Rethinking and Refining Endometrial Cancer Care in the Modern Age of Precision Medicine: How to Translate Clinical Evidence Into Meaningful Improvements for Patients
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Sep 26, 2024
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About This Presentation
Co-Chairs Ramez N. Eskander, MD, and Shannon N. Westin, MD, MPH, discuss endometrial cancer in this CME/MOC/NCPD/AAPA/IPCE activity titled “Rethinking and Refining Endometrial Cancer Care in the Modern Age of Precision Medicine: How to Translate Clinical Evidence Into Meaningful Improvements for P...
Slide Content
Rethinking and Refining Endometrial Cancer
Care in the Modern Age of Precision Medicine
How to Translate Clinical Evidence Into Meaningful
Improvements for Patients
Ramez N. Eskander, MD
Professor of Gynecologic Oncology
Rebecca and John Moores NCI Designated Comprehensive Cancer Center
University of California San Diego Health
La Jolla, California
Shannon N. Westin, MD, MPH
Professor
Medical Director, Gynecologic Oncology Center
Director, Early Drug Development
Dept. of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas
Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Care in the Modern Age of Precision Medicine
How to Translate Clinical Evidence Into Meaningful
Improvements for Patients
Ramez N. Eskander, MD
Professor of Gynecologic Oncology
Rebecca and John Moores NCI Designated Comprehensive Cancer Center
University of California San Diego Health
La Jolla, California
Shannon N. Westin, MD, MPH
Professor
Medical Director, Gynecologic Oncology Center
Director, Early Drug Development
Dept. of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas
Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Our Goals for Today
Bolster your knowledge of the evidence supporting modern
approaches for patients with advanced endometrial cancer
Provide insight for effective integration of the latest options into
personalized care plans
Equip you with skills to confidently create proactive and collaborative
strategies to mitigate and manage adverse events
Copyright © 2001
Bolster your knowledge of the evidence supporting modern
approaches for patients with advanced endometrial cancer
Provide insight for effective integration of the latest options into
personalized care plans
Equip you with skills to confidently create proactive and collaborative
strategies to mitigate and manage adverse events
Copyright © 2001
How Common Is Endometrial Cancer?!
a Cases by Stage
Q Across all cancer types in the Unknown,
29 United States, uterine cancer represents hera
3.4% of new cases 2.2% of deaths a
J f
Estimates for 2024 Locate,
67,880 new cases 13,250 deaths
5-Year Relative Survival by Stage
a 100 94.8
Y 63 years Pi !
CY median age at diagnosis. E 60.7 we
35 0
es
gg“
80.8% 3° m EE)
5-year relative survival (2014-2020) o
Localized Regional Distant — Unknown
4. Mtps:/scer cancer govistatfacismloorp Nm PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
a Cases by Stage
Q Across all cancer types in the Unknown,
29 United States, uterine cancer represents hera
3.4% of new cases 2.2% of deaths a
J f
Estimates for 2024 Locate,
67,880 new cases 13,250 deaths
5-Year Relative Survival by Stage
a 100 94.8
Y 63 years Pi !
CY median age at diagnosis. E 60.7 we
35 0
es
gg“
80.8% 3° m EE)
5-year relative survival (2014-2020) o
Localized Regional Distant — Unknown
4. Mtps:/scer cancer govistatfacismloorp Nm PeerView.com
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Survival Disparities for Endometrial Cancer!
» 4
+ Overall, mortality rates for endometrial g “
cancer are increasing (2% annually, LS “ Pr E
2008-2018) i i s 5
+ However, the burden for Black patients | 23 |. pes EN En a
has increased disproportionately and 32 os E
now represents one of the largest racial 3 : =
disparities in cancer settings ren See
‘o_o tere me 8
D rene Arme
1. Monk BJ et al. Gynecol Oncal 2022:164:325 332. PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
» 4
+ Overall, mortality rates for endometrial g “
cancer are increasing (2% annually, LS “ Pr E
2008-2018) i i s 5
+ However, the burden for Black patients | 23 |. pes EN En a
has increased disproportionately and 32 os E
now represents one of the largest racial 3 : =
disparities in cancer settings ren See
‘o_o tere me 8
D rene Arme
1. Monk BJ et al. Gynecol Oncal 2022:164:325 332. PeerView.com
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Shifting the Paradigm:
Personalizing Treatment With Molecular Profiling‘
POLE (ultramutated)
100
Copy-number low
(endometrioid)
80
MSI (hypermutated)
60
Copy-number high
PFS, %
40 (serous like)
2
Log-rank P = .02
o
0 20 4 6 so 100 120
Time, mo
41. The Cancer Genome Alas Research Network Nature, 2013:487 67-73,
PeerView.com/XJE827
POLE: ultramutated,
100-500 mutations/Mb
AMMRIMSIH:
10-20 mutations/Mb
CN lowINSMPITPS3
WTIMSS:
2-3 mutations/Mb,
‘endometrioid, G1
CN high/TPS3 abn:
2-3 mutations/Mb,
high grade
5%-10% of endometrial cancers
High mutation burden leads to better immune
response, excessive mutations lead to
inability to proliferate
20%-30% of endometrial cancers
Hereditary (Lynch syndrome) or somatic
‘Most common endometrial cancer
Low-grade tumors.
Estrogen/progesterone positve
PTEN, PIK3CA, ARIDIA, and KRAS
mutations
Often serous or mixed histology
Poorest prognosis
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Personalizing Treatment With Molecular Profiling‘
POLE (ultramutated)
100
Copy-number low
(endometrioid)
80
MSI (hypermutated)
60
Copy-number high
PFS, %
40 (serous like)
2
Log-rank P = .02
o
0 20 4 6 so 100 120
Time, mo
41. The Cancer Genome Alas Research Network Nature, 2013:487 67-73,
PeerView.com/XJE827
POLE: ultramutated,
100-500 mutations/Mb
AMMRIMSIH:
10-20 mutations/Mb
CN lowINSMPITPS3
WTIMSS:
2-3 mutations/Mb,
‘endometrioid, G1
CN high/TPS3 abn:
2-3 mutations/Mb,
high grade
5%-10% of endometrial cancers
High mutation burden leads to better immune
response, excessive mutations lead to
inability to proliferate
20%-30% of endometrial cancers
Hereditary (Lynch syndrome) or somatic
‘Most common endometrial cancer
Low-grade tumors.
Estrogen/progesterone positve
PTEN, PIK3CA, ARIDIA, and KRAS
mutations
Often serous or mixed histology
Poorest prognosis
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Guidelines: Principles of Molecular Analysis
Pathology and Genomics in Endometrial Carcinoma!
POLE sequencing
No POLE hotspot mutation POLE hotspot mutation
POLE status
DNA MMR protein
immunohistochemistry ee
el states;
eg 53 In histochemisti
lost 53 immunohistochemistry ris
Normalwilé-type pattern | _Aberrantimutant pattern
NMR CN low! CN high ose
MSI-H NSMP/pS3wt/MSS pS3mut ea
NCCN
1.NCEN Cini Pracice Guidelines in Oncology. Uterine Neoplasms. Version 22024. hitpslwwv ncen cmprolessionai/physisan chuter pe
2. Oaknin A. ESMO Guidelines Commitee, Ann Oncol 2022,33:860-877,
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Endometrial Carcinoma
(histological subtype independent?
Tr —
POLE POLEwt or
pathogenic non-pathogenic
dMMR PMR
psa PS3mut
Ec, EC, Ec, EC,
POLEmut dMMR NSMP P53mut
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Pathology and Genomics in Endometrial Carcinoma!
POLE sequencing
No POLE hotspot mutation POLE hotspot mutation
POLE status
DNA MMR protein
immunohistochemistry ee
el states;
eg 53 In histochemisti
lost 53 immunohistochemistry ris
Normalwilé-type pattern | _Aberrantimutant pattern
NMR CN low! CN high ose
MSI-H NSMP/pS3wt/MSS pS3mut ea
NCCN
1.NCEN Cini Pracice Guidelines in Oncology. Uterine Neoplasms. Version 22024. hitpslwwv ncen cmprolessionai/physisan chuter pe
2. Oaknin A. ESMO Guidelines Commitee, Ann Oncol 2022,33:860-877,
PeerView.com/XJE827
Endometrial Carcinoma
(histological subtype independent?
Tr —
POLE POLEwt or
pathogenic non-pathogenic
dMMR PMR
psa PS3mut
Ec, EC, Ec, EC,
POLEmut dMMR NSMP P53mut
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MMR Incidence in Endometrial Cancer‘?
Endometrial cancer can be classified as
+ pMMR/MSS (70%-75%)
+ dMMR/MSI-H (25%-30%)
MSI-H Cancers, %
UCECCOAD STAD READ KIRC OV PRAD LUADHNSC LIHC LUSC BLCA GEM LGG BRCA KIRP SKCMTHCA
= 908): LHC (n= 338) LUSC. (n= 443)
AUCEC (n= 437} COAD (n= 298) STAD (n= 278 READ (n = 96): KIRC(n = 279) OV
BLCA (n= 2531 GBM fn 262 LOG (n= S13), BRCA (n= 260) KIRP In = 207), SKEM ei
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1. Hause Rue al Nat Mod. 2016:22:1342-1350.
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Endometrial cancer can be classified as
+ pMMR/MSS (70%-75%)
+ dMMR/MSI-H (25%-30%)
MSI-H Cancers, %
UCECCOAD STAD READ KIRC OV PRAD LUADHNSC LIHC LUSC BLCA GEM LGG BRCA KIRP SKCMTHCA
= 908): LHC (n= 338) LUSC. (n= 443)
AUCEC (n= 437} COAD (n= 298) STAD (n= 278 READ (n = 96): KIRC(n = 279) OV
BLCA (n= 2531 GBM fn 262 LOG (n= S13), BRCA (n= 260) KIRP In = 207), SKEM ei
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1. Hause Rue al Nat Mod. 2016:22:1342-1350.
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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 + MSlis characterized by mutation clustering
+ Absence/loss of function in one of the four MMR in microsatellites typically consisting of repeat
proteins results in dMMR length alterations
The presence of MSI represents
MMR is the cause of MSI-H phenotypic evidence that MMR is not
functioning normally (dMMR)
MSI-H provides phenotypic evidence of dMMR;
thus, MSI-H and dMMR are considered biologically the same population
+ dMMR/MSI-H refers to patients with mismatch repair deficiency
+ pMMRIMSS refers to patients with mismatch repair proficiency
1. Kloor M eta. Trends Cancer. 2016:121-133. 2. Luchini et al Ann Oncol 2018:30:1232-1243 PeerView.com
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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 + MSlis characterized by mutation clustering
+ Absence/loss of function in one of the four MMR in microsatellites typically consisting of repeat
proteins results in dMMR length alterations
The presence of MSI represents
MMR is the cause of MSI-H phenotypic evidence that MMR is not
functioning normally (dMMR)
MSI-H provides phenotypic evidence of dMMR;
thus, MSI-H and dMMR are considered biologically the same population
+ dMMR/MSI-H refers to patients with mismatch repair deficiency
+ pMMRIMSS refers to patients with mismatch repair proficiency
1. Kloor M eta. Trends Cancer. 2016:121-133. 2. Luchini et al Ann Oncol 2018:30:1232-1243 PeerView.com
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Educating Your Patients and Staff About
the Importance of and Access to Clinical Trials
Why Is Clinical Trial Participation Important?
Clinical trials are a key step in translating research
into medicines that can cure illness, slow disease,
and improve QOL for patients
* Robust participation in clinical trials with diverse
enrollment means a shorter timeline between
medical discovery and patient access to potentially
life-changing treatments
Clinical Trial Participation
Offers Dual Benefits for Patients
. Potential personal benefit: patients may experience
improved disease outcomes and better health if they
receive otherwise unavailable medical therapies Increasing diversity in clinical trial
. Social benefit: clinical trial participation helps provide enrollment is cru
access for patients who may benefit from the new Providers need to discuss with and offer
treatment option by moving a new therapy closer clinical trial opportunities to all patients
to market
3
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the Importance of and Access to Clinical Trials
Why Is Clinical Trial Participation Important?
Clinical trials are a key step in translating research
into medicines that can cure illness, slow disease,
and improve QOL for patients
* Robust participation in clinical trials with diverse
enrollment means a shorter timeline between
medical discovery and patient access to potentially
life-changing treatments
Clinical Trial Participation
Offers Dual Benefits for Patients
. Potential personal benefit: patients may experience
improved disease outcomes and better health if they
receive otherwise unavailable medical therapies Increasing diversity in clinical trial
. Social benefit: clinical trial participation helps provide enrollment is cru
access for patients who may benefit from the new Providers need to discuss with and offer
treatment option by moving a new therapy closer clinical trial opportunities to all patients
to market
3
E
2
E
3
E
E
A
3
2
=
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PeerView.com
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Combination Approaches: Leveraging ICI Activity’
+ The combination of
immunotherapy and
chemotherapy can
increase tumor sensitivity
to PD-L1-targeted mAbs
+ Chemotherapy
— Induces upregulation of
PD-L1 on cancer cells
— Facilitates infiltration of
CD8* T cells and NK cells
= Increases maturation of
APCs (including dendritic
Immunotherapy alone Immunotherapy + chemotherapy
Immune suppressive
ee @ coe rt trmunorescto tuner
amor menant 1
microenvronment
Y CE
e. t of
‘APC, MDSC'
“Cold tumor” o—— 0 “Hot tumor" cells and tumor
macrophages)
1. Baily Cet al, NAR Cancer 2020:22c00002. PeerView.com
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+ The combination of
immunotherapy and
chemotherapy can
increase tumor sensitivity
to PD-L1-targeted mAbs
+ Chemotherapy
— Induces upregulation of
PD-L1 on cancer cells
— Facilitates infiltration of
CD8* T cells and NK cells
= Increases maturation of
APCs (including dendritic
Immunotherapy alone Immunotherapy + chemotherapy
Immune suppressive
ee @ coe rt trmunorescto tuner
amor menant 1
microenvronment
Y CE
e. t of
‘APC, MDSC'
“Cold tumor” o—— 0 “Hot tumor" cells and tumor
macrophages)
1. Baily Cet al, NAR Cancer 2020:22c00002. PeerView.com
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Frontline Approaches in Endometrial Cancer:
Immunotherapy Plus Chemotherapy
Key Eligibility Criteria
+ Advanced or
recurrent EC
No previous
chemotherapy
for EC (previous
adjuvant
chemotherapy
allowed if completed
212 mo ago)
+ ECOG PS 0-2
* MMR status as randomized,
1. ps (nicolas govistudy/NCTO3914612, 2. Eskander RN etal N Engl J Med. 2023:388:2159-2170,
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Phase 3 NRG-GY018:
Pembrolizumab + Chemotherapy‘?
Stratification
dMMR status
(yes vs no)
ECOG PS
( or 1 vs 2)
Prior
chemotherapy
(yes vs no)
Pembrolizumab + Pembrolizumab
mg carboplatin/paclitaxel Q6W for
Q3W for up to 6 cycles up to 14 cycles
Placebo +
mud carboplatin/paclitaxel WW for
Q3W for up to 6 cy up to 14 cy
Primary endpoints: PFS in dMMR, PFS in pMMR
Select secondary and exploratory endpoints*: OS in pMMR and dMMR,
PD-L1 status (positive vs negative) in pMMR and dMMR, INV PFS by PD-L1
status in pMMR and dMMR, BICR vs investigator-assessed outcomes by
MMR status
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Immunotherapy Plus Chemotherapy
Key Eligibility Criteria
+ Advanced or
recurrent EC
No previous
chemotherapy
for EC (previous
adjuvant
chemotherapy
allowed if completed
212 mo ago)
+ ECOG PS 0-2
* MMR status as randomized,
1. ps (nicolas govistudy/NCTO3914612, 2. Eskander RN etal N Engl J Med. 2023:388:2159-2170,
PeerView.com/XJE827
Phase 3 NRG-GY018:
Pembrolizumab + Chemotherapy‘?
Stratification
dMMR status
(yes vs no)
ECOG PS
( or 1 vs 2)
Prior
chemotherapy
(yes vs no)
Pembrolizumab + Pembrolizumab
mg carboplatin/paclitaxel Q6W for
Q3W for up to 6 cycles up to 14 cycles
Placebo +
mud carboplatin/paclitaxel WW for
Q3W for up to 6 cy up to 14 cy
Primary endpoints: PFS in dMMR, PFS in pMMR
Select secondary and exploratory endpoints*: OS in pMMR and dMMR,
PD-L1 status (positive vs negative) in pMMR and dMMR, INV PFS by PD-L1
status in pMMR and dMMR, BICR vs investigator-assessed outcomes by
MMR status
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NRG-GY018:
PFS Benefit With Pembrolizumab Plus Chemotherapy’
MMR Cohort PMMR Cohort
mPFS NR vs 7.7 mo
HR = 0.3 (95% Cl, 0.19-0.48) E
P<.001 an
mPFS 13.1 vs 8.7 mo
HR = 0.54 (95% Cl, 0.41-0.71)
P< 001
Pembrolizumab + chemo Pembrolizumab + chemo
PFS, Probability
E
PFS, Probability
Placebo + chemo
Placebo + chemo
Pembrolizumab improved INV PFS regardless of PD-L1 status for both dMMR and pMMR populations
PFS by investigator and BICR were consistent
1. Eskander RN etal. N Engl J Med. 2023;388:2158-2170, 2. Eskander RNet al SGO 2024, Abstract LBA PeerView.com
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PFS Benefit With Pembrolizumab Plus Chemotherapy’
MMR Cohort PMMR Cohort
mPFS NR vs 7.7 mo
HR = 0.3 (95% Cl, 0.19-0.48) E
P<.001 an
mPFS 13.1 vs 8.7 mo
HR = 0.54 (95% Cl, 0.41-0.71)
P< 001
Pembrolizumab + chemo Pembrolizumab + chemo
PFS, Probability
E
PFS, Probability
Placebo + chemo
Placebo + chemo
Pembrolizumab improved INV PFS regardless of PD-L1 status for both dMMR and pMMR populations
PFS by investigator and BICR were consistent
1. Eskander RN etal. N Engl J Med. 2023;388:2158-2170, 2. Eskander RNet al SGO 2024, Abstract LBA PeerView.com
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NRG-GY018:
OS Benefit With Pembrolizumab Plus Chemotherapy’
Favorable Trend in OS With Pembro + CT for (MMR EC Favorable Trend in OS With Pembro + CT for pMMR EC
‘OS Data Immature at IA (18.0% Information fraction) ‘OS Data Immature at 1A (27.2% Information fraction)
Eve fem Dur, Median O8 eyo,
tn M mg NE PC
Pombro +CT among hee wnociuconinves
‘eam mere pente o
cas + CT gr va pare
CT ar au nenne muet
Placebo + CT Sopot ena sesh ve
ci ame
08,%
csussssansi
08,%
csvuessasasi
Pembro + CT.
Emeuroumn Mesas
Er nt Eee mapeo Among those uno donnes vestmert.
egies _ (re, ‘nor pant nt pacte + CT group ve
TETE TT
RON asian
apart Er prop emos Placebo + CT
gue POPOL! ners (8
Ernest
‘Time Since Randomization, mo Time Since Randomization, mo
June 17, 2024:
Pembrolizumab + chemotherapy followed by single-agent pembrolizumab approved by the FDA for
patients with either MMR or pMMR endometrial carcinoma?
1. Eskander RN et a SGO 2024 LBA 2, hips. nw da govlcrugsresources-nformaton-epproved:rugs ide approwes-pembrtizume-chemother spy primary
scvanced-or-recurent-endometial-cardnomatum_medium=emalautm sourcesgendeihen.
3. tps uw acoessdatn da govidrugsaida_docs/abel/2024/125514S157RH pot
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OS Benefit With Pembrolizumab Plus Chemotherapy’
Favorable Trend in OS With Pembro + CT for (MMR EC Favorable Trend in OS With Pembro + CT for pMMR EC
‘OS Data Immature at IA (18.0% Information fraction) ‘OS Data Immature at 1A (27.2% Information fraction)
Eve fem Dur, Median O8 eyo,
tn M mg NE PC
Pombro +CT among hee wnociuconinves
‘eam mere pente o
cas + CT gr va pare
CT ar au nenne muet
Placebo + CT Sopot ena sesh ve
ci ame
08,%
csussssansi
08,%
csvuessasasi
Pembro + CT.
Emeuroumn Mesas
Er nt Eee mapeo Among those uno donnes vestmert.
egies _ (re, ‘nor pant nt pacte + CT group ve
TETE TT
RON asian
apart Er prop emos Placebo + CT
gue POPOL! ners (8
Ernest
‘Time Since Randomization, mo Time Since Randomization, mo
June 17, 2024:
Pembrolizumab + chemotherapy followed by single-agent pembrolizumab approved by the FDA for
patients with either MMR or pMMR endometrial carcinoma?
1. Eskander RN et a SGO 2024 LBA 2, hips. nw da govlcrugsresources-nformaton-epproved:rugs ide approwes-pembrtizume-chemother spy primary
scvanced-or-recurent-endometial-cardnomatum_medium=emalautm sourcesgendeihen.
3. tps uw acoessdatn da govidrugsaida_docs/abel/2024/125514S157RH pot
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NRG-GY018: Improved ORR With Pembrolizumab Plus
Chemotherapy on dMMR and pMMR Populations’
dMMR? pMMR>
82%
(95% Cl, 72%-89%)
71% 71%
(95% CI, 60%-80%) (95% Cl, 64%-77%)
58%
(95% Cl, 52%-65%)
ORR, %
ORR, %
Pembro + CP Placebo + CP
Pembro + CP
N=92 2 N=212 N=234
median DOR, 28.7 vs 6.2 mo median DOR, 9.2 vs 6.2 mo
»Ods ratio for response wih pembro + CP: 1.83 (85% CI, 0:92-3.66).° Odds ratio or response with pembro + CP: 1.74 (95% Cl, 1.16-2.58) e
1. Eskander RN etal, ESMO 2023, Abstract 6564, PeerView.com
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Chemotherapy on dMMR and pMMR Populations’
dMMR? pMMR>
82%
(95% Cl, 72%-89%)
71% 71%
(95% CI, 60%-80%) (95% Cl, 64%-77%)
58%
(95% Cl, 52%-65%)
ORR, %
ORR, %
Pembro + CP Placebo + CP
Pembro + CP
N=92 2 N=212 N=234
median DOR, 28.7 vs 6.2 mo median DOR, 9.2 vs 6.2 mo
»Ods ratio for response wih pembro + CP: 1.83 (85% CI, 0:92-3.66).° Odds ratio or response with pembro + CP: 1.74 (95% Cl, 1.16-2.58) e
1. Eskander RN etal, ESMO 2023, Abstract 6564, PeerView.com
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NRG-GY018: PFS by Methylation Status
in dMMR Population!
, Methylation Status
Methylation No Methylation ab D CRIA
pace sce | sum | 786219 | oupgsaun | [rwcr | mr | saco | ooo || L'on > | TCE)
Tenor | me IET | °° Perser | am | mmmezm | Po mener EME
*
E vo jc
¿on so Puntos ee mi
ion ES i
i © ER so le
Es so Lo
HS “o Lo
E ” ho
§ = Placebos er æ Pracabo + CF El
» so wo
ol ot °
9 5 © ee » » à à of eh à » % à à 9 5 2 à à » » à à
‘ine Since Rancomzation, mo Time Since Rendomkaton,me “tne since Rancomaton. mo
The mechanism of MMR loss (mutation vs epigenetic alteration) did not appear to be
prognostic of response to chemotherapy or pembrolizumab
1. Eskander RN etal. ESMO 2023, Abstract 6564 PeerView.com
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in dMMR Population!
, Methylation Status
Methylation No Methylation ab D CRIA
pace sce | sum | 786219 | oupgsaun | [rwcr | mr | saco | ooo || L'on > | TCE)
Tenor | me IET | °° Perser | am | mmmezm | Po mener EME
*
E vo jc
¿on so Puntos ee mi
ion ES i
i © ER so le
Es so Lo
HS “o Lo
E ” ho
§ = Placebos er æ Pracabo + CF El
» so wo
ol ot °
9 5 © ee » » à à of eh à » % à à 9 5 2 à à » » à à
‘ine Since Rancomzation, mo Time Since Rendomkaton,me “tne since Rancomaton. mo
The mechanism of MMR loss (mutation vs epigenetic alteration) did not appear to be
prognostic of response to chemotherapy or pembrolizumab
1. Eskander RN etal. ESMO 2023, Abstract 6564 PeerView.com
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Frontline Approaches in Endometrial Cancer:
Immunotherapy Plus Chemotherapy
Phase 3 AtTEnd: Atezolizumab Plus Chemotherapy?
Key Eligibility Criteria
+ Newly diagnosed
advanced or recurrent
endometrial cancer,
naive to first-line
systemic therapy
One previous line of
platinum-based
regimen permitted if
platinum-free interval
26 mo
+ ECOG PS 0-2
Stratification
Histology
Disease
status
Microsatellite
status
Country
Endpoints (in hierarchical order)
Atezolizumab
Q3W until progression +
carboplatin/paclitaxel
Q3W for up to 6-8 cycles
Placebo
Q3W until progression +
carboplatin/paclitaxel
Q3W for up to cles
PFS PFS os
dMMR De All comers. ee All comers,
a (two-sided) 4% a (two-sided) 4% | a (two-sided) 5
HR=0.5 HR=0.7 HR=0.7
1. hps:fetnicalrals gowet2/showNCTO3608184. 2. Colombo N et al. ESMO 2023, Abstract LBAGO.
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Immunotherapy Plus Chemotherapy
Phase 3 AtTEnd: Atezolizumab Plus Chemotherapy?
Key Eligibility Criteria
+ Newly diagnosed
advanced or recurrent
endometrial cancer,
naive to first-line
systemic therapy
One previous line of
platinum-based
regimen permitted if
platinum-free interval
26 mo
+ ECOG PS 0-2
Stratification
Histology
Disease
status
Microsatellite
status
Country
Endpoints (in hierarchical order)
Atezolizumab
Q3W until progression +
carboplatin/paclitaxel
Q3W for up to 6-8 cycles
Placebo
Q3W until progression +
carboplatin/paclitaxel
Q3W for up to cles
PFS PFS os
dMMR De All comers. ee All comers,
a (two-sided) 4% a (two-sided) 4% | a (two-sided) 5
HR=0.5 HR=0.7 HR=0.7
1. hps:fetnicalrals gowet2/showNCTO3608184. 2. Colombo N et al. ESMO 2023, Abstract LBAGO.
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Phase 3 AtTEnd:
PFS Benefit With Atezolizumab Plus Chemotherapy‘
Primary Endpoint: PFS in dMMR (Median Follow-Up of 26.2 mo)
Atezollzumab
bo.
so Events/otal ET] EZ
80 Median PFS (98% Cl) mo — NE(IZ3NE) 69(62-00)
pe HR (95% CD) 0.36 (0.23-0.57); P=.0005
62.7
Atezolizumab
PFS, %
g
Median follow-up: 26.2 months
o
o 6 1 18 24 30 36 42 48
El Time, mo
‘Atozoizuma 81 6 4 ” 25 2 3 4 o
Placebo “ a 10 6 ‘ 1 1 o
1. Colombo N et al Lancet Oncol 2024; 25:1135-1146
PeerView.com/XJE827
+ PFS was also
improved in the
0.61-0.91)
Co-primary
endpoint of OS
had a trend for
improvement,
but data are not
yet mature
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PFS Benefit With Atezolizumab Plus Chemotherapy‘
Primary Endpoint: PFS in dMMR (Median Follow-Up of 26.2 mo)
Atezollzumab
bo.
so Events/otal ET] EZ
80 Median PFS (98% Cl) mo — NE(IZ3NE) 69(62-00)
pe HR (95% CD) 0.36 (0.23-0.57); P=.0005
62.7
Atezolizumab
PFS, %
g
Median follow-up: 26.2 months
o
o 6 1 18 24 30 36 42 48
El Time, mo
‘Atozoizuma 81 6 4 ” 25 2 3 4 o
Placebo “ a 10 6 ‘ 1 1 o
1. Colombo N et al Lancet Oncol 2024; 25:1135-1146
PeerView.com/XJE827
+ PFS was also
improved in the
0.61-0.91)
Co-primary
endpoint of OS
had a trend for
improvement,
but data are not
yet mature
PeerView.com
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Frontline Approaches in Endometrial Cancer:
Immunotherapy Plus Chemotherapy
Phase 3 RUBY (Part 1): Dostarlimab + Chemotherapy’?
i teri: Stratification
Key Eligibility Criteria E Migosaialiie Dostarlimab 500 mg + Dostarlimab
+ Advanced or recurrent status (MSI-H carboplatin/paclitaxel 1,000 mg
endometrial cancer
Q6W for up to 3 y
not treated with SS) i Bee
chemotherapy + Disease status
+ Previous adjuvant (stage Ill vs IV
vs recurrent)
chemotherapy allowed Prior e Placebo
if completed 26 mo ago =! Q6W for up to 3
ds radiotherapy 3W fo N for up to 3 y
(yes vs no)
Y
+ Primary endpoints: PFS, OS
+ Secondary endpoints: ORR, DOR, safety, PRO
A Mps:/nicatl gorenyNNCTO3S8170.2. Miza MR et Eng J Med. 2020.00 21452158 PeerView.com
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Immunotherapy Plus Chemotherapy
Phase 3 RUBY (Part 1): Dostarlimab + Chemotherapy’?
i teri: Stratification
Key Eligibility Criteria E Migosaialiie Dostarlimab 500 mg + Dostarlimab
+ Advanced or recurrent status (MSI-H carboplatin/paclitaxel 1,000 mg
endometrial cancer
Q6W for up to 3 y
not treated with SS) i Bee
chemotherapy + Disease status
+ Previous adjuvant (stage Ill vs IV
vs recurrent)
chemotherapy allowed Prior e Placebo
if completed 26 mo ago =! Q6W for up to 3
ds radiotherapy 3W fo N for up to 3 y
(yes vs no)
Y
+ Primary endpoints: PFS, OS
+ Secondary endpoints: ORR, DOR, safety, PRO
A Mps:/nicatl gorenyNNCTO3S8170.2. Miza MR et Eng J Med. 2020.00 21452158 PeerView.com
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Phase 3 RUBY (Part 1):
Improved Survival With Dostarlimab Plus Chemotherapy’
‘Substantial PFS Benefit in dMMR/MSI-H Population Substantial OS Benefit in dMMR/MSI-H Population?
Medan dwationot HR2022
* ne ante
= ze oes
© } «oz
E H (one 01605) » Bevin + cp
» | g Pr;
FEI ! pa. ¿ H
2 aH 83780) » i
Ez i Memamınn i pecan cm vert 0 Paso cP
x ¡A —
5 Role Me men | panne
Y NN LR iin
; i rose san Less À nase
Tie Soe Randomization mo Fame Since Randomtaton mo
August 1, 2024
Expanded FDA approval of dostarlimab + chemotherapy followed by single-agent dostarlimab for
patients with either dMMR or pMMR endometrial carcinoma”
08 inthe dMMRIMSI-H and pMMRIMSS populations was a prespecified exploratory endpoint. ? Mecian expected duration of folow-up: range 31.048.7 months
1. Meza MR et al N Engl J Med, 2023;388:21452158, 2. Powell MA et al SGO 2024. 3. ps fda govirugstescur
¡cesta opos n
‘expands endometia-cancer indication <ostarimab-giy-chemolherapy 4. ps ww, access fda govdrugsalida_docs/label/2024/761 1745009 pdf PeerView.com
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Improved Survival With Dostarlimab Plus Chemotherapy’
‘Substantial PFS Benefit in dMMR/MSI-H Population Substantial OS Benefit in dMMR/MSI-H Population?
Medan dwationot HR2022
* ne ante
= ze oes
© } «oz
E H (one 01605) » Bevin + cp
» | g Pr;
FEI ! pa. ¿ H
2 aH 83780) » i
Ez i Memamınn i pecan cm vert 0 Paso cP
x ¡A —
5 Role Me men | panne
Y NN LR iin
; i rose san Less À nase
Tie Soe Randomization mo Fame Since Randomtaton mo
August 1, 2024
Expanded FDA approval of dostarlimab + chemotherapy followed by single-agent dostarlimab for
patients with either dMMR or pMMR endometrial carcinoma”
08 inthe dMMRIMSI-H and pMMRIMSS populations was a prespecified exploratory endpoint. ? Mecian expected duration of folow-up: range 31.048.7 months
1. Meza MR et al N Engl J Med, 2023;388:21452158, 2. Powell MA et al SGO 2024. 3. ps fda govirugstescur
¡cesta opos n
‘expands endometia-cancer indication <ostarimab-giy-chemolherapy 4. ps ww, access fda govdrugsalida_docs/label/2024/761 1745009 pdf PeerView.com
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RUBY Part 1: Post Hoc Analysis of PFS and OS
by MMR Protein Loss’
Ta (N= 494)
PS, HR (95% CI)
PFS and OS in dMMR/MSI-H Population
028 (0.16-0.50); P< 0001
4 by PRO
PBO+ CP
folowed by Dostar
Dostar
OS, HR (95% Ch,
0.32 (0.17-0.63); nominal
0002
EE) duration of Response
UMASS
Eo n= 192)
PBO + CP
PBo+cp
(Ne 39)
Responders. 0
DOR, median (95% Cl mo | NR(E2NR | 2827101) | 387548) | 426881
25,000) 533) 4400) 16685 | 12480)
212.006) 41687) 24200) 114478) 3020)
Probably of remaining
Patients categories An response, %(95%C))
MR 12m0 20.0 (20.486)| 200131475 | 503285687] 13334301)
Amo 200(20:496:9)| 10008358) | s03(28.508.7)| 8915245)
Ei now) ne | 503(285687)| 89616248)
1. Mirza MR et al ASCO 2024. Abstract 5606,
PeerView.com/XJE827
Dostarlimab + CP led to substantial PFS and OS benefits vs PBO in dMMR EC regardless of mechanism of MMR protein loss
PeerView.com
Copyright © 2000-2024, PeerView
by MMR Protein Loss’
Ta (N= 494)
PS, HR (95% CI)
PFS and OS in dMMR/MSI-H Population
028 (0.16-0.50); P< 0001
4 by PRO
PBO+ CP
folowed by Dostar
Dostar
OS, HR (95% Ch,
0.32 (0.17-0.63); nominal
0002
EE) duration of Response
UMASS
Eo n= 192)
PBO + CP
PBo+cp
(Ne 39)
Responders. 0
DOR, median (95% Cl mo | NR(E2NR | 2827101) | 387548) | 426881
25,000) 533) 4400) 16685 | 12480)
212.006) 41687) 24200) 114478) 3020)
Probably of remaining
Patients categories An response, %(95%C))
MR 12m0 20.0 (20.486)| 200131475 | 503285687] 13334301)
Amo 200(20:496:9)| 10008358) | s03(28.508.7)| 8915245)
Ei now) ne | 503(285687)| 89616248)
1. Mirza MR et al ASCO 2024. Abstract 5606,
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Dostarlimab + CP led to substantial PFS and OS benefits vs PBO in dMMR EC regardless of mechanism of MMR protein loss
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Frontline Approaches in Endometrial Cancer:
Inclusion of a PARP Inhibitor in the Maintenance Phase
Phase 3 RUBY (Part 2): Dostarlimab + Chemotherapy + Niraparib!-2
Dostarlimab
1000 mg IV Q6W up to 3 years
Dostarimab
Key Eligibility Criteria Stratification
3 N=192
+ Microsatellite +
+ Advanced or recurrent
endometrial cancer CES (MEA Moers es
He vs MSS) 200 or 300 mg QD up to 3
chemotherapy + Disease status 2:1 (6 cycles)
+ Previous adjuvant (stage Ill vs IV
chemotherapy allowed ao Placebo IV Placebo IV
> 9 (aw) Q6W up to 3 years
iLcomple ted 2e mo Sac, radiothera| Nao
+ ECOGPS 0-1 Py
(yes vs no)
cycles)
+ Primary endpoints: PFS (Overall, pMMR)
+ Secondary endpoints: OS, ORR, DOR, safety, PRO
1. itpsctnicatrials gowstudyiNCTO3861786. 2. Miza MR et al. SGO 2024. PeerView.com
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Inclusion of a PARP Inhibitor in the Maintenance Phase
Phase 3 RUBY (Part 2): Dostarlimab + Chemotherapy + Niraparib!-2
Dostarlimab
1000 mg IV Q6W up to 3 years
Dostarimab
Key Eligibility Criteria Stratification
3 N=192
+ Microsatellite +
+ Advanced or recurrent
endometrial cancer CES (MEA Moers es
He vs MSS) 200 or 300 mg QD up to 3
chemotherapy + Disease status 2:1 (6 cycles)
+ Previous adjuvant (stage Ill vs IV
chemotherapy allowed ao Placebo IV Placebo IV
> 9 (aw) Q6W up to 3 years
iLcomple ted 2e mo Sac, radiothera| Nao
+ ECOGPS 0-1 Py
(yes vs no)
cycles)
+ Primary endpoints: PFS (Overall, pMMR)
+ Secondary endpoints: OS, ORR, DOR, safety, PRO
1. itpsctnicatrials gowstudyiNCTO3861786. 2. Miza MR et al. SGO 2024. PeerView.com
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RUBY (Part 2): PFS Benefit for the pMMR Population With
Inclusion of a PARP Inh
Statistically Significant PFS Benefit in Overall Population
Primary endpoint
or in the Maintenance Phase!
Statistically Significant PFS Benefit in PMMRIMSS Population
Primary endpoint
parco as)
PS mary: 61.1%
Dostar + ira + CP
placebo oral + CP
= din (85.6 me a
ena moe
“m Pocsto+cP non oa 5 © Fe
£ ' €
= PFS maturty: 884%. 3
2 2,
i se | |
Ë » Piacobolv + a Saw
placebo ral + CP ay
opti a tuwa sane ae crite eenuweauna®
121" Si since ri,
Herr Tie Sines Randomization, mo
+ Met primary endpoint, showing significant and clinically meaningful improvement in PFS for
dostarlimab + chemotherapy followed by dostarlimab + niraparib in the overall and
PMMR/MSS populations
+ The trial is ongoing for OS follow-up
1. Meza MR et al. S60 2024 LBA2.
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Inclusion of a PARP Inh
Statistically Significant PFS Benefit in Overall Population
Primary endpoint
or in the Maintenance Phase!
Statistically Significant PFS Benefit in PMMRIMSS Population
Primary endpoint
parco as)
PS mary: 61.1%
Dostar + ira + CP
placebo oral + CP
= din (85.6 me a
ena moe
“m Pocsto+cP non oa 5 © Fe
£ ' €
= PFS maturty: 884%. 3
2 2,
i se | |
Ë » Piacobolv + a Saw
placebo ral + CP ay
opti a tuwa sane ae crite eenuweauna®
121" Si since ri,
Herr Tie Sines Randomization, mo
+ Met primary endpoint, showing significant and clinically meaningful improvement in PFS for
dostarlimab + chemotherapy followed by dostarlimab + niraparib in the overall and
PMMR/MSS populations
+ The trial is ongoing for OS follow-up
1. Meza MR et al. S60 2024 LBA2.
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Frontline Approaches in Endometrial Cancer:
Inclusion of a PARP Inhibitor in the Maintenance Phase!
Phase 3 DUO-E: Durvalumab + Chemotherapy + Olaparib1-
+ Newly diagnosed
stage III/IV or
recurrent EC
+ Naive to 1L systemic
anticancer treatment
+ Prior adjuvant
chemotherapy
allowed if 212 mo
from last treatment
torelapse
+ Known MMR status
+ Prior radiotherapy
allowed
+ Allhistologies except
sarcomas; including
high-risk such as
carcinosarcoma
PeerView.com/XJE827
Key Eligibility Criteria
Stratification
MMR status
Recurrent
disease
Geographic
region
Maintenance Phase
(Cycles 7 and on)
Olaparib
mg tablets
Primary endpoints: PFS for Arm B vs Arm A and Arm C vs Arm A
Secondary endpoints: OS, PFS2, ORR, DOR
1. hts fenicalrials govistudyINCTO4268200, 2 Westin SN et al ESMO 2023. Abstract LEAST. 3, Westin SN et al J Cin Oncol 2024:42:283289,
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Inclusion of a PARP Inhibitor in the Maintenance Phase!
Phase 3 DUO-E: Durvalumab + Chemotherapy + Olaparib1-
+ Newly diagnosed
stage III/IV or
recurrent EC
+ Naive to 1L systemic
anticancer treatment
+ Prior adjuvant
chemotherapy
allowed if 212 mo
from last treatment
torelapse
+ Known MMR status
+ Prior radiotherapy
allowed
+ Allhistologies except
sarcomas; including
high-risk such as
carcinosarcoma
PeerView.com/XJE827
Key Eligibility Criteria
Stratification
MMR status
Recurrent
disease
Geographic
region
Maintenance Phase
(Cycles 7 and on)
Olaparib
mg tablets
Primary endpoints: PFS for Arm B vs Arm A and Arm C vs Arm A
Secondary endpoints: OS, PFS2, ORR, DOR
1. hts fenicalrials govistudyINCTO4268200, 2 Westin SN et al ESMO 2023. Abstract LEAST. 3, Westin SN et al J Cin Oncol 2024:42:283289,
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Phase 3 DUO-E: PFS Benefit in the ITT Population’
Durvalumab + Olapari Bunalumab Arm Control
(n=239) (12209) (n=241)
Events, n (%) 126 (52.7) 139 (58.4) 173 (71.8)
100 Median PFS (95% Cl), mo 15.1(126-20.7) 102(97-147) 969.099)
HR (95% Cl) vs control 0.55(0.43-0. 03 -
; P<.0001 0.74 (0.57-0.89); P=
Durvalumab + olaparib
we
Proportion of Patients Alive
and Progression-Free, %
Time From Randomization, mo
1. Westin SN et al ESMO 2023, AbstactLBA41.2. Westin SN et al. J in Oncol. 2024:42:283-298. PeerView.com
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Durvalumab + Olapari Bunalumab Arm Control
(n=239) (12209) (n=241)
Events, n (%) 126 (52.7) 139 (58.4) 173 (71.8)
100 Median PFS (95% Cl), mo 15.1(126-20.7) 102(97-147) 969.099)
HR (95% Cl) vs control 0.55(0.43-0. 03 -
; P<.0001 0.74 (0.57-0.89); P=
Durvalumab + olaparib
we
Proportion of Patients Alive
and Progression-Free, %
Time From Randomization, mo
1. Westin SN et al ESMO 2023, AbstactLBA41.2. Westin SN et al. J in Oncol. 2024:42:283-298. PeerView.com
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Phase 3 DUO-E: PFS Benefit in MMR Subgroups‘?
Durvalumab + Durvalumab
Olaparib Arm Arm
(n= 48) (1248) (n
18675) 15(326)
31.8 NR
(124-NR) — (NRNR)
0.41 0.42
0.21-0.7! (0.22-0.81
Control
Arm
9)
25 (51.0)
70
(67-148)
Events, n (%)
Median PFS (95% Cl), mo
Dorvalamab + olapario
HR (95% Cl) vs control
4. Westin SN et al ESMO 2023. AbstactLBA41. 2. Westin SN etal J Cin Oncol 2024:42-283 286.
PeerView.com/XJE827
Time From Randomization, mo.
Durvalumab + Durvalumab Control
Olaparib Arm Arm Arm
| (n=191) (n=192) _(n= 192)
i Events, n(%) 108 (56.5) 1241646) 148(77-1)
i Medan PFS (95% Cl), mo 49 0 ae yi
i van spe MO (124180 (94-125) (92-101)
| + 0.57 o77
si | HR (95% Cvs control (0407 (080.097) =
Time From Randomization, mo
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Durvalumab + Durvalumab
Olaparib Arm Arm
(n= 48) (1248) (n
18675) 15(326)
31.8 NR
(124-NR) — (NRNR)
0.41 0.42
0.21-0.7! (0.22-0.81
Control
Arm
9)
25 (51.0)
70
(67-148)
Events, n (%)
Median PFS (95% Cl), mo
Dorvalamab + olapario
HR (95% Cl) vs control
4. Westin SN et al ESMO 2023. AbstactLBA41. 2. Westin SN etal J Cin Oncol 2024:42-283 286.
PeerView.com/XJE827
Time From Randomization, mo.
Durvalumab + Durvalumab Control
Olaparib Arm Arm Arm
| (n=191) (n=192) _(n= 192)
i Events, n(%) 108 (56.5) 1241646) 148(77-1)
i Medan PFS (95% Cl), mo 49 0 ae yi
i van spe MO (124180 (94-125) (92-101)
| + 0.57 o77
si | HR (95% Cvs control (0407 (080.097) =
Time From Randomization, mo
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Phase 3 DUO-E: OS‘
To 10
90 Durva + ola ES
so E
fa Duna o Durva + ola
æ 60 = 0 Dura
g © Control | g 5
8 « 8 +
30 20
2 2
10 dMMR 10
o o
0245810 12 da 16 18 20 22 24 26 28 30 32% 0 2 4 6 8 10 12 16 16 18 20 22 À 26 28 0 323%
Time Since Randomization, mo Time Since Randomization, mo
CITY 152 NETA Banalumab sep 302 | HAGEN
Placebo + cp 367 [3371163 Placebo + CP 33 | 259 05.1-NA)
[OS data maturity 217% [os data maturity 20.2%
ET PHMR
HR = 0.28 (95% Cl, 0.10-0.68); Durva + Ola + C/P arm HR = 0.69 (95% Cl, 0.47-1.00); Durva + Ola + C/P arm
HR = 0.34 (95% Cl, 0.13-0.79), Durva + C/P arm HR = 0.91 (95% Cl, 0.64-1.30); Durva + OP am
June 14, 2024: Durvalumab + chemotherapy followed by single-agent durvalumab
approved by the FDA for patients with dMMR endometrial carcinoma?*
(EMA approval of all-comer population)!
August 1,203 EMA approval Ounalumab + ele flowed by nge-agentdrvaımab lr patents wi HR endomeacreinom; uretra +
‘heater foloned D curvaherab par or patents wh PUR erdomalalcaranoma
{Westin SN cal J ln Oncol 203442282 200 2. ps hu a govdugerescurces mato approed-rugsde approves durveumab chemotherapy
mismatestepa-deietprmay-acionced-oc recone 3. ipswu acces la gouge. Socsabel 2024 76105930470 PA A
4. ps nmema.europa eulenimedeinestumanEPAR mina. PeerView.com
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To 10
90 Durva + ola ES
so E
fa Duna o Durva + ola
æ 60 = 0 Dura
g © Control | g 5
8 « 8 +
30 20
2 2
10 dMMR 10
o o
0245810 12 da 16 18 20 22 24 26 28 30 32% 0 2 4 6 8 10 12 16 16 18 20 22 À 26 28 0 323%
Time Since Randomization, mo Time Since Randomization, mo
CITY 152 NETA Banalumab sep 302 | HAGEN
Placebo + cp 367 [3371163 Placebo + CP 33 | 259 05.1-NA)
[OS data maturity 217% [os data maturity 20.2%
ET PHMR
HR = 0.28 (95% Cl, 0.10-0.68); Durva + Ola + C/P arm HR = 0.69 (95% Cl, 0.47-1.00); Durva + Ola + C/P arm
HR = 0.34 (95% Cl, 0.13-0.79), Durva + C/P arm HR = 0.91 (95% Cl, 0.64-1.30); Durva + OP am
June 14, 2024: Durvalumab + chemotherapy followed by single-agent durvalumab
approved by the FDA for patients with dMMR endometrial carcinoma?*
(EMA approval of all-comer population)!
August 1,203 EMA approval Ounalumab + ele flowed by nge-agentdrvaımab lr patents wi HR endomeacreinom; uretra +
‘heater foloned D curvaherab par or patents wh PUR erdomalalcaranoma
{Westin SN cal J ln Oncol 203442282 200 2. ps hu a govdugerescurces mato approed-rugsde approves durveumab chemotherapy
mismatestepa-deietprmay-acionced-oc recone 3. ipswu acces la gouge. Socsabel 2024 76105930470 PA A
4. ps nmema.europa eulenimedeinestumanEPAR mina. PeerView.com
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DUO-E Responses‘
Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
uxt (n= 184) (n =202) (n = 188)
‘ORR, (4) 117 (638) 125 (619) 108 (55.1)
CR, %:PR, % 163,473 129,49 96,455
am (n=125) (n=10)
DOR Rate, % (18-mo; 24.mo) 557,474 466,380 148,148
Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
MR (n=37) (n=30) (n=42)
ORR.n.) 27 10) EIGEN 1705)
CR, %: PR, % 189,541 286,429 95;310
(n=27) (n=30) (n=17)
Compor.mo 239 NR. 10% )
DOR Rate, % (18:M0;24.m0) 726,736 752,602 482.482
Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
Css (n = 147) (n= 160) (n = 156)
‘ORR, n(%) 80 (61.2) 95 (604) 92 (68)
CR, %:PR,% 156,456 88,506 95,494
(n=90) (n=95) (0
aa A 7
DOR Rate, % (18:mo; 24-mo) 50.0, 37.8 374,324 121,124
* Median Um lo onset of response: 2.1 months fr al arms. ESA
1. Van Niewwenhuysen E et al, ESMO-GYN 2024 Abstract: 4OMO, PeerView.com
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Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
uxt (n= 184) (n =202) (n = 188)
‘ORR, (4) 117 (638) 125 (619) 108 (55.1)
CR, %:PR, % 163,473 129,49 96,455
am (n=125) (n=10)
DOR Rate, % (18-mo; 24.mo) 557,474 466,380 148,148
Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
MR (n=37) (n=30) (n=42)
ORR.n.) 27 10) EIGEN 1705)
CR, %: PR, % 189,541 286,429 95;310
(n=27) (n=30) (n=17)
Compor.mo 239 NR. 10% )
DOR Rate, % (18:M0;24.m0) 726,736 752,602 482.482
Durvalumab + Olaparib Arm Durvalumab Arm Control Arm
Css (n = 147) (n= 160) (n = 156)
‘ORR, n(%) 80 (61.2) 95 (604) 92 (68)
CR, %:PR,% 156,456 88,506 95,494
(n=90) (n=95) (0
aa A 7
DOR Rate, % (18:mo; 24-mo) 50.0, 37.8 374,324 121,124
* Median Um lo onset of response: 2.1 months fr al arms. ESA
1. Van Niewwenhuysen E et al, ESMO-GYN 2024 Abstract: 4OMO, PeerView.com
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Exploratory Analyses by Mutation Status
DUO-E exploratory PFS subgroup analysis12 RUBY part 2 exploratory PFS analysis by mutation status?
Overall Population
Overall Population
een
an man,
pomo mown cero»
A Homes man amener
en He emocion mme mon
een
Mapa ms on e ceros
se 1008 me —e bo nens
De ras om aeo@ars01)
ne 1900 7197439
ne al
ont» Pete Pisa CP Bate
+ Enhanced beneft in the pMMR population with Durya + Ola + CP was
observed irespective of BRCAm status“
+ PFS oulcomes wäh Duva + Ola + CP in non-BRCAm patients were
‘consistent withthe ITT population and pMMR subpopulation!
1. Westin SN et al ESMO 2023 Abstract LBAAT. 2. Westin SN el al. / Gin Once. 2024,42:283-200. 3. Mirza MR eta. SGO 2024. Abstract LEA,
4. Van Nieuwenhuysen E etal, ASCO 2024 Abstract 5595,
PeerView.com/XJE827
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Copyright © 2000-2024, PeerView
DUO-E exploratory PFS subgroup analysis12 RUBY part 2 exploratory PFS analysis by mutation status?
Overall Population
Overall Population
een
an man,
pomo mown cero»
A Homes man amener
en He emocion mme mon
een
Mapa ms on e ceros
se 1008 me —e bo nens
De ras om aeo@ars01)
ne 1900 7197439
ne al
ont» Pete Pisa CP Bate
+ Enhanced beneft in the pMMR population with Durya + Ola + CP was
observed irespective of BRCAm status“
+ PFS oulcomes wäh Duva + Ola + CP in non-BRCAm patients were
‘consistent withthe ITT population and pMMR subpopulation!
1. Westin SN et al ESMO 2023 Abstract LBAAT. 2. Westin SN el al. / Gin Once. 2024,42:283-200. 3. Mirza MR eta. SGO 2024. Abstract LEA,
4. Van Nieuwenhuysen E etal, ASCO 2024 Abstract 5595,
PeerView.com/XJE827
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Copyright © 2000-2024, PeerView
What About Replacing Chemo?
Frontline Immunotherapy Versus Chemotherapy
KEYNOTE-C93* DOMENICA?*
LEAP-00115
Lenvatinib +
pembrolizumab
Pembrolizumab Dostarlimab
Chemo Chemo
Primary endpoints:
PFS, OS
Key secondary endpoints:
ORR, HRQOL, safety
dMMR and pMMR
patient populations
Primary endpoints: Primary endpoint:
PFS, OS PFS
Key secondary endpoints: Key secondary endpoints:
ORR, DCR, DOR OS, PROs, ORR, DOR
dMMR patient population dMMR patient population
Awaiting Results Dual primary endpoints not met
1. tps lances gowstudy/NCTOS173667. 2. htps:/cnicarias govstdy/NCTOS201547. 3. Joy Fetal. ASCO 2023. Abstract TPSSE3. AA
4. hups:fcinicalias govÍstudy/NCTOSE84101. 5. Pignata Set al. ESMO Open 2024: Abstract 390. PeerView.com
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Frontline Immunotherapy Versus Chemotherapy
KEYNOTE-C93* DOMENICA?*
LEAP-00115
Lenvatinib +
pembrolizumab
Pembrolizumab Dostarlimab
Chemo Chemo
Primary endpoints:
PFS, OS
Key secondary endpoints:
ORR, HRQOL, safety
dMMR and pMMR
patient populations
Primary endpoints: Primary endpoint:
PFS, OS PFS
Key secondary endpoints: Key secondary endpoints:
ORR, DCR, DOR OS, PROs, ORR, DOR
dMMR patient population dMMR patient population
Awaiting Results Dual primary endpoints not met
1. tps lances gowstudy/NCTOS173667. 2. htps:/cnicarias govstdy/NCTOS201547. 3. Joy Fetal. ASCO 2023. Abstract TPSSE3. AA
4. hups:fcinicalias govÍstudy/NCTOSE84101. 5. Pignata Set al. ESMO Open 2024: Abstract 390. PeerView.com
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LEAP-001:
Lenvatinib Plus Pembrolizumab vs Chemotherapy" *?
OS: pMMR Population OS: All-comers
ral 3660682 1.02 (083126) Overall 442842 083 (077-112)
Prior nootagjurant chemo Prior nesadhuvant chemo
Yes EU et CEA Yes map ETT)
No je 111008619) No sam | + 08 0791.10)
0 a ”
—— — ——
Tebetter LENPEMERO boter TC honor
PFS: pMMR Population PFS: All-comers
al 11682 089 0821.20) [overall ET 091076109)
Prior nestadjuvant cheno Prior necadjuvant chemo
Yer me e 0601037057) Yes Sn | 052 (039080)
No 339538 Je 109 (086-135) No 29721 094 (078-418)
0
0 1 o 01 1
——
LENPEMERO betor _ TC bet LENPEMERO better TC beior
OS and PFS were similar between arms for the pMMR and all-comer populations
+ Numerical increases in OS and PFS were observed with len/pembro
among patients with prior neoadjuvant/adjuvant chemotherapy
Data ett eae: October 2 2023. View.
1. mps [nietas gowstudy/NCTO38E4101. 2NorthC et al ESGO 2024. 3 Marth C etal. SG 2024. 4. Pignata Set al ESMO-GYN 2024 Abstract 390. PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
Lenvatinib Plus Pembrolizumab vs Chemotherapy" *?
OS: pMMR Population OS: All-comers
ral 3660682 1.02 (083126) Overall 442842 083 (077-112)
Prior nootagjurant chemo Prior nesadhuvant chemo
Yes EU et CEA Yes map ETT)
No je 111008619) No sam | + 08 0791.10)
0 a ”
—— — ——
Tebetter LENPEMERO boter TC honor
PFS: pMMR Population PFS: All-comers
al 11682 089 0821.20) [overall ET 091076109)
Prior nestadjuvant cheno Prior necadjuvant chemo
Yer me e 0601037057) Yes Sn | 052 (039080)
No 339538 Je 109 (086-135) No 29721 094 (078-418)
0
0 1 o 01 1
——
LENPEMERO betor _ TC bet LENPEMERO better TC beior
OS and PFS were similar between arms for the pMMR and all-comer populations
+ Numerical increases in OS and PFS were observed with len/pembro
among patients with prior neoadjuvant/adjuvant chemotherapy
Data ett eae: October 2 2023. View.
1. mps [nietas gowstudy/NCTO38E4101. 2NorthC et al ESGO 2024. 3 Marth C etal. SG 2024. 4. Pignata Set al ESMO-GYN 2024 Abstract 390. PeerView.com
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Endometrial Cancer
Case Discussion
Patient
A 61-year-old woman presented with stage IIIC2 clear cell
carcinoma with a large uterine mass and positive pelvic and
para-aortic lymph nodes
Molecular profiling
- dMMR (Loss of MLH1, MSH6)
- p53 WT
— ER 0+/HER2 IHC 0+
What if her tumor was puMR?
PeerView.com
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Case Discussion
Patient
A 61-year-old woman presented with stage IIIC2 clear cell
carcinoma with a large uterine mass and positive pelvic and
para-aortic lymph nodes
Molecular profiling
- dMMR (Loss of MLH1, MSH6)
- p53 WT
— ER 0+/HER2 IHC 0+
What if her tumor was puMR?
PeerView.com
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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
However, up to 50% of patients may experience disease progression on
immunotherapy, so further therapeutic options are needed
PeerView.com
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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
However, up to 50% of patients may experience disease progression on
immunotherapy, so further therapeutic options are needed
PeerView.com
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Single-Agent Immunotherapy Approaches
Monotherapy immune checkpoint inhibition is an effective strategy for
biomarker-selected patients with advanced or recurrent endometrial cancer
Phase 2 KEYNOTE-158 Phase 1 GARNET
Pembrolizumab1 Dostarlimab?
FDA Approval Pembrolizumab Single-Agent Indication
2017: 20232 — "ISSue-agnostic approval for the treatment of unresectable or metastatic MSI-H or MMR
ö solid tumors that have progressed following prior treatment
2020* 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 progression
” or prior treatment
2021? Tissue-agnostic approval for dMMR recurrent or advanced solid tumors that have
progressed on or following prior treatment
* Acoserated FDA approval. Fu FOA approval
1 Kaya pertrottmas) rec ing bfemnston, ms vu accessdata fd gourugsatés_doestabel 202312251451 Sebi be
2. Jempert(dostarimab) Prescribing Information. ps Mn Bccessdata fda. govidrugsatide_ docs labe¥2020761 1745003500488 pd PeerView.com
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Monotherapy immune checkpoint inhibition is an effective strategy for
biomarker-selected patients with advanced or recurrent endometrial cancer
Phase 2 KEYNOTE-158 Phase 1 GARNET
Pembrolizumab1 Dostarlimab?
FDA Approval Pembrolizumab Single-Agent Indication
2017: 20232 — "ISSue-agnostic approval for the treatment of unresectable or metastatic MSI-H or MMR
ö solid tumors that have progressed following prior treatment
2020* 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 progression
” or prior treatment
2021? Tissue-agnostic approval for dMMR recurrent or advanced solid tumors that have
progressed on or following prior treatment
* Acoserated FDA approval. Fu FOA approval
1 Kaya pertrottmas) rec ing bfemnston, ms vu accessdata fd gourugsatés_doestabel 202312251451 Sebi be
2. Jempert(dostarimab) Prescribing Information. ps Mn Bccessdata fda. govidrugsatide_ docs labe¥2020761 1745003500488 pd PeerView.com
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KEYNOTE-158: Improved Responses With Pembrolizumab
in dMMR Endometrial Cancer‘?
dMMR EC
Variable Best Percentage Change From Baseline
Median follow-up, mo 100 in Target Lesion Size*
ORR, % so
CR, % & 60
PR, % io
SD, % 8 20 >.
PD, % 28 a fl
mDOR, mo 63.2 Pi
Estimated DOR at 4 y, % 66 Sao p> -30%
mPFS, mo 13.1 Es
Estimated PFS at 4 y, % 37 © =
mOS, mo 65.4
Estimated OS at 4 y, % 59 19
* As assessed per RECIST vi. by Independent central radiologic ic
1/0 Mokey Det al Cho Oo 202240752782 2 OMatey OM e al, ESMO 202, Abstract AEP. PeerView.com
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in dMMR Endometrial Cancer‘?
dMMR EC
Variable Best Percentage Change From Baseline
Median follow-up, mo 100 in Target Lesion Size*
ORR, % so
CR, % & 60
PR, % io
SD, % 8 20 >.
PD, % 28 a fl
mDOR, mo 63.2 Pi
Estimated DOR at 4 y, % 66 Sao p> -30%
mPFS, mo 13.1 Es
Estimated PFS at 4 y, % 37 © =
mOS, mo 65.4
Estimated OS at 4 y, % 59 19
* As assessed per RECIST vi. by Independent central radiologic ic
1/0 Mokey Det al Cho Oo 202240752782 2 OMatey OM e al, ESMO 202, Abstract AEP. PeerView.com
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GARNET: Dostarlimab Showed Durable Antitumor Activity
in dMMR Endometrial Cancer!
dMMR
Medan town. mo En En E
ORR nw EX EX
x ch eros | arıso
Best confined response, 8)
cr 22088) 2000 ===>
PR 28) na
5 21049) zu SS
PO 51 (36.2) 51 (35.7) E
NE 565) 6(42) E
DCR, n (%) 85 (60.3) 86 (60.1) ===
‘mDOR (95% CI), mo NR (38.9-NR) NR (38.9-NR) == dure
Draion 12 mon D soon 52000) =. re
Draion 240.109 20108) ET) : Ba
Probably mala response (8% Ch = r tS
At 12 mo 93127979) | 93.3 (83.0-97.4) oa Wm Ow Rw wm Wo WO TD We KO we EE
At 24 mo 834003910) | 837 (70.8-91.2) ltd
1. aknin A et al. Gin Cancer Res 2025 294564 4574 PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
in dMMR Endometrial Cancer!
dMMR
Medan town. mo En En E
ORR nw EX EX
x ch eros | arıso
Best confined response, 8)
cr 22088) 2000 ===>
PR 28) na
5 21049) zu SS
PO 51 (36.2) 51 (35.7) E
NE 565) 6(42) E
DCR, n (%) 85 (60.3) 86 (60.1) ===
‘mDOR (95% CI), mo NR (38.9-NR) NR (38.9-NR) == dure
Draion 12 mon D soon 52000) =. re
Draion 240.109 20108) ET) : Ba
Probably mala response (8% Ch = r tS
At 12 mo 93127979) | 93.3 (83.0-97.4) oa Wm Ow Rw wm Wo WO TD We KO we EE
At 24 mo 834003910) | 837 (70.8-91.2) ltd
1. aknin A et al. Gin Cancer Res 2025 294564 4574 PeerView.com
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Checkpoint Inhibitor Monotherapy Resulted in
Low Response Rates in pMMR Recurrent EC
KEYNOTE-028* NCTO13758422 GARNETS NcT02912572¢ PHAEDRAS
Pembrolizumab Atezolizumab Dostarlimab Avelumab Durvalumab
4b 112 2 2
Previously treated locally Incurableor Previously treated pMMRrecurrentEC Recurrent pMMR EC
advanced or metastatic metastaticEC recurrent/advanced
PD-L1+ EC PMMR EC
Patients,n 23 in efficacy analysis te 156 16 35
mPFS 1.8mo 1.4 mo 2.7 mo 1.9 mo =
mos NR 9.6 mo 16.9 mo 6.6 mo _
(o) What about a combination approach?
Of the 3 responder, 1 had POLE disease; the 1 MSI-H patient had progressive disease as best response.
© Of te 2 responders, had MSI-H disease.
1 QUPA etal J Cin nel. 2017:35(2)2595.2341.2. Fleming GF «tl ASCO 2017. Anar SEES 3. Ooknin Atl. Inmunalner Cancer 2022 101: 6009777. Deer View,
4. Konstantnopoulos et al. J Clin Oncol. 2019:37-2786-2794. 5. Anti et al, ASCO 2019 LBA12. eerview.com
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Low Response Rates in pMMR Recurrent EC
KEYNOTE-028* NCTO13758422 GARNETS NcT02912572¢ PHAEDRAS
Pembrolizumab Atezolizumab Dostarlimab Avelumab Durvalumab
4b 112 2 2
Previously treated locally Incurableor Previously treated pMMRrecurrentEC Recurrent pMMR EC
advanced or metastatic metastaticEC recurrent/advanced
PD-L1+ EC PMMR EC
Patients,n 23 in efficacy analysis te 156 16 35
mPFS 1.8mo 1.4 mo 2.7 mo 1.9 mo =
mos NR 9.6 mo 16.9 mo 6.6 mo _
(o) What about a combination approach?
Of the 3 responder, 1 had POLE disease; the 1 MSI-H patient had progressive disease as best response.
© Of te 2 responders, had MSI-H disease.
1 QUPA etal J Cin nel. 2017:35(2)2595.2341.2. Fleming GF «tl ASCO 2017. Anar SEES 3. Ooknin Atl. Inmunalner Cancer 2022 101: 6009777. Deer View,
4. Konstantnopoulos et al. J Clin Oncol. 2019:37-2786-2794. 5. Anti et al, ASCO 2019 LBA12. eerview.com
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KEYNOTE-775: Continued Benefit
With Additional Follow-Up in the pMMR Population’
Median PFS (95% Cl) Median OS (95% Cl)
w Lenvatinib + pembrolizumab: 6.7 mo (6.6-7.4) we Lenvatnib + pembrolizumab: 18.0 mo (14.9-20.5)
so Chemotherapy: 3.8 mo (3.6-5.0) yo ‘Chemotherapy: 12.2 mo (11.0-14.1)
#0 HR for progression or death = 0.60 (95% Cl, 0.50-0.72) Zo HR for death = 0.70 (95% Cl, 0.58-0.83)
3% <7
£ g
2s ¿o
3 so Ex Lenvatinib +
28 25 penbreizumab
se =
ga» Lenvatinib + 2»
En pembrolizumab 5»
0 Foo
Chemotherapy = o Chemotherapy
LEAR EA 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time, mo.
Time, mo
ORR: 32.4%
CR: 5.8% vs
PR: 26.6% vs 12.5%
2021: Full FDA-approved for patients with advanced
endometrial carcinoma that is not MSI-H or dMMR, who
OR DS mo ve 5 7 MO have disease progression following prior systemic therapy
‘Median follow-up Ime: 14.7 months; data cut date: March 1, 2022; >16 months of aciicnal fol up from intl pubscaion PFS by BICR per RECIST v1.1.
1 Maier Vet al N Eng Med. 2022:386 437-448. 2. Maker Vet al. Cán Oncol 2023:412904-2910, 3. hips rw da govidrugeresourcee-nformaton-approved-
rugs grants regular approva-perbrolaumab and lenvatnb-advanced-endometnal-carcinora PeerView.
4 Ms fon accessdata da gov[erupsatida, docs/abel/2024/125514s157EA pdf iew.com
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With Additional Follow-Up in the pMMR Population’
Median PFS (95% Cl) Median OS (95% Cl)
w Lenvatinib + pembrolizumab: 6.7 mo (6.6-7.4) we Lenvatnib + pembrolizumab: 18.0 mo (14.9-20.5)
so Chemotherapy: 3.8 mo (3.6-5.0) yo ‘Chemotherapy: 12.2 mo (11.0-14.1)
#0 HR for progression or death = 0.60 (95% Cl, 0.50-0.72) Zo HR for death = 0.70 (95% Cl, 0.58-0.83)
3% <7
£ g
2s ¿o
3 so Ex Lenvatinib +
28 25 penbreizumab
se =
ga» Lenvatinib + 2»
En pembrolizumab 5»
0 Foo
Chemotherapy = o Chemotherapy
LEAR EA 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time, mo.
Time, mo
ORR: 32.4%
CR: 5.8% vs
PR: 26.6% vs 12.5%
2021: Full FDA-approved for patients with advanced
endometrial carcinoma that is not MSI-H or dMMR, who
OR DS mo ve 5 7 MO have disease progression following prior systemic therapy
‘Median follow-up Ime: 14.7 months; data cut date: March 1, 2022; >16 months of aciicnal fol up from intl pubscaion PFS by BICR per RECIST v1.1.
1 Maier Vet al N Eng Med. 2022:386 437-448. 2. Maker Vet al. Cán Oncol 2023:412904-2910, 3. hips rw da govidrugeresourcee-nformaton-approved-
rugs grants regular approva-perbrolaumab and lenvatnb-advanced-endometnal-carcinora PeerView.
4 Ms fon accessdata da gov[erupsatida, docs/abel/2024/125514s157EA pdf iew.com
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Trastuzumab Deruxtecan (T-DXd): An Anti-HER2 ADC
IgG1 mAb Seven Key Attributes1-5
+ Payload MOA: topoisomerase |
inhibitor
+ High potency of payload
» High DAR: ~8
+ Payload with short systemic
half-life
Stable linker payload
¿e
da EN * Tumor-selective cleavable linker
Topoisomerase | inhibitor payload + Bystander antitumor effect
(DXd = DX-8951f derivative
1. Nakada T etal. Chem Pharm Bul (Tokyo). 2019:67:173-185, 2. Ola Y et a. Cin Cancer Res. 2016:22:5097-5108. Peerview,
3. Tral PA et al Pharmacol Ther. 2018:181:126-142. 4. Okamoto H etal. Xenabiotica, 2020:50-1242-1250. 5, Nagi et al. Xenobiotica, 2019:49:1086-1096, eerview.com
tetrapeptide-based linker
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
IgG1 mAb Seven Key Attributes1-5
+ Payload MOA: topoisomerase |
inhibitor
+ High potency of payload
» High DAR: ~8
+ Payload with short systemic
half-life
Stable linker payload
¿e
da EN * Tumor-selective cleavable linker
Topoisomerase | inhibitor payload + Bystander antitumor effect
(DXd = DX-8951f derivative
1. Nakada T etal. Chem Pharm Bul (Tokyo). 2019:67:173-185, 2. Ola Y et a. Cin Cancer Res. 2016:22:5097-5108. Peerview,
3. Tral PA et al Pharmacol Ther. 2018:181:126-142. 4. Okamoto H etal. Xenabiotica, 2020:50-1242-1250. 5, Nagi et al. Xenobiotica, 2019:49:1086-1096, eerview.com
tetrapeptide-based linker
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DESTINY-PanTumor02:
T-DXd in HER2-Expressing Solid Tumors’?
An open-label, multicenter study (NCT04482309)
Y? Endometrial cancer
Key Eligibility Criteria 7 + Primary endpoint:
+ Advanced solid tumors not eligible for curative therapy ble confirmed ORR
+ 2L+ patient population Sy? Ovarian cancer (investigator)
+ HER2 expression (IHC 3+ or 2+) + Secondary endpoints:
— Local test or central test by HercepTest if local test DOR, DCR, PFS, OS,
not feasible (ASCO/CAP gastric cancer scoring)® aa safety
+ Prior HER2-targeting therapy allowed > + Exploratory analysis:
+ ECOGMHO PS 0-1 Biliary tract cancer ‘subgroup analysis by
Pancreatic cancer HER? statue
Baseline Characteristics
+ 267 patients received treatment; 202 (75.7%) based on local HER2 testing
= 111 (41.6%) patients were IHC 3+ based on HER2 test (local or central) at enrollment; primary efficacy analysis (all patients)
ES Bladder cancer
— 75 (28.1%) patients were IHC 3+ on central testing; sensitivity analysis on efficacy endpoints (subgroup analyses)
+ Median age was 62 years (23-85), and 109 (40.8%) patients had received 23 lines of therapy
> Primary ana dal elo Dune E, 2023, median lwp. 12.75 ma * Patients were ig for ether ton All patent were canraly confemod
‘Planned recrutment cohorts wih no objective responses n the fst 15 patients were o be closed. * Patents wth tumors thal express HERZ. excluding tumors in the
tumor spectic cohorts, and breast cancer, NSCLC, st cancer, and CRC.
1 ps esictra's govstudyINCTO4482309.2 Homann Met l Hixopatology 2008:52797-305, 3. Neto Bernstam F et al. ESMO 2023. Abstract LBASS eo
4. MenoBernstam F etl. J Cin Oncol, 2024 4247-58, PeerView.com
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T-DXd in HER2-Expressing Solid Tumors’?
An open-label, multicenter study (NCT04482309)
Y? Endometrial cancer
Key Eligibility Criteria 7 + Primary endpoint:
+ Advanced solid tumors not eligible for curative therapy ble confirmed ORR
+ 2L+ patient population Sy? Ovarian cancer (investigator)
+ HER2 expression (IHC 3+ or 2+) + Secondary endpoints:
— Local test or central test by HercepTest if local test DOR, DCR, PFS, OS,
not feasible (ASCO/CAP gastric cancer scoring)® aa safety
+ Prior HER2-targeting therapy allowed > + Exploratory analysis:
+ ECOGMHO PS 0-1 Biliary tract cancer ‘subgroup analysis by
Pancreatic cancer HER? statue
Baseline Characteristics
+ 267 patients received treatment; 202 (75.7%) based on local HER2 testing
= 111 (41.6%) patients were IHC 3+ based on HER2 test (local or central) at enrollment; primary efficacy analysis (all patients)
ES Bladder cancer
— 75 (28.1%) patients were IHC 3+ on central testing; sensitivity analysis on efficacy endpoints (subgroup analyses)
+ Median age was 62 years (23-85), and 109 (40.8%) patients had received 23 lines of therapy
> Primary ana dal elo Dune E, 2023, median lwp. 12.75 ma * Patients were ig for ether ton All patent were canraly confemod
‘Planned recrutment cohorts wih no objective responses n the fst 15 patients were o be closed. * Patents wth tumors thal express HERZ. excluding tumors in the
tumor spectic cohorts, and breast cancer, NSCLC, st cancer, and CRC.
1 ps esictra's govstudyINCTO4482309.2 Homann Met l Hixopatology 2008:52797-305, 3. Neto Bernstam F et al. ESMO 2023. Abstract LBASS eo
4. MenoBernstam F etl. J Cin Oncol, 2024 4247-58, PeerView.com
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Responses With T-DXd Observed
In Endometrial Cancer‘22?
3 100
>
Z e
x 60
5
go
= 20
=
6
oo
Total nin subgroup o 9 7 4 8
1 of responders mou 8 1 3
Median DOR, months" NR NR 182 NR 99
m 99, 98 30, 28,
sence NE NE NE NE
Probability of PFS
Probability of OS
HE 3e NR (95% Cl, 7.3-NR)
Total 11-1 mo (95% CL, 74-NR)
IHC2+ 8.5 mo (95% Cl, 46-151)
Time From First Dose, mo
THC 3+ 26.0 (95% Cl, 189.NR)
Total 260
(95% CI 128.NR)
IHC2+ 164
(5% CI EONR
Time Since First Dose, mo
“HER? status by central testing © Similar ORR and DOR results were reported by retrospective independent central review. € Median DOR reported for patients wth a
‘confirmed an cbjectue response ony °C not shown where a= 1 responder
1. Lee Jet al. nt! Gynecol Concer 2028:33:A8-A7.2. Meno Bernstam Fetal. J Gin Oncol, 2024 42-47-58.
PeerView.com/XJE827
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Copyright © 2000-2024, PeerView
In Endometrial Cancer‘22?
3 100
>
Z e
x 60
5
go
= 20
=
6
oo
Total nin subgroup o 9 7 4 8
1 of responders mou 8 1 3
Median DOR, months" NR NR 182 NR 99
m 99, 98 30, 28,
sence NE NE NE NE
Probability of PFS
Probability of OS
HE 3e NR (95% Cl, 7.3-NR)
Total 11-1 mo (95% CL, 74-NR)
IHC2+ 8.5 mo (95% Cl, 46-151)
Time From First Dose, mo
THC 3+ 26.0 (95% Cl, 189.NR)
Total 260
(95% CI 128.NR)
IHC2+ 164
(5% CI EONR
Time Since First Dose, mo
“HER? status by central testing © Similar ORR and DOR results were reported by retrospective independent central review. € Median DOR reported for patients wth a
‘confirmed an cbjectue response ony °C not shown where a= 1 responder
1. Lee Jet al. nt! Gynecol Concer 2028:33:A8-A7.2. Meno Bernstam Fetal. J Gin Oncol, 2024 42-47-58.
PeerView.com/XJE827
PeerView.com
Copyright © 2000-2024, PeerView
Application of T-DXd Across Gynecologic Tumors
Updated NCCN Guidelines for
Endometrial, Cervical, and Ovarian Cancers‘?
Second- or subsequent-line therapy:
T-DXd added for HER2-positive tumors (IHC 3+ or 2+)
Useful in certain circumstances
pl
satisfactory alternative treatment options
1.NCCN Ginical Pracice Guidelines in Oncology. Uteine Neoplasms. Version 2 2024. ps non orglprofessionals/phystian_gls/pdterne pf.
2. NOCN Cinieal Pracice Gudelines in Oncology. Cervical Cancer. Version 2.2024. ps Tin neon omgiprofesional/physican_gi/palcer eal po.
3. NCCN Cineal Pracice Guidelines in Oncology. Ovarian Cancer. Version 1.2024. hllps:/Mun nee ergiprotessonals/physiam_g/pdovaran pe.
4. hip ih da govldrugsresources information-epproved-drugsitéa-grants-accelerated-approva/-onntrastuzumab-deruecan-fukrunresecableor- a
metasttioner2. View.com
Copyright © 2000-2024, Peerview
Updated NCCN Guidelines for
Endometrial, Cervical, and Ovarian Cancers‘?
Second- or subsequent-line therapy:
T-DXd added for HER2-positive tumors (IHC 3+ or 2+)
Useful in certain circumstances
pl
satisfactory alternative treatment options
1.NCCN Ginical Pracice Guidelines in Oncology. Uteine Neoplasms. Version 2 2024. ps non orglprofessionals/phystian_gls/pdterne pf.
2. NOCN Cinieal Pracice Gudelines in Oncology. Cervical Cancer. Version 2.2024. ps Tin neon omgiprofesional/physican_gi/palcer eal po.
3. NCCN Cineal Pracice Guidelines in Oncology. Ovarian Cancer. Version 1.2024. hllps:/Mun nee ergiprotessonals/physiam_g/pdovaran pe.
4. hip ih da govldrugsresources information-epproved-drugsitéa-grants-accelerated-approva/-onntrastuzumab-deruecan-fukrunresecableor- a
metasttioner2. View.com
Copyright © 2000-2024, Peerview
Phase 3 ENGOT-en23/GOG-3095/MK-2870-005'
TROP2: transmembrane glycoprotein overexpressed by several gynecologic tumor types
TROP2
antibody ——"
High affinity
Linker
+ Relatively stable in
blood circulation
+ Tripeptide linker
+ Non-site specific
+ Cleavable
Payload
+ Novel TOPO!
inhibitor
+ DAR=74
MK-2870
{sacituzumab
tirumotecan)
1. ts flickr gowstudy/NCTO6 132858.
PeerView.com/XJE827
(belotecan derivatve)
Key Eligibility Criteria MK 28708 ma
+ Histologically confirmed endometrial
‘carcinoma or carcinosarcoma
+ Radiographically evaluable disease,
either measurable or nonmeasurable
per RECIST v1.1 (by BICR)
+ Must have received prior platinum-
based chemo and ant-PD-1/ant-PD-
L1 therapy, either separately or in
‘combination
g IV
Doxorubicin €
Paclitaxel 60
n days 1, 8, and 15
+ Primary endpoints: PFS, OS
+ Secondary endpoints: ORR, DOR, safety, HRQOL
PeerView.com
Copyright © 2000-2024, PeerView
TROP2: transmembrane glycoprotein overexpressed by several gynecologic tumor types
TROP2
antibody ——"
High affinity
Linker
+ Relatively stable in
blood circulation
+ Tripeptide linker
+ Non-site specific
+ Cleavable
Payload
+ Novel TOPO!
inhibitor
+ DAR=74
MK-2870
{sacituzumab
tirumotecan)
1. ts flickr gowstudy/NCTO6 132858.
PeerView.com/XJE827
(belotecan derivatve)
Key Eligibility Criteria MK 28708 ma
+ Histologically confirmed endometrial
‘carcinoma or carcinosarcoma
+ Radiographically evaluable disease,
either measurable or nonmeasurable
per RECIST v1.1 (by BICR)
+ Must have received prior platinum-
based chemo and ant-PD-1/ant-PD-
L1 therapy, either separately or in
‘combination
g IV
Doxorubicin €
Paclitaxel 60
n days 1, 8, and 15
+ Primary endpoints: PFS, OS
+ Secondary endpoints: ORR, DOR, safety, HRQOL
PeerView.com
Copyright © 2000-2024, PeerView
irAEs From Immune Checkpoint Inhibitors
Can Affect Any Organ System!
‘à E
Dermatologic | Gastrointestinal | Endocrine Pulmonary
Rash, pruritus | Diarrhea, nausea, Hypothyroidism Pneumonitis
i vomiting I
Consider Treating Wit!
Topical steroids, Steroids, antiemetics,
topical antihistamines | antidiarrheals
Synthroid Steroids
1. Marlin Fetal. Nat Rev Cin Oncol. 2018;16:563-580, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, Peerview
Can Affect Any Organ System!
‘à E
Dermatologic | Gastrointestinal | Endocrine Pulmonary
Rash, pruritus | Diarrhea, nausea, Hypothyroidism Pneumonitis
i vomiting I
Consider Treating Wit!
Topical steroids, Steroids, antiemetics,
topical antihistamines | antidiarrheals
Synthroid Steroids
1. Marlin Fetal. Nat Rev Cin Oncol. 2018;16:563-580, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, Peerview
Immune-Related Adverse Events
Can Occur at Any Time
Variable Timing of irAEs!
Patient Communication
Is Essential
Pneumonitis
+ Discuss potential onset,
duration, and symptoms
of irAEs
Toxicity, grade
+ Patients may be more
likely to adhere to treatment
when they have a full
picture of irAEs
Duration of Treatment, wk
1. Marin Fetal Nat Rev Gi Oncol. 2018;16:563-580, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
Can Occur at Any Time
Variable Timing of irAEs!
Patient Communication
Is Essential
Pneumonitis
+ Discuss potential onset,
duration, and symptoms
of irAEs
Toxicity, grade
+ Patients may be more
likely to adhere to treatment
when they have a full
picture of irAEs
Duration of Treatment, wk
1. Marin Fetal Nat Rev Gi Oncol. 2018;16:563-580, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
Common AEs With PARP Inhibitors’?
Nonhematologic
8 Nausea/Vomiting/
Anemia Diarrhea/Constipation
Thrombocytopenia Asthenia/Fatigue
observed with PARPi + 10 + Chemo combination therapy?
1.Lynparza (olaparb) Prsciin tomaten. ps nm accessla 1d govidugsatió,docslabel/20232085S8s0269 pat 2 Ze (apr) Presa DER,
Information, tos www aocessdat fa. govidugsettda_docsabet2023/214876s0001bLpd. 3, Tomes Pep Jet al. ASCO 2024Abstac 569, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
Nonhematologic
8 Nausea/Vomiting/
Anemia Diarrhea/Constipation
Thrombocytopenia Asthenia/Fatigue
observed with PARPi + 10 + Chemo combination therapy?
1.Lynparza (olaparb) Prsciin tomaten. ps nm accessla 1d govidugsatió,docslabel/20232085S8s0269 pat 2 Ze (apr) Presa DER,
Information, tos www aocessdat fa. govidugsettda_docsabet2023/214876s0001bLpd. 3, Tomes Pep Jet al. ASCO 2024Abstac 569, PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
Management of AEs in IO Plus TKI Therapy‘
+ Itis important to determine which >
+ Two mechanisms of action result
in'Wwo'sets oF AE profiles nat are 10 + TKI Combination Toxicities
not mutually exclusive €.
therapy is causing the AE in order
to plan a management strate: reer TKI
f Hold TKI (shorter half-life than en Hypertension
checkpoint inhibitor) I Dane Taste changes
— In certain cases, use appropriate | Hepatitis Stomatitis
supportive care | & ” Hypothyroid Dyspepsia
— If symptoms resolve in a few \ AMS Cytopenia
days, TKI was likely the cause à HFSR
* Y O PRES
| Postow MA tal N Engl /Me TEST 158168. 2 Sener tal Cam Ont 2021384073 4126 3 NCCN Gina rate Gueines in Oncle
Management o Immunoiherap)-Related Tosces. Version 1.2024. tips w.necn org/professional/physician_gi/patimmunctherapy pat —
coral RE eto Oynnau Oncol 29021662538 8 Gras al Journ! immune ep) of Cancer 21 38 erView.com
Copyright © 2000-2024, PeerView
+ Itis important to determine which >
+ Two mechanisms of action result
in'Wwo'sets oF AE profiles nat are 10 + TKI Combination Toxicities
not mutually exclusive €.
therapy is causing the AE in order
to plan a management strate: reer TKI
f Hold TKI (shorter half-life than en Hypertension
checkpoint inhibitor) I Dane Taste changes
— In certain cases, use appropriate | Hepatitis Stomatitis
supportive care | & ” Hypothyroid Dyspepsia
— If symptoms resolve in a few \ AMS Cytopenia
days, TKI was likely the cause à HFSR
* Y O PRES
| Postow MA tal N Engl /Me TEST 158168. 2 Sener tal Cam Ont 2021384073 4126 3 NCCN Gina rate Gueines in Oncle
Management o Immunoiherap)-Related Tosces. Version 1.2024. tips w.necn org/professional/physician_gi/patimmunctherapy pat —
coral RE eto Oynnau Oncol 29021662538 8 Gras al Journ! immune ep) of Cancer 21 38 erView.com
Copyright © 2000-2024, PeerView
Consistent Safety Findings With the
Established Profile for T-DXd'*
PeerView.com/XJE827
EF ‘Most Common Drug-Related TEAEs (>10%) in Gynecologic Cohorts
x) Aa) Nausea 64.2
Fatigue? 442
Any drug-related TEAES 106 (88.3)
Drug-related TEAEs grade 23 54 (45.0) Diarrhea 32.5
18 (15. Anemia 308
(58) Vomiting 08 275
Drug-related TEAEs associated Decreased appetite 192
with dose interruptions HET) Alopecia. 183 Morae 23
Drug-related TEAEs associated Any grade
with dose reductions 35(29.2) Thrombocytopenia”. 15.0
Drug-related TEAEs associated o 20 40 60 80
with deaths EOS
ILD/Pneumonitis Adjudicated
as T-DXd Related, n (%)
Gynecologic cohorts (N = 120) 4 86. o 0
"ne ere permea ln parts vio ce des TONS (Y= 12) men al atenta 91,60, ad 8 morts in e corea
id sar ns epoch Cop len De pradera ne ee ei “Cepo dese pore re rn
count decreased and neutropenia. * Category includes the preferred terms platelet count decreased and thrombocytopenia. * Induded pneumonia (n = 1), organizing
am PeerView.com
Grade1 Grade2 Grade3 Grade4 Grades Any Grade
1 13 (10.8)
Copyright © 2000-2024, Peerview
Established Profile for T-DXd'*
PeerView.com/XJE827
EF ‘Most Common Drug-Related TEAEs (>10%) in Gynecologic Cohorts
x) Aa) Nausea 64.2
Fatigue? 442
Any drug-related TEAES 106 (88.3)
Drug-related TEAEs grade 23 54 (45.0) Diarrhea 32.5
18 (15. Anemia 308
(58) Vomiting 08 275
Drug-related TEAEs associated Decreased appetite 192
with dose interruptions HET) Alopecia. 183 Morae 23
Drug-related TEAEs associated Any grade
with dose reductions 35(29.2) Thrombocytopenia”. 15.0
Drug-related TEAEs associated o 20 40 60 80
with deaths EOS
ILD/Pneumonitis Adjudicated
as T-DXd Related, n (%)
Gynecologic cohorts (N = 120) 4 86. o 0
"ne ere permea ln parts vio ce des TONS (Y= 12) men al atenta 91,60, ad 8 morts in e corea
id sar ns epoch Cop len De pradera ne ee ei “Cepo dese pore re rn
count decreased and neutropenia. * Category includes the preferred terms platelet count decreased and thrombocytopenia. * Induded pneumonia (n = 1), organizing
am PeerView.com
Grade1 Grade2 Grade3 Grade4 Grades Any Grade
1 13 (10.8)
Copyright © 2000-2024, Peerview
Detecting and Managing T-DXd-Related ILD:
The Five “S” Rules!
2 E "YN
Treatment
6 T-DXd should al
be interrupted ifILD is treating T-DXd-
ed; it can only induced ILD remains
corticosteroids, with
ose adapted to
the toxicity grad
ction is warranted
before initiating T-DXd
to optimize the
in
jogical scans,
with preference
tution CT
x the chest as multi
Abaseline scan is management
ILD is suspected
Screening contin
during treatment,
with regular clinical
‘assessments to
exclude signs!
symptoms of ILD
repeat
med e
2 weeks.
Oncol Pract. 2023:19:526-527. PeerView.com
PeerView.com/XJE827 Copyrigh
The Five “S” Rules!
2 E "YN
Treatment
6 T-DXd should al
be interrupted ifILD is treating T-DXd-
ed; it can only induced ILD remains
corticosteroids, with
ose adapted to
the toxicity grad
ction is warranted
before initiating T-DXd
to optimize the
in
jogical scans,
with preference
tution CT
x the chest as multi
Abaseline scan is management
ILD is suspected
Screening contin
during treatment,
with regular clinical
‘assessments to
exclude signs!
symptoms of ILD
repeat
med e
2 weeks.
Oncol Pract. 2023:19:526-527. PeerView.com
PeerView.com/XJE827 Copyrigh
Case Modification...
+ A61-year-old woman presented with stage IIIC2 clear cell carcinoma with a large
uterine mass and positive pelvic and para-aortic lymph nodes
Prior to coming to your clinic, she was treated with 6 cycles of paclitaxel and
carboplatin with good response of measurable disease but has now recurred
Molecular profiling Would IO + TKI be an option?
= pMMR Would an ADC be an option?
What if her tumor was dMMR?
- HER2 IHC3+
What do you discuss with her?
PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
+ A61-year-old woman presented with stage IIIC2 clear cell carcinoma with a large
uterine mass and positive pelvic and para-aortic lymph nodes
Prior to coming to your clinic, she was treated with 6 cycles of paclitaxel and
carboplatin with good response of measurable disease but has now recurred
Molecular profiling Would IO + TKI be an option?
= pMMR Would an ADC be an option?
What if her tumor was dMMR?
- HER2 IHC3+
What do you discuss with her?
PeerView.com
PeerView.com/XJE827 Copyright © 2000-2024, PeerView
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