotherapy

o
“GTiisvunarnes se Serer ee See
Time, mo
Time, mo

ORR: 32.4% vs 15.1%
CR: 5.8% vs 2.6%

PR: 26.6% vs 12.5%

"Median flows time: 14:7 months: data culo date: March 1, 2022: >18 months o atonal olow-up from inital publication; PFS by BICR per RECIST v1.1 mn
1. Makker Vet al, N Eng J Med 2022:388-497-448. 2 Makker Vet al. J Gin Oncol 202341:2904-2910 PeerView.com

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18. Radical Changes in Standard
of Care for Recurrent and
Advanced Endometrial Cancer

in the Frontline Setting

19. Rationale for Combining ICI and PARPi
With Chemotherapy

Durable activity in both dMMR/MSI-H and MMRp/MSS previously treated EC’
dMMR/MSI-H EC is associated with:

— High TMB/TILs?

— Higher response rate to anti-PD-11

Enhances immunogenic cell death?
UC - Reduces immunosuppression in TME?4
Broad clinical activity when combined with anti-PD-1 in several cancers$8

Adding a PARPi to ICI may further improve outcomes, including in patients
with MMRP/MSS disease, a population with high unmet need?-12

1. Oaknin A et al J Immunother Cancer. 2022:10:2003777. 2. Song Y et a. Onco Targets Thr. 202%:14:4485-4497. 3. Emens LA, Midaiton G. Cancer Immunol
12015:3:438-443. 4 Hato SV et a. Cin Cancer Res. 2014:202031.2837. 5. Gandhi Let al. N Eng! Med. 201878 2078-2002. 6. Paz-Ares Leta N Engl J Med.

2018:379-2040-2051. 7 Janigian YY et a. Lancet 2021;39827-40. 8. Burness B et al. Lance? 2019;394 1915-1928, 9. MeGranahan N et a. Science.

2016:351:1483-1469, 10. io Stal. Cin Cancer Ras. 2017.233711-3720. 11. Bang Y- et al. J Cin Oncol. 2019:37(supp 4 140. e

12 Westin SN eta. J Cin Oncol 2024:42283-299. PeerView.com

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20. Paradigm-Shifting Data for the Management
of Endometrial Carcinoma!-1%a

Investigational Agent

‘Concomitant
Maintenance

Readout

x

RUBY

Be AtTEnd
Dostarimab + ‘Atezolizumab +
chemo ‘chemo
494 550
NEJM 2023 ESMO 2023
Statistically Statistically
significant PFS MMR significant PFS
and ITT; OS ITT MMR and ITT
Not powered for ar

MRD

NRG-GY018
Pembrolzumab +
chemo
ns

NEJM 2023

Statistically
significant PFS.
MMR and MMRP

Not testing for OS

EN-11

Pembrolizumab +
‘chemo
‘990

Negative

RUBY
Ru puce
Dosis + Duval
A
m co
3602004 esuo 2023
statotcaty
statistically
signteant DES rr Scan PFS IT or
SOL ERS MAE) durvalumab + olaparib
enme cum ponerte
is missing; .
Re
CAE MMRp or dMMR

Cross-study comparisons: side is or information purposes only and is not intended to imp or iner he noninferiority or superior of any agent

1.Mirza MR eta. N Engl J Med, 2028;388:2145-2188. 2 Mirza MR etal. Ann Oncol 2023;34:500-501. 3. Eskander RN
4. Arend RC eta. S60 2023. 5. Colombo N etal. ESMO 2023, Abstract LBAAO. 6. Westin SN et a. J Cin Oncol 2024.42283-299. 7. Powell MA et al SGO 2024.
Abstract LBAT. 8. Eskander RN et a SGO 2024. Abstract LEA. 9. Baurain JF eta. SGO 2024, Scientfe Plenary V. 10. Mirza MR etal SGO 2024, Abstract LBA,

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IN Eng J Med, 2023:3882150-2170.

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21. Substantial and Unprecedented PFS and OS Benefit
of ICI + Chemotherapy in dMMR EC?

RUBY Part 115 NRG-GV0184 AtTEnd? DUO-E0

os

oeuuesezesd

on

5
x
el

=
EMAL ene Lam, => |
si Se ia saa 5 —
= ee, en |
PFS HR 0.28 HR 0.30 x HR 0.42
ee ee ua rat
er En I ee
os HR 0.32 HR 0.55 HR 0.41 HR 0.34
A ee jxme bno
eee a

Gross-stuéy comparisons: lie is or information purposes only and is at intended to imply o infer he noninferrty or superior of any agent.

1, Mirza MR et al. N Engl J Med. 2023:388:2145-2158, 2 Powell MA et al. SGO 2024. LBA. 3. ts www da goänugsdnug-approvals-and-atabasesitda-approves-
<ostarimab-gxy-chematherapy-endometa-cancer. 4. Eskander RN et al. N Engl J Med. 2023:388:2159-2170. 5. Eskander RN etal. SGO 2024. Abstract LBAS.

8 Mps we ba govidrugsresources informa rugstéa-approves-pembroizumab-chemotherapy primary advanced.orrecunent endometral carcnoma

7. Colombo N et at ESMO 2023. Abstract LBAdO. 8. Westn SN et al ESMO 2023 Abstract LBA41. 9. Westn SN etal. J Clin Oncol 2024:42283-299, aka

10. tp fa govldrugsiresoureesinformation-approved-drugsida-approves-durvalumab-chematherapy-mismatch-epai-deficient rimary-advanced-orrecurent. Peer View.com

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22. No Additional Benefit of PARPi in dMMR EC?

The effect is predominantly driven by anti-PD-L1

RUBY Part 2 DUO.

PFS os PFS os

Not mature

Proportion Pate Ave
Be
saunssnansE

En
couecesest

Tona Since Random mo “Tin Since Radiation mo

“or
1. Mia MR etal, SGO 2024. Abstract LBA2. 2. Westin SN et al. J Cin Oncol 2024:42:283-299,

side str information purposes only and is not intended to imply o infer the noninferiority or superiority of any agent. Peace

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23. Clinically Meaningful PFS and OS Benefit
of ICI Plus Chemotherapy in MMRp EC?

RUBY Part 113 NRG-GY018** AtTEnd” DUO-E*0
« m :
Fl 2 3 *i
I - = E

“ine Sica Romi, mo

a ee ca ET me ae TEE rae
EE CT EE [os mar = ES
san ao 3 mes
PFS HR 0.76 HR 0.54 HR 0.92 HR 0.77
(05% 1.050.058) (oom ch 041-070 Pen Rc osa,
os HR 0.79 HR 0.79 HR 1.00 HR 0.91
ER men rater CEE

+ Cross-study comparisons: aie is or information purposes only and is at intended to imply o infer the noninenorty or superior of any agent.

1. Niza MR et al. N Engl J Med. 2023:388:2145-2158, 2 Powell MA et al. SGO 2024. LEA. 3. ts hw da govdrugs/érug-approvals and databases/da-approves-
ostarimab-gxy-chematherapy-endometa-cancer. 4. Eskander RN et al. N Engl J Med. 2023:388:2159-2170. 5, Eskander RN etal. SGO 2024, Abstract LBAS,

$. hitos ww fda goVIdru resources informaton-approved:Jugsda-approves pembrolzumab <hemotherapy- primary advanced.or recut!

7. Colombo N et at ESMO 2023. Abstract LBAKO, 8. Westn SN etal ESMO 2023 Abstract LSA41. 9. Westin SN etal. J Clin Oncol 2024:42283-299, u

10. Maps vw fa govidrugs/resoures-infrmationapproved-arugstéa-approves-durvalumab-chemotherapy-mismatch-tepai-cefient-prmary-advanced-orsecurent Pe erView.com

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ntendometia-earcinom,

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24. Potential Benefit With Addition of PARPi
to ICI Plus Chemotherapy in MMRp EC?

More analysis needed to identify which subgroup derives the most benefit

RUBY Part 21 DUO-E?

Pony oP,

de

Not mature i
5
h

ie sfr information only and is ot intended to imply or inter the noninferonty or superionty of any agent.
283-208,

Cross-study comparisons:
‘Stent oo 600 2024 Posvact LBAZ 2 Mes SN eta. Cin Oncol 202442

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25. Potential Benefit With Addition of PARPi
to ICI Plus Chemotherapy in MMRp EC

Significant improvement in PFS, but pending mature OS results

The OS improvement with ICI + PARPi + chemotherapy will
need to be incremental to 7-month OS improvement seen with
dostarlimab + chemotherapy in RUBY part 1 MMRp cohort

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26. Potential Biomarker to Predict Benefit From
ICI Plus Chemotherapy With or Without PARPi?

RUBY Part 11 RUBY Part 2?

‘Molecular subgroup analysis based on 400/494 patients Exploratory PFS molecular subgroup analyses in overall population
ular classification per WES.

ES os
RE

3 (05%C1,0.30099) (95% C1.0.20082)
‘ os
E pars D wre = SE
É tc
breed
er ® E a
Pe or |
135
5 me E77 Meine,
E NE»
= = tHe H (0.37-1.37)

Tostar + CP Pete | Placebo + CP De >

( Potential benefit observed in the TPS3mut group; need to understand more about the NSMP group given its heterogenous nature |

"POL? was assessed by CPS score per Dako PO-L1 IHC 22C3 pharmD with a CPS 21 cut o deine PO-L1 postviy. Sample not availabe rn
1. Miza MR et al ESMO 2023. Abstract 740MO. 2. Mirza MR et al 500 2024. Abstract LEA. PeerView.com

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27. PD-L1 Status Is Not a Predictive Biomarker
for ICI With or Without PARPi Use in Patients With EC?

DUO-E exploratory PFS analysis in PD-L1+ subgroupt? RUBY Part 2 exploratory analysis by PD-L1 status?

100

88

33

Durva + ola + CP. oso

Proportion of Patients Alive
‘and Progression ree, %

10

É H Em MMRPIMSS

9 2 4 8 8

Ko

=n = com u ee
Median PFS (95% Cl), mo 20.8 (15.1-NR), 1307-54) 951999) ‚en Y 24 H m
HR (05% CH vs control 042 (031-057) 0.63 048-083) E es ann

* Cross study comparisons: side sfr information purposes only and snot intended to imply o infer ine noninferiority or superior of any agent.
*PO-L1 was assessed by CPS score per Dako PO-L1 IHC 2203 pharmDx wih a CPS 21 cute to define PD-L1 posit. “Sample not avaiable.

1. Westin SN eta. ESMO 2023, Abstract LBA41. 2. Westin SN ei al. J Cin Oncol 2024:42.283-299 3. Mirza MR etal. SGO 2028, Abstract LBAZ. PeerView.com

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28. Exploratory Analyses by Mutation Status?

DUO-E exploratory PFS subgroup analysis? RUBY part 2 exploratory PFS analysis by mutation status?

Overall Population Overall Population
repent cP So PO + HR (5% cn
O er men
02001508 emotes)
oso am an,
osrexosy oia curan,
— —— —— ——
Pose. se se m
Negetve rene u 081 049088)
ne 1908 ma onen
pates ef omen eme Vas HR man
wen PE aa = sa sona m
Non Hei onosom emer) an
nun joan om amos Negatve rae 22 089 (047-101)
err dam rave cout 071 (037437)

* Cross-study comparisons; sie is for information purposes only and isnot intended 1 imply o infer the noninferiority or superiority of any agent À
1. Westin SN et al ESMO 2023. Abstract LBA41. 2. Westin SN et al. J Cin Oncol 2024:42:283-200 3. Mirza MR et al. SGO 2024. Abstract LBAZ PeerView.com

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29. RUBY Part 1: Post Hoc Analysis of PFS and OS
by MMR Protein Loss!

PFS and OS in dMMR/MSI-H Population

Dostar + CP PBO + CP
3) (N=65)

Dostar + CP folowed by Dostar PES, HR (95% Cl) 0.28 (0.16-0.50); P<.0001
“bp LOS. HR (95% CI) 0.32 (0.17.0.63); nominal P = 0002

Duration of Response

PRO + ce Pao + cP
Kan (W238)
Patente win aMMRMISIHEE en s #0 = =
DOR, median (5% Ch,mo NR(E2NR) 4827-101) 36.7(54NR) 426881)
28,000) sa (00) 16:69.) 1280)
212.0%) 487) 200) 11478) 30120)

Probab of remaining

In response, % (95% Cl)

MR, 25 ep SM 12mo 900204989) 200(3:1475) RESET) 133040.)

ing Dostar + “cp 24 mo. 800204969) 10.0(06-958) 50348547 8.9(1.6245)
36 mo 800(204068) NE SO3(85S87 8.916245)

(estaria + cP et substantial PF and OS benef vs PRO in NE ES regaciss of mechanism of MMR protntoss )

1. Mirza MR et al ASCO 2024, Abstract 5806. PeerView.com

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30. Patient Characteristics in First-Line EC Trials

ProMisE molecular classifier’
Substantial and
unprecedented benefit of ICI
‘addition to chemotherapy
in dMMR tumors

Potential benefit with
ICI + chemotherapy (2) PARPI
In MMRp tumors

No additional bene
atic on top of
Shemonerepy X

for PoLEmut

No additional benefit
‘of PARPI on top of
ICI in aR EC

POLEmut

No significant difference in PFS outcomes
In patients with dMMR EC based on
‘mechanism of MMR loss

Petal nce A Dai HEM grep
e a rose
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1 Konmes ea Am Oc! 182880118 eerView.com

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31. What About Replacing Chemotherapy?
Frontline Immunotherapy Versus Chemotherapy

KEYNOTE-C93* DOMENICA?* LEAP-001#$

Lenvatinib +
pembrolizumab

Pembrolizumab Dostarlimab
Chemo

Primary endpoints: Primary endpoint: Primary endpoints:
PFS, OS PFS PFS, OS
Key secondary endpoint Key secondary endpoints: Key secondary endpoints:
ORR, DCR, DOR OS, PROs, ORR, DOR ORR, HRQOL, safety

dMMR and MMRp
patient populations

dMMR patient population dMMR patient population

— ‘Awaiting results y

Ius encart govstudyNCTOSIT3087.2. psc goVsta NCTOSZO1547. 3 dl Fetal ASCO 202, Asa TPSS630 a
4 ps cnica govstugyNCT03884101.5. Marth C et al. ESGO 2024. 6, Marth Cet al. SGO 2024. Oral rese PeerView.com

not meet dual primary endı

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32. Take-Home Points

Molecular profiling of endometrial Checkpoint inhibitor + carboplatin/paclitaxel
carcinoma has completely is the new standard of care for patients with
transformed our therapeutic approach advanced/recurrent endometrial cancer

However, this is just the beginning of an unprecedented improvement in patients outcomes; we still need
to understand

Who are the patients with MMR EC who do not benefit from ICI + chemotherapy?

Can we replace chemotherapy in patients with dMMR EC in view of ICl-only treatment?

And in which patients?

How do we treat patients who experience relapse post-chemotherapy + immunotherapy?

How do we further validate the prognostic value of molecular subgroups for identifying those patients
who will benefit the most?

What are the predictive biomarkers to understand which patients benefit most from PARPi addition to
ICI in MMRp EC?

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33. PeerView.com/RZJ827

Practical Tips for Discussing Molecular Testing
With Patients With EC

it could be described as the “last name” of the tumor

M | Explaining the importance of molecular classification to patients is critical;

M Patients should understand that the molecular profile of their tumor will affect
the choice of therapy and their potential outcomes

M Although ICIs are benefitting all patients, depth of response to each treatment
varies based on molecular subgroup — individualized therapy is crucial

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34. Safety Considerations
With Immunotherapy Regimens

Copyright © 2000-2024, PeerView

35. How Should Clinicians Manage irAEs in Patients
Treated With Immune Checkpoints Inhibitors?12

Know tho inmune toy spectrum
der drama rex actor
Int patents ander Reaheate powders

pectin Kina a a usina cheep
‘eee Orar os
s Y
ita vic en
omar &) « © mat pognon
ay eier pam ocen

Discus:
Retro organ specs?
Omar mmunosupptesie gs?
1.NCCN Cinial Pracice Guideines in Oncology. Management of Immunotherapy-Related Toncies. Version 12024, a
tos vw ncon orgiprtessionas/physician.gis/patimmunotherapy pal. 2. Champiat Set al Ann Oncol 201627559574, PeerView.com

irAEs should be managed based on severity

of symptoms

+ Supportive care, holding/discontinuing
immunotherapy, and administering
corticosteroids, as appropriate

Health providers must learn how to detect and
manage irAEs before starting therapy
+ Make use of resources and guidelines
(ESMO, SGO, NCCN, ASCO) on identification
and management of irAEs

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36. irAEs From Immune Checkpoint Inhibitors
Can Affect Any Organ System!

Dermatologic Gastrointestinal Endocrine | Pulmonary

Rash, pruritus Diarrhea, nausea, Hypothyroidism Pneumonitis
vomiting |
Consider Treating Wii
Topical steroids, | Steroids, antiemetics, Synthroid | Steroids
topical antihistamines | antidiarrheals

Identify experts in each specialty for collaboration; use e-consults to start early
intervention while the specialist appointment is being made

1. Marins F et al Nat Rev Gin Oncol, 201918:583-580 PeerView.com

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37. Immune-Related Adverse Events
Can Occur at Any Time

Variable Timing of irAEs*
Patient Communication

Is Essential

Colitis Pneumonitis (ap)

3
3
5 23
2
É + Discuss potential onset,
x Endocrinopathy duration, and symptoms
F | skin, of IRAEs
Hotel + Patients may be more
ruri a
ikely to adhere
0 4 6 8 0 12 14 >30
Duration of Treatment, wk
1. Marins Fetal, Nat Rev Cin Oncol 2018:16569-580. PeerView.com

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38. Common AEs With PARP Inhibitors’?

© Hematologic @ Nonhematologic O Rare

Anemia Nausea/Vomiting

Thrombocytopenia Asthenia/Fatigue

Neutropenia Diarrhea/Constipation Pneumonitis

| No greater incidence of AEs was observed with PARPi + IO + chemo combination therapy |

1. Lynparea (laparb)Prescrbing Information. htps hw accessdaa a govidrugsatia_docsabe/2023/208558s02 pa. 2 Zeil Inraparb] Prescribing m
Information. ps www accessdata da govidrugsatda_docs/abel2029/21487650001 pal PeerView.com

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39. sg Patient Case: 54-Year-Old Asian Woman

r

History
+ Diabetes mellitus type 2 under pharmacological treatment
+ Previous operations: tubal ligation at age of 27 y; umbilical hernia repair
+ Metrorrhagia of 4 days’ duration associated with asthenia

Family history

+ Brother diagnosed with gastric cancer at age of 56 y

+ Sister died of liver cancer at age of 59 y

+ Paternal cousin diagnosed with uterine cancer at age of 50 y

Pathology (endometrial biopsy): well-differentiated endometrioid carcinoma (G1)

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40. Y Patient Case:
2 Molecular Profile Performed on Initial Biopsy

POLE: not mutated MMR proteins: MLH1/MSH2/PMS2: PRESERVED
p53: wild-type pattern MSH6: LOST (refer to genetic counselor)

x

Images provided by A. Oaknin

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41. Patient Case and Discussion

2

Pelvic MRI
Endometrial thickening of 12x13mm at fundal level with no signs of myometrial infiltration >50%
No signs of lymph node or distant spread
Thoraco-abdomen-pelvis CT scan
+ Absence of lesions suggestive of malignancy at thoracic, abdominal or pelvic level
Robot-assisted laparoscopic surgery
+ Radical abdominal hysterectomy, bilateral salpingo-oophorectomy and bilateral sentinel node biopsy
Pathological anatomy:
Endometrial Neoplasia:
+ Histological type: endometroid carcinoma with sarcomatoid differentiation
Myometrial invasion: 10-15%
No vascular invasion
Tumor extension: left fallopian tube infiltration by carcinoma; right fallopian tube, bilateral ovaries and cervix without infiltration
Sentinel nodes followed by lymphadenectomy
- Sentinel node 1 left external iliac: infiltration by carcinoma (1/1)
Diameter of largest lymph node metastasis 4.2 mm; no associated extracapsular disease
Sentinel lymph node 1 right external iliac: absence of neoplastic invasion
Pelvic lymphadenectomy: 0/11
Para-aortic lymphadenectomy: 2/7

Stage: IIIC2ii (FIGO 2023); IIIC2 (FIGO 2018)

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42. Patient Case Recommendations

y MIC2ii (FIGO 2023); IIIC2 (FIGO 2018)

+ Radiation therapy is not recommended
+ Recommend six cycles of paclitaxel-carboplatin with concurrent dostarlimab Q3W

+ After chemotherapy, if she is still in complete response with no evidence of disease,
she will be given maintenance therapy with dostarlimab Q6W

+ Potential adverse events were explained, including the typically low rate of discontinuation
due to adverse events (<20%)

The patient agreed to this approach;
she started the first cycle of chemotherapy with dostarlimab
and has had an excellent tolerance to the treatment

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43. Closing Points

+ There is strong evidence supporting the use of immunotherapy in treating
patients with EC

— Data show activity in the frontline setting when adding ICls to
chemotherapy, with substantial benefit for those patients with
dMMR/MSI-H and MMRp/MSS recurrent EC

— PARPi used in combination with ICI and chemotherapy may further
improve outcomes, including in patients with MMRp/MSS disease

+ Guidelines lay out effective approaches for integrating ICls into clinical
care to support optimal patient outcomes

+ Guidelines and resources from ASCO, ESMO, NCCN, and SGO should
be utilized, and include best practices for identifying and managing irAEs

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