Strengthening the Immunotherapy Paradigm in Biliary Tract Cancer: Standardizing Team-Based Strategies With Immune Checkpoint Inhibitors in Advanced Disease
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Oct 07, 2024
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About This Presentation
Chair, Arndt Vogel, MD, PhD, discusses biliary tract cancer in this CME/MOC activity titled “Strengthening the Immunotherapy Paradigm in Biliary Tract Cancer: Standardizing Team-Based Strategies With Immune Checkpoint Inhibitors in Advanced Disease.” For the full presentation, downloadable Pract...
Slide Content
Strengthening the Immunotherapy
Paradigm in Biliary Tract Cancer
Standardizing Team-Based Strategies With
Immune Checkpoint Inhibitors in Advanced Disease
Arndt Vogel, MD, PhD Eli
Professor of Medicine, University of Toronto «
Longo Family Chair in Liver Cancer Research 7
Toronto, Canada
Paradigm in Biliary Tract Cancer
Standardizing Team-Based Strategies With
Immune Checkpoint Inhibitors in Advanced Disease
Arndt Vogel, MD, PhD Eli
Professor of Medicine, University of Toronto «
Longo Family Chair in Liver Cancer Research 7
Toronto, Canada
Our Goals for Today
Improve your understanding of molecular profiling, the latest
safety/efficacy evidence on immunotherapy platforms, and guideline
recommendations in BTC.
Enhance your skills in building personalized treatment plans with
immunotherapies in BTC based on molecular profiling results, the latest
clinical trial evidence, and updated clinical practice guidelines
Provide you with tools to develop team-based strategies to address the
intricacies of care delivery in BTC, including care coordination, patient
engagement, and immune-mediated AE management
Copyright © 2000-:
Improve your understanding of molecular profiling, the latest
safety/efficacy evidence on immunotherapy platforms, and guideline
recommendations in BTC.
Enhance your skills in building personalized treatment plans with
immunotherapies in BTC based on molecular profiling results, the latest
clinical trial evidence, and updated clinical practice guidelines
Provide you with tools to develop team-based strategies to address the
intricacies of care delivery in BTC, including care coordination, patient
engagement, and immune-mediated AE management
Copyright © 2000-:
Taking the First Step
in Personalizing BTC Care
The Essential Role of Molecular Profiling
and Its Impact on Treatment Decisions
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
in Personalizing BTC Care
The Essential Role of Molecular Profiling
and Its Impact on Treatment Decisions
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
Biliary Tract Cancers: Anatomic Heterogeneity
Patient Population Characterized by Primary Tumor Location
Included in Key Studies in BTC
Classification of BTC*
be ES ca In
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1. Vale JW el, Lancet 2021:307:428-44.2, Pose JN a al. Lanct Oncol 2019:20563.679. 2. Eden Jet a. Cin Oncol 2019137958267,
oc M ta. ASCO GI 2022. Abstac 82 5 Vall ta. N Engl Ao. 2010.382.1273.1281.8. Maka Det a. Lance Oncol. 2014.15 619-8267. Vogel À e a
Eur Concer. 201832 1118.8 Val JW etl Lancet Orca 2021 22:1408-1482 9. Oh OY etal, MEUM Evid. 2022.EVIDOR2200015, 10 Keley RK ea Lance
2023401 1059-1065. 11. Lamarca Acta. Lance Oncol 2021:22.6%0701. 12, Yo etal, Lancet Oncol 2024:22 1860-1572. 19 Iequirdo Sanchez Let ñ
Hope. 2022.76:1109-1121. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, Peerview
Patient Population Characterized by Primary Tumor Location
Included in Key Studies in BTC
Classification of BTC*
be ES ca In
SE oa. à
ses D Le eh | a
Ramen 208 2021 56 2 15
HN fi + à æ
NON 0 D D D 0
E a a
2 NIFTY? cy 2021 40 35 25
re 0 wm
1. Vale JW el, Lancet 2021:307:428-44.2, Pose JN a al. Lanct Oncol 2019:20563.679. 2. Eden Jet a. Cin Oncol 2019137958267,
oc M ta. ASCO GI 2022. Abstac 82 5 Vall ta. N Engl Ao. 2010.382.1273.1281.8. Maka Det a. Lance Oncol. 2014.15 619-8267. Vogel À e a
Eur Concer. 201832 1118.8 Val JW etl Lancet Orca 2021 22:1408-1482 9. Oh OY etal, MEUM Evid. 2022.EVIDOR2200015, 10 Keley RK ea Lance
2023401 1059-1065. 11. Lamarca Acta. Lance Oncol 2021:22.6%0701. 12, Yo etal, Lancet Oncol 2024:22 1860-1572. 19 Iequirdo Sanchez Let ñ
Hope. 2022.76:1109-1121. PeerView.com
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Rising Incidence of Cholangiocarcinoma!
so
20
20
100
ese Se Sere
RERRERER
Time, y
1. Jade Metal. Oncologist. 2022:27:874-883,
PeerView.com/HFK827
me
CCA (n= 40030)
ECC (n= 26821)
foc (n= 13,174)
Survival Probability
Age-Adjusted Incidence Rates
(per 100,000 Patient-Years)
0 3 % 75 100 25 190 15 mo 25
Time, mo
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so
20
20
100
ese Se Sere
RERRERER
Time, y
1. Jade Metal. Oncologist. 2022:27:874-883,
PeerView.com/HFK827
me
CCA (n= 40030)
ECC (n= 26821)
foc (n= 13,174)
Survival Probability
Age-Adjusted Incidence Rates
(per 100,000 Patient-Years)
0 3 % 75 100 25 190 15 mo 25
Time, mo
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Current Shortcomings in the Management
of Advanced Biliary Tract Cancers‘?
idvanced CCA found that
Moreover...
First line Second line Third line
|
SFU chomo: 135, »
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a a
ar
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Si oe
—
1. Parikh K otal, ASCO GI 2021. Abstract 347. 2 Valdorrama A et al. ASCO GI 2022. Abstract 398,
PeerView.com/HFK827
advanced CCA
85% of patients initiated gemcitabine-based
chemotherapy as their first-line treatment
About 46% of patients initiated second-line
treatments, which were predominantly
5-FU-based chemotherapies
Few patients (17%) moved to third line
of treatment
Median time on treatment in the first line
was 3.2 months and in both the second
and third lines was 2.7 months
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Copyright © 2000-2024, PeerView
of Advanced Biliary Tract Cancers‘?
idvanced CCA found that
Moreover...
First line Second line Third line
|
SFU chomo: 135, »
meme aoe
een Sa
a a
ar
ma]
Si oe
—
1. Parikh K otal, ASCO GI 2021. Abstract 347. 2 Valdorrama A et al. ASCO GI 2022. Abstract 398,
PeerView.com/HFK827
advanced CCA
85% of patients initiated gemcitabine-based
chemotherapy as their first-line treatment
About 46% of patients initiated second-line
treatments, which were predominantly
5-FU-based chemotherapies
Few patients (17%) moved to third line
of treatment
Median time on treatment in the first line
was 3.2 months and in both the second
and third lines was 2.7 months
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Copyright © 2000-2024, PeerView
BTCs: Important Molecular Markers’
Intrahepatic Cholangiocarcinoma Extrahepatic Cholangiocarcinoma
1. Kentke 6 tal. J Hepatol 2023:78:614 626. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Intrahepatic Cholangiocarcinoma Extrahepatic Cholangiocarcinoma
1. Kentke 6 tal. J Hepatol 2023:78:614 626. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Many Targeted Therapies Are Already Available Today’
Intrahepatic Cholangiocarcinoma AMG193
Pemigatinib, futibatinib, RLY-4008, erdafininib
Trastzumab, pertuzumab, trastuzumab-deruxtecan,
zanidatimab, tucatinib, neratinib
Nivolumab + ipilimumab, pembrolizumab
Dabrafenib/trametinib, vemurafenib/cobimetinib.
Ivosidenib
Brigimadlin
Olaparib, rucaparib, nivofipilimumab
Lunresertib
@ Sotorasib, adagrasib
And more...
NTRK_ Larotecinib, entrectnib RET" Pralsetinib,selpercatinib MRGtm Zenscuhmzumab, ERRFIÍ. Edoïnib, case reports
1. Kentke 6 tal. J Hapotol 2023:78:614 629. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Intrahepatic Cholangiocarcinoma AMG193
Pemigatinib, futibatinib, RLY-4008, erdafininib
Trastzumab, pertuzumab, trastuzumab-deruxtecan,
zanidatimab, tucatinib, neratinib
Nivolumab + ipilimumab, pembrolizumab
Dabrafenib/trametinib, vemurafenib/cobimetinib.
Ivosidenib
Brigimadlin
Olaparib, rucaparib, nivofipilimumab
Lunresertib
@ Sotorasib, adagrasib
And more...
NTRK_ Larotecinib, entrectnib RET" Pralsetinib,selpercatinib MRGtm Zenscuhmzumab, ERRFIÍ. Edoïnib, case reports
1. Kentke 6 tal. J Hapotol 2023:78:614 629. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
: Mutation Load!
Immunotherapy
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4. Alexandrov LB et al. Mature. 2018:500:416-421
Copyright © 2000-2024, PeerView
PeerView.com/HFK827
Immunotherapy
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4. Alexandrov LB et al. Mature. 2018:500:416-421
Copyright © 2000-2024, PeerView
PeerView.com/HFK827
Guideline-Recommended Approaches
for Molecular Profiling!
+ Comprehensive molecular profiling is
recommended for patients with
unresectable or metastatic BTC who
Anatomic Subsite
Gallbladder | Intrahepatic CA Extrahepati
are candidates for systemic therapy NTRK gene fusion x % x
+ If tissue is too scant or not available, MSSM 2 x =
consider repeat biopsy depending on TMB-H x x x
tumor accessibility, safety, and clinical 8Rarv600E mutation x x x
contas FGFR2 fusion or _ sa x
+ NGS or cell-free DNA test may be rarement
considered for identifying gene (0H mutation - x x
mutations HER? (ERBB2)
+ For MSI, there are three possible a as * 5
methods for testing: IHC, NGS, PCR
RET gene fusion x x x
» TMB can be tested with NGS panel but ATA z x x
has inherent platform variation
1. NCON Giinical Practico Guidelines. Bilary Tract Cancers. Version 4.2024. hpsi/wur.nccn.orgprofessionaliphysician_glipafiepd PeerView.com
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for Molecular Profiling!
+ Comprehensive molecular profiling is
recommended for patients with
unresectable or metastatic BTC who
Anatomic Subsite
Gallbladder | Intrahepatic CA Extrahepati
are candidates for systemic therapy NTRK gene fusion x % x
+ If tissue is too scant or not available, MSSM 2 x =
consider repeat biopsy depending on TMB-H x x x
tumor accessibility, safety, and clinical 8Rarv600E mutation x x x
contas FGFR2 fusion or _ sa x
+ NGS or cell-free DNA test may be rarement
considered for identifying gene (0H mutation - x x
mutations HER? (ERBB2)
+ For MSI, there are three possible a as * 5
methods for testing: IHC, NGS, PCR
RET gene fusion x x x
» TMB can be tested with NGS panel but ATA z x x
has inherent platform variation
1. NCON Giinical Practico Guidelines. Bilary Tract Cancers. Version 4.2024. hpsi/wur.nccn.orgprofessionaliphysician_glipafiepd PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Microsatellite-Unstable Tumors: Which Test to Order?
PCR
Functional test: will
detect the 5%
of cancers with
defective MMR but
retention of antigen
Remarkably sensitive
(each marker
is >90% sensitive)
Avoid: minute, low
tumor cellularity
tumors; endometrial
PeerView.com/HFK827
IHC
More widely
available
Can direct which
gene to sequence
Establishes protein
retention or loss
Will miss defective
alleles that retain
antigenicity (~5%)
NGS
+ Comprehensive
genomic testing
Determines if there
are inactivating
mutations in MMR
gene
May be associated
with long turnaround
time; costly
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Copyright © 2000-2024, PeerView
PCR
Functional test: will
detect the 5%
of cancers with
defective MMR but
retention of antigen
Remarkably sensitive
(each marker
is >90% sensitive)
Avoid: minute, low
tumor cellularity
tumors; endometrial
PeerView.com/HFK827
IHC
More widely
available
Can direct which
gene to sequence
Establishes protein
retention or loss
Will miss defective
alleles that retain
antigenicity (~5%)
NGS
+ Comprehensive
genomic testing
Determines if there
are inactivating
mutations in MMR
gene
May be associated
with long turnaround
time; costly
PeerView.com
Copyright © 2000-2024, PeerView
NCCN Practice Guidelines: First-Line Treatment Options
for Unresectable and Metastatic BTC’
Primary Treatment for Unresectable and Metastatic Disease
Useful in Certain Circumstances:
Preferred Regimens Other Recommended Regimens. Targeted Therapy"
+ Durvalumab + gemcitabine + Gemcitabine + cisplatin For MSI-H/dMMR tumors
cisplatin (category 1) (category 1) — Pembrolizumab
+ Pembrolizumab + gemcitabine + Capecitabine + oxaliplatin For TMB-H tumors
cisplatin (category 1) FOLFOX — Nivolumab + ipilimumab
Gemcitabine + albumin-bound
paclitaxel For NTRK gene fusion—positive
Gemcitabine + capecitabine tumors
Gemcitabine + oxaliplatin — Entrectinib; larotrectinib;
Single agents repotrectinib
— 5-fluorouracil For RET gene fusion-positive
- Capecitabine tumors
- Gemcitabine — Pralsetinib; selpercatinib
(category 2B)
Based on the evidence, durvalumab or pembrolizumab + gemcitabine/cisplatin are preferred regimens
for all patients with advanced BTC, including th th MSI-H/dMMR statu:
1. NCGN Clinical Practice Guidelines in Oncology. Bilary Tract Cancers. Version 4 2024. itp: nocnorp/protessionals/physician_gs/pdtc pdt. PeerView.com
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for Unresectable and Metastatic BTC’
Primary Treatment for Unresectable and Metastatic Disease
Useful in Certain Circumstances:
Preferred Regimens Other Recommended Regimens. Targeted Therapy"
+ Durvalumab + gemcitabine + Gemcitabine + cisplatin For MSI-H/dMMR tumors
cisplatin (category 1) (category 1) — Pembrolizumab
+ Pembrolizumab + gemcitabine + Capecitabine + oxaliplatin For TMB-H tumors
cisplatin (category 1) FOLFOX — Nivolumab + ipilimumab
Gemcitabine + albumin-bound
paclitaxel For NTRK gene fusion—positive
Gemcitabine + capecitabine tumors
Gemcitabine + oxaliplatin — Entrectinib; larotrectinib;
Single agents repotrectinib
— 5-fluorouracil For RET gene fusion-positive
- Capecitabine tumors
- Gemcitabine — Pralsetinib; selpercatinib
(category 2B)
Based on the evidence, durvalumab or pembrolizumab + gemcitabine/cisplatin are preferred regimens
for all patients with advanced BTC, including th th MSI-H/dMMR statu:
1. NCGN Clinical Practice Guidelines in Oncology. Bilary Tract Cancers. Version 4 2024. itp: nocnorp/protessionals/physician_gs/pdtc pdt. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
NCCN Practice Guidelines: Subsequent-Line Treatment
Options for Unresectable and Metastatic CCA!
Subsequent-Line Therapy for Biliary Tract Cancers If Disease Progression
Useful in Certain Circumstances:
Preferred Regimens Other Recommended Regimens’ Targeted mnentine heracva
+ FOLFOX FOLFIRI + For MSI-H/dMMR tumors
Liposomal irinotecan + — Pembrolizumab
fluorouracil + — Dostarlimab-gxly (category 28)
leucovorin (category 2B) + For TMB-H tumors
Regorafenib (category 2B — Nivolumab + ipilimumab
Durvalumab + gemcitabine + — Pembrolizumab
cisplatin (category 1) + Nivolumab (category 2B)
Pembrolizumab + gemcitabine +
cisplatin (category 1)
For patients who have not been previously treated with a checkpoint inhibitor when used
ent-line therapy
1.NCCN Cinial Practoe Guidelines in Oncology. Biliary Tract Cancers. Version 4.2024. his mm nccn-rgorafessionalphysician. s/t pt. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Options for Unresectable and Metastatic CCA!
Subsequent-Line Therapy for Biliary Tract Cancers If Disease Progression
Useful in Certain Circumstances:
Preferred Regimens Other Recommended Regimens’ Targeted mnentine heracva
+ FOLFOX FOLFIRI + For MSI-H/dMMR tumors
Liposomal irinotecan + — Pembrolizumab
fluorouracil + — Dostarlimab-gxly (category 28)
leucovorin (category 2B) + For TMB-H tumors
Regorafenib (category 2B — Nivolumab + ipilimumab
Durvalumab + gemcitabine + — Pembrolizumab
cisplatin (category 1) + Nivolumab (category 2B)
Pembrolizumab + gemcitabine +
cisplatin (category 1)
For patients who have not been previously treated with a checkpoint inhibitor when used
ent-line therapy
1.NCCN Cinial Practoe Guidelines in Oncology. Biliary Tract Cancers. Version 4.2024. his mm nccn-rgorafessionalphysician. s/t pt. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
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ESMO Clinical Practice Guidelines for Biliary Tract Cancers!
£ +
Cr]
Cisplatin/gemcital
¡durvalumab [1 A;
ne
{Molecuarprofing |
‘Adjuvant capecitabine
[A]
Cisplatin/gomcitabine +
durvalumab ||, A; MCES 4]
: I I I I I 1
Uvertnited HER2neu
1041 mutaton | FGARZ sion | [arar mutation] [sieur
A oe Exe ¡Escarte] || tescarrs) | | tescar toy ee)
en FOLFOX
1. Ames n | Dabrateniby À pomprotzuman | Trastuzumab!
mato... | vosidenib ; trametinib | Pembrolizumab | ortuzumab
seus dl ma 1. A MCBS A
irinotecan (I, C} iba
+. Vogel ta Ann Oncol 20238127140, PeerView.com
Copyright © 2000-2024, PeerView
ESMO Clinical Practice Guidelines for Biliary Tract Cancers!
£ +
Cr]
Cisplatin/gemcital
¡durvalumab [1 A;
ne
{Molecuarprofing |
‘Adjuvant capecitabine
[A]
Cisplatin/gomcitabine +
durvalumab ||, A; MCES 4]
: I I I I I 1
Uvertnited HER2neu
1041 mutaton | FGARZ sion | [arar mutation] [sieur
A oe Exe ¡Escarte] || tescarrs) | | tescar toy ee)
en FOLFOX
1. Ames n | Dabrateniby À pomprotzuman | Trastuzumab!
mato... | vosidenib ; trametinib | Pembrolizumab | ortuzumab
seus dl ma 1. A MCBS A
irinotecan (I, C} iba
+. Vogel ta Ann Oncol 20238127140, PeerView.com
Copyright © 2000-2024, PeerView
Introduction to Jonathan, a 67-Year-Old Male Patient
With Newly Diagnosed Disease
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
What patient-specific findings indicate the presence of biliary tract cancer?
What additional baseline testing would you perform
to inform subsequent treatment selection?
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With Newly Diagnosed Disease
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
What patient-specific findings indicate the presence of biliary tract cancer?
What additional baseline testing would you perform
to inform subsequent treatment selection?
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Collaborative Strategies
to Integrate Immunotherapy Platforms
in the First Line and Beyond
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
Copyright © 2
to Integrate Immunotherapy Platforms
in the First Line and Beyond
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
Copyright © 2
Back to Jonathan’s Case: How Can Patient-Specific
Findings Help to Guide Frontline Treatment Selection?
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
+ IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
+ NGS: TP53, CDKN2A
+ ECOGPS1
What options can be considered for upfront treatment selection for this patient?
Let's review the evidence...
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Findings Help to Guide Frontline Treatment Selection?
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
+ IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
+ NGS: TP53, CDKN2A
+ ECOGPS1
What options can be considered for upfront treatment selection for this patient?
Let's review the evidence...
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Copyright © 2000-2024, PeerView
Review of Immunotherapy Targets and Options!
AMt-PDA1 Anti-CTLA4
‘Atezolizumab iplimumab
Durvalumab Tremelimumab
Envefolimab
Pembrolizumab
Tislelizumab Cadoniimab
Toripalimab Volrustomig
Vudalimab
Immune Checkpoint
CD27 agonist
Varilumab
APC and others
pS CAR-T targets
x CD133 GPC3 Mesothelin
E Er so we
CART. da EGER Integrin of 0,65
= Ea
i Ej Anti-PO-L1 = Dickkopt-1 inhibitor
3 == Bintrafusp alfa A DKN-O1
"Tumor ol Tore Tumor ai
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1.10.Metal. Cancors. 2023,16:9312.
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
AMt-PDA1 Anti-CTLA4
‘Atezolizumab iplimumab
Durvalumab Tremelimumab
Envefolimab
Pembrolizumab
Tislelizumab Cadoniimab
Toripalimab Volrustomig
Vudalimab
Immune Checkpoint
CD27 agonist
Varilumab
APC and others
pS CAR-T targets
x CD133 GPC3 Mesothelin
E Er so we
CART. da EGER Integrin of 0,65
= Ea
i Ej Anti-PO-L1 = Dickkopt-1 inhibitor
3 == Bintrafusp alfa A DKN-O1
"Tumor ol Tore Tumor ai
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1.10.Metal. Cancors. 2023,16:9312.
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Phase 3 TOPAZ-1 Trial: First-Line Immunotherapy +
Chemotherapy in Patients With Advanced Biliary Cancers!
TOPAZ-1 is a randomized, double-blind, multicenter, global phase 3 study
Key eligibility Durvalumab 1,500 mg Q3W
Durvalumab 1,500 mg
Locally advanced or metastatic BTC x Q4W until PD
(ICC, ECC, or GBC) (
Previously untreated if unresectable
or metastatic at initial diagnosis
Recurrent disease >6 months after Era
curative surgery or adjuvant therapy + gemcitabine/cisplatin
ECOG PS 0 or 1 pta
Stratification factors
+ Disease status
— Initially unresectable vs recurrent
Primary tumor location
— ICC vs ECC vs GBC
+ Primary endpoint: OS
+ Key secondary endpoints: PFS, ORR, DOR, and safety
+ Exploratory endpoints: efficacy and safety by primary tumor location (ICC vs ECC vs GBC)
1. hipsitinicalals govlet2/showNCTO3875236, PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
Chemotherapy in Patients With Advanced Biliary Cancers!
TOPAZ-1 is a randomized, double-blind, multicenter, global phase 3 study
Key eligibility Durvalumab 1,500 mg Q3W
Durvalumab 1,500 mg
Locally advanced or metastatic BTC x Q4W until PD
(ICC, ECC, or GBC) (
Previously untreated if unresectable
or metastatic at initial diagnosis
Recurrent disease >6 months after Era
curative surgery or adjuvant therapy + gemcitabine/cisplatin
ECOG PS 0 or 1 pta
Stratification factors
+ Disease status
— Initially unresectable vs recurrent
Primary tumor location
— ICC vs ECC vs GBC
+ Primary endpoint: OS
+ Key secondary endpoints: PFS, ORR, DOR, and safety
+ Exploratory endpoints: efficacy and safety by primary tumor location (ICC vs ECC vs GBC)
1. hipsitinicalals govlet2/showNCTO3875236, PeerView.com
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Phase 3 TOPAZ-1 Trial: 3-Year OS Update of Durvalumab +
Gem/Cis vs Placebo + Gem/Cis'
OS benefit with durvalumab + gem/cis continued at the updated DCO
OS at 3-Year OS Analysis
Primary Anal
DCO: Au
©
Poe
Loi GomCis
m
Bw Megnos aa
ps oo Mn lea Goes
3 a4 08%
Ê of ose Ex dé is ween 0m 086007) 074 (063087)
2 mt 69
o OS rate ratio: 2.12
» Danaea + panic (n= 241)
® Oscar |
of | i
ToT Hee eT NT oH Hea aE TD a F
eue Time From Randomization, mo At 36 months, the survival rate in the
Bren qu sop an a sas durvalumab + gem/cis arm was more
ES one me ne we vo 5 à 7 % 2 mo 8 4 0 0 0 than double the survival rate in the
1.0N DY eta. Lancet. 2024 9:694-704
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placebo + gem/cis arm
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Gem/Cis vs Placebo + Gem/Cis'
OS benefit with durvalumab + gem/cis continued at the updated DCO
OS at 3-Year OS Analysis
Primary Anal
DCO: Au
©
Poe
Loi GomCis
m
Bw Megnos aa
ps oo Mn lea Goes
3 a4 08%
Ê of ose Ex dé is ween 0m 086007) 074 (063087)
2 mt 69
o OS rate ratio: 2.12
» Danaea + panic (n= 241)
® Oscar |
of | i
ToT Hee eT NT oH Hea aE TD a F
eue Time From Randomization, mo At 36 months, the survival rate in the
Bren qu sop an a sas durvalumab + gem/cis arm was more
ES one me ne we vo 5 à 7 % 2 mo 8 4 0 0 0 than double the survival rate in the
1.0N DY eta. Lancet. 2024 9:694-704
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placebo + gem/cis arm
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TOPAZ-1: Subgroup Analysis of OS!
Durvalumas Paceto os ne
+ Game INS) + Gems, WN (4) sx ch
Al participants He 2480341 (72.7) 2791394 (81.1) 076084091)
Sex: men He OR MENÉS) 075050000)
Sex women 12272 (109) 191/168 ro) 081-064-108)
Age al randomization: <65 years of age heal 125/181 (68) 150/184 (61.5) 0.72 (0.56081)
Age a ancomzaton 285 years of age NASEN TBB) 084068108)
POLI expression: ng (TAP 21%) He Mao) ROTEN 075(060009)
PDL! expression: lowinogatve (TAP <1%) 71103 (68.9) e1097e6) ——_079(058-1.00)
Disease status at randomization: na unresectable ES 200274 6.3) 240/279 (88) 070 055085)
Disease stan at randomization: rcuren 39967 (8.2) 30184 (009) 076(0.49-120)
Primary uma location: traepaic crolargiocarónoma 136/190(716) 1593/0 078(062099)
Primary tumor locaton: extanepati cholangocaranoma E= 4566682) sans (046) 061 0.41091)
Pray tumor location: gl cancer 6786 (78.0) 7196 (826) 090 (064-425)
Race: Asian bed Was TA 8 (084085)
Race: ronAsion MANN STAR 062(070120)
Region: asia he 1301178 ma) mans 0.68 (0.54085)
Region: rest of he word vanes (724) OASIS) OS (070-118)
WHOYECOG PS: (0) nomalacivty ENTE) —«$28163(767) 087/0682)
WHOYECOG PS: (1) resis actity ho man WIE 070(055080)
Diagnostic stage: locally advanced ns | 22/38 (57.9) 45/57 (78.9) 0.54 (0.32-0.88)
Diagnostic stage: metastatic RAS) zB 0200087097)
or 05 10 1520
OS HR (95% CI)
1.08 DY etal ESMO 2022. Abstract SP, PeerView.com
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Durvalumas Paceto os ne
+ Game INS) + Gems, WN (4) sx ch
Al participants He 2480341 (72.7) 2791394 (81.1) 076084091)
Sex: men He OR MENÉS) 075050000)
Sex women 12272 (109) 191/168 ro) 081-064-108)
Age al randomization: <65 years of age heal 125/181 (68) 150/184 (61.5) 0.72 (0.56081)
Age a ancomzaton 285 years of age NASEN TBB) 084068108)
POLI expression: ng (TAP 21%) He Mao) ROTEN 075(060009)
PDL! expression: lowinogatve (TAP <1%) 71103 (68.9) e1097e6) ——_079(058-1.00)
Disease status at randomization: na unresectable ES 200274 6.3) 240/279 (88) 070 055085)
Disease stan at randomization: rcuren 39967 (8.2) 30184 (009) 076(0.49-120)
Primary uma location: traepaic crolargiocarónoma 136/190(716) 1593/0 078(062099)
Primary tumor locaton: extanepati cholangocaranoma E= 4566682) sans (046) 061 0.41091)
Pray tumor location: gl cancer 6786 (78.0) 7196 (826) 090 (064-425)
Race: Asian bed Was TA 8 (084085)
Race: ronAsion MANN STAR 062(070120)
Region: asia he 1301178 ma) mans 0.68 (0.54085)
Region: rest of he word vanes (724) OASIS) OS (070-118)
WHOYECOG PS: (0) nomalacivty ENTE) —«$28163(767) 087/0682)
WHOYECOG PS: (1) resis actity ho man WIE 070(055080)
Diagnostic stage: locally advanced ns | 22/38 (57.9) 45/57 (78.9) 0.54 (0.32-0.88)
Diagnostic stage: metastatic RAS) zB 0200087097)
or 05 10 1520
OS HR (95% CI)
1.08 DY etal ESMO 2022. Abstract SP, PeerView.com
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TOPAZ-1: Durvalumab + Gem/Cis Demonstrated
a Higher ORR and More Rapid Tumor Responses!
s >
à ‘ORR’ DOR'
= Odds ratio: 1.60 2
(95% 01. 1:11-231: P=.011) €
so ARO 3 Remaining in Remaining in
. response 28 mo: response 212 mo:
=> 267 5 ESA EA
ER E 253% 15%
ö 187 2
s 7 E Dunahmab + gomiés
© Ê
5 ce E Placebo + gemiis
o o [q
Dumalımab + Geriis (n= 341)” Pracabo + GomiCia(n= 345) 5 5 6 89 2 5 © à
No. at Risk Time From Randomization, mo
Duara + comes m 4 2 1 M 5 1
er Paco + gemes AA
Semlcis Durvalumab + Placebo +
(n= 241), n (%) GomiCis
‘ORR 91267) 64 (187) (n=91)
cR 7021 2(0.6) Median DOR, mo (quartile 1-3) 64 (46-17.2) 62(5:6:9)
PR 84 (246) 62 (18.1) Median time to response, mo
DCR: 291 (85.3) 284 (82.6) quartile 1-3) A A
* By Investgator assossments using RECIST v1.1 based on patents in the nal analysis sat who had measurable diseaso at basolne.* Analysis of DOR was based on
patos inthe ful analysis set who had an objective response and measurable disease at Dascine, "Analysis of DCR was based on al patents in tho fll analyse
1.0h DY otal. ASCO GI 2022. Abstract 378.
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a Higher ORR and More Rapid Tumor Responses!
s >
à ‘ORR’ DOR'
= Odds ratio: 1.60 2
(95% 01. 1:11-231: P=.011) €
so ARO 3 Remaining in Remaining in
. response 28 mo: response 212 mo:
=> 267 5 ESA EA
ER E 253% 15%
ö 187 2
s 7 E Dunahmab + gomiés
© Ê
5 ce E Placebo + gemiis
o o [q
Dumalımab + Geriis (n= 341)” Pracabo + GomiCia(n= 345) 5 5 6 89 2 5 © à
No. at Risk Time From Randomization, mo
Duara + comes m 4 2 1 M 5 1
er Paco + gemes AA
Semlcis Durvalumab + Placebo +
(n= 241), n (%) GomiCis
‘ORR 91267) 64 (187) (n=91)
cR 7021 2(0.6) Median DOR, mo (quartile 1-3) 64 (46-17.2) 62(5:6:9)
PR 84 (246) 62 (18.1) Median time to response, mo
DCR: 291 (85.3) 284 (82.6) quartile 1-3) A A
* By Investgator assossments using RECIST v1.1 based on patents in the nal analysis sat who had measurable diseaso at basolne.* Analysis of DOR was based on
patos inthe ful analysis set who had an objective response and measurable disease at Dascine, "Analysis of DCR was based on al patents in tho fll analyse
1.0h DY otal. ASCO GI 2022. Abstract 378.
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TOPAZ-1: Summary of AEs and Treatment Exposure’
Durvalumab + Gem/Cis Placebo + Gem/Ci
(n= 342)
Median duration of exposure, mo (range)
Durvalumab/placebo 7.33 (0.1-24.5) 5.77 (0.2-21.5)
Gemcitabine 5.19 (0.1-83) 5.03 (0.2-8.6)
Cisplatin 5.13 (0.1-8.3) 4.88 (0.2-8.5)
Event, n (%)
Any AE 336 (99.4) 338 (98.8)
Any TRAE 314 (92.9) 308 (90.1)
Any grade 3/4 AE 256 (75.7) 266 (77.8)
Any grade 3/4 TRAE 212 (62.7) 222 (64.9)
Any serious AE 160 (47.3) 149 (43.6)
Any serious TRAE 53(15.7) 59(17.3)
Any AE leading to discontinuation 44 (13) 52 (15.2)
Any TRAE leading to discontinuation 30 (8.9) 39 (11.4)
Any AE leading to death 12 (3.6) 14 (441)
Any TRAE leading to death 2(0.6) 1(0.3)
Any
mun
jediated AE 43 (12.
16 (4.7)
‘Includes AEs wth onset dato on or aer the date ofthe frst dose or AES that wersened afte no fest dose. Includes AES cecuing Upto 90 days folowing the date of
tno ast dose or up 10 the fst subsoquent therapy
1.0h DY otal. ASCO GI 2022. Abstract 378. PeerView.com
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Durvalumab + Gem/Cis Placebo + Gem/Ci
(n= 342)
Median duration of exposure, mo (range)
Durvalumab/placebo 7.33 (0.1-24.5) 5.77 (0.2-21.5)
Gemcitabine 5.19 (0.1-83) 5.03 (0.2-8.6)
Cisplatin 5.13 (0.1-8.3) 4.88 (0.2-8.5)
Event, n (%)
Any AE 336 (99.4) 338 (98.8)
Any TRAE 314 (92.9) 308 (90.1)
Any grade 3/4 AE 256 (75.7) 266 (77.8)
Any grade 3/4 TRAE 212 (62.7) 222 (64.9)
Any serious AE 160 (47.3) 149 (43.6)
Any serious TRAE 53(15.7) 59(17.3)
Any AE leading to discontinuation 44 (13) 52 (15.2)
Any TRAE leading to discontinuation 30 (8.9) 39 (11.4)
Any AE leading to death 12 (3.6) 14 (441)
Any TRAE leading to death 2(0.6) 1(0.3)
Any
mun
jediated AE 43 (12.
16 (4.7)
‘Includes AEs wth onset dato on or aer the date ofthe frst dose or AES that wersened afte no fest dose. Includes AES cecuing Upto 90 days folowing the date of
tno ast dose or up 10 the fst subsoquent therapy
1.0h DY otal. ASCO GI 2022. Abstract 378. PeerView.com
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KEYNOTE-966: Pembrolizumab + Gem/Cis vs Gem/Cis
Alone in First-Line Advanced and/or Unresectable BTC’
Screening/baseline
+ Histologically confirmed diagnosis of advanced
(metastatic) and/or unresectable (locally advanced)
BTC (ampullary cancer excluded)
+ Measurable disease based on RECIST v1.1, as
determined by the site investigator
+ No prior systemic therapies
+ No CNS metastases and/or carcinomatous meningitis
+ Participants with a history of hepatitis B/C can be
enrolled if they meet study criteria
+ Availability of archival tumor tissue sample or newly
‘obtained core or excisional biopsy of a tumor lesion
+ Life expectancy >3 months
‘Adequate organ function
+ Primary objective: OS
+ Secondary obj
Pembrolizumab 200 mg
gemcitabine/
(up to
gemcitabine
until PD
isplatin
Placebo Q3W +
gemcitabine until PD
Placebo Q3\
gemcitabine/cisplatin
maximum of 35 cyc
d beyond 8 cyc
a maximum
: ORR (RECIST v1.1; BICR), DOR (RECIST v1.1; BICR), and PFS (RECIST v1.1; BICR)
+ Safety outcomes: number of patients experiencing >1 AE and discontinuations due to AES
4. Kolley RK ot al Lancot 2023:401:1853-1865,
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Alone in First-Line Advanced and/or Unresectable BTC’
Screening/baseline
+ Histologically confirmed diagnosis of advanced
(metastatic) and/or unresectable (locally advanced)
BTC (ampullary cancer excluded)
+ Measurable disease based on RECIST v1.1, as
determined by the site investigator
+ No prior systemic therapies
+ No CNS metastases and/or carcinomatous meningitis
+ Participants with a history of hepatitis B/C can be
enrolled if they meet study criteria
+ Availability of archival tumor tissue sample or newly
‘obtained core or excisional biopsy of a tumor lesion
+ Life expectancy >3 months
‘Adequate organ function
+ Primary objective: OS
+ Secondary obj
Pembrolizumab 200 mg
gemcitabine/
(up to
gemcitabine
until PD
isplatin
Placebo Q3W +
gemcitabine until PD
Placebo Q3\
gemcitabine/cisplatin
maximum of 35 cyc
d beyond 8 cyc
a maximum
: ORR (RECIST v1.1; BICR), DOR (RECIST v1.1; BICR), and PFS (RECIST v1.1; BICR)
+ Safety outcomes: number of patients experiencing >1 AE and discontinuations due to AES
4. Kolley RK ot al Lancot 2023:401:1853-1865,
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KEYNOTE-966: Pembrolizumab + Gem/Cis Demonstrated
Significant Overall Survival Improvement
ationts With Event, % Median OS, mo (95% CI)
Pombo + gems 85 127 (145-136)
Placebo + gone us 109 (89-116)
HR = 0.86 (95% CI, 0.75-0.98)
OS, %
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
No. at Risk Time, mo
Pombro +gomiis 533 496 430 350 275 217 176 147 131 113 88 64 39 21 15
Placebo +gemicis — 536 483 394 313 236 195 149 125 102 86 63 43 27 20 10
After an additional 11 months of follow-up from final analysis, improvement of OS was maintained, and DOR remained
longer in the pembrolizumab arm (8.3 vs 6.9 mo)!
In October 2023, the FDA approved the combination for locally advanced unresectable or metastatic BTC
1. Finn Ret al ASCO 2024. Abstract 4083.2. Moss a govcrugslescurces information approved-crugatsa-approves-pembrokzumab-chemeterapy-blary-
vactcaneet
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Significant Overall Survival Improvement
ationts With Event, % Median OS, mo (95% CI)
Pombo + gems 85 127 (145-136)
Placebo + gone us 109 (89-116)
HR = 0.86 (95% CI, 0.75-0.98)
OS, %
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
No. at Risk Time, mo
Pombro +gomiis 533 496 430 350 275 217 176 147 131 113 88 64 39 21 15
Placebo +gemicis — 536 483 394 313 236 195 149 125 102 86 63 43 27 20 10
After an additional 11 months of follow-up from final analysis, improvement of OS was maintained, and DOR remained
longer in the pembrolizumab arm (8.3 vs 6.9 mo)!
In October 2023, the FDA approved the combination for locally advanced unresectable or metastatic BTC
1. Finn Ret al ASCO 2024. Abstract 4083.2. Moss a govcrugslescurces information approved-crugatsa-approves-pembrokzumab-chemeterapy-blary-
vactcaneet
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KEYNOTE-966: Overall Survival Subgroup Analysis!
subgrou; Patents With Event HR (95% Cl
All patients. 936/1,069 eo 0.86 (0.75-0.98)
265 497/567 eee 0.90 (0.76-4.08)
ay <65 4391502 0.82 (0.68-0.99)
= Women 460/517 0.88 (072-103)
Men 476/552 0.87 (073.109)
Asta 0.90 (074-109)
Geographic region Non-Asia 0.83 (0.70-0.99)
Ls ‘Extrahepatic 0.97 (0.72-1.31)
it of origin Gallbladder 0.94 (072-123)
Inrehepaic e 0.81 (0.69-0.96)
Locally advanced 0.87 (059-128)
Diese presenti Metastatic 0.85 (0.74-0.98)
o 0.92 (075-4.11)
psa ji 0.85 (0.71-1.00)
Yes 079(049-128)
Biliary stendrain No 0.87 (0.76-0.99)
Never 1.02 (0871.54)
Smoking status. Former 3382 0.92 (0.75-1.13)
Current 3382 re 0.81 (0630.97)
Yes 7798 ef 0.72(0.46-1.13)
PARENT No 859/971 +8 0.88 (0.77-1.01)
cPsa1 6467728 0.88 (075-1.02)
POL status CPS <1 191/223 0.88 (0.88-1.17)
Ingeterminate Sara 0771052114
ds 10 15
Favors Pembro + GemiCis_ Favors Placebo + GemiCis.
Frans Roribro + Conti Favors Phicab + Banich .
1. Finn Rot aL ASCO 2024, Abstract 4093. PeerView.com
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subgrou; Patents With Event HR (95% Cl
All patients. 936/1,069 eo 0.86 (0.75-0.98)
265 497/567 eee 0.90 (0.76-4.08)
ay <65 4391502 0.82 (0.68-0.99)
= Women 460/517 0.88 (072-103)
Men 476/552 0.87 (073.109)
Asta 0.90 (074-109)
Geographic region Non-Asia 0.83 (0.70-0.99)
Ls ‘Extrahepatic 0.97 (0.72-1.31)
it of origin Gallbladder 0.94 (072-123)
Inrehepaic e 0.81 (0.69-0.96)
Locally advanced 0.87 (059-128)
Diese presenti Metastatic 0.85 (0.74-0.98)
o 0.92 (075-4.11)
psa ji 0.85 (0.71-1.00)
Yes 079(049-128)
Biliary stendrain No 0.87 (0.76-0.99)
Never 1.02 (0871.54)
Smoking status. Former 3382 0.92 (0.75-1.13)
Current 3382 re 0.81 (0630.97)
Yes 7798 ef 0.72(0.46-1.13)
PARENT No 859/971 +8 0.88 (0.77-1.01)
cPsa1 6467728 0.88 (075-1.02)
POL status CPS <1 191/223 0.88 (0.88-1.17)
Ingeterminate Sara 0771052114
ds 10 15
Favors Pembro + GemiCis_ Favors Placebo + GemiCis.
Frans Roribro + Conti Favors Phicab + Banich .
1. Finn Rot aL ASCO 2024, Abstract 4093. PeerView.com
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KEYNOTE-966: Safety Profiles Remain Consistent
and Comparable Between Treatment Arms!
aA 5 mbro + Gem/Cis Placebo + Ge
ubaroup, n|(%) (n= 529) (n= 534)
Any 524 (99.9) 532 (99.6)
Treatment related 493 (93.2) 500 (93.6)
Grade 3-4 as maximum grade 420 (79.4) 399 (74.7)
Treatment related 370 (69.9) 367 (68.7)
Led to death 31 (5.9) 50 (9.4)
Treatment related 8(1.5) 3 (0.6)
Led to discontinuation of 21 study medication 140 (26.5) 124 (23.2)
Treatment related 103 (19.5) 82 (15.4)
Led to discontinuation of all study medication 35 (6.6) 39 (7.3)
Treatment related 18 (3.4) 14 (26)
1.Finn Ret al ASCO 2024. Abstract 4093. PeerView.com
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and Comparable Between Treatment Arms!
aA 5 mbro + Gem/Cis Placebo + Ge
ubaroup, n|(%) (n= 529) (n= 534)
Any 524 (99.9) 532 (99.6)
Treatment related 493 (93.2) 500 (93.6)
Grade 3-4 as maximum grade 420 (79.4) 399 (74.7)
Treatment related 370 (69.9) 367 (68.7)
Led to death 31 (5.9) 50 (9.4)
Treatment related 8(1.5) 3 (0.6)
Led to discontinuation of 21 study medication 140 (26.5) 124 (23.2)
Treatment related 103 (19.5) 82 (15.4)
Led to discontinuation of all study medication 35 (6.6) 39 (7.3)
Treatment related 18 (3.4) 14 (26)
1.Finn Ret al ASCO 2024. Abstract 4093. PeerView.com
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KEYNOTE-966 HR-QOL:
EORTC QLQ-C30 Longitudinal Changes!
2° GHS/QOL _, 57 Physical Functioning _, § Role Functioning + &
E E E Ik
o A do
Fi É E É
hs ¿ is
ie i i
2 5 A 2
¿o 3 gu £
E | mPembro + gomiis ‘ E
À 15 | m Placebo + gemicis 5 as
@ | oiteronce ints Mean 95% cy: 5 | ditfernceinsMean (95% Ci: % | Ditferenee in LS Mean (95% Ci):
0.04 (-2.52 to 2.60); P= 98 a 1.24 (-1.42 to 3.90); P= .36 = 2.68 (-0.76 to 6.11); P= 13
2 À
ERELITIITZIIT) PRLEITITITZIITEETTEETITITZTTT
Time, wk Time, wk
Role Functioning
Pembro + gem NR (7.69-NR) 6.47 (4639.48)
Plocobe + gemicts 2122(834NR) - 1199 (SER) - 575 (467-930) 2
Higher scores indicative of better health a
1. Yoa G et al. J Gin Oncol. 2023;41.4003.4008. PeerView.com
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EORTC QLQ-C30 Longitudinal Changes!
2° GHS/QOL _, 57 Physical Functioning _, § Role Functioning + &
E E E Ik
o A do
Fi É E É
hs ¿ is
ie i i
2 5 A 2
¿o 3 gu £
E | mPembro + gomiis ‘ E
À 15 | m Placebo + gemicis 5 as
@ | oiteronce ints Mean 95% cy: 5 | ditfernceinsMean (95% Ci: % | Ditferenee in LS Mean (95% Ci):
0.04 (-2.52 to 2.60); P= 98 a 1.24 (-1.42 to 3.90); P= .36 = 2.68 (-0.76 to 6.11); P= 13
2 À
ERELITIITZIIT) PRLEITITITZIITEETTEETITITZTTT
Time, wk Time, wk
Role Functioning
Pembro + gem NR (7.69-NR) 6.47 (4639.48)
Plocobe + gemicts 2122(834NR) - 1199 (SER) - 575 (467-930) 2
Higher scores indicative of better health a
1. Yoa G et al. J Gin Oncol. 2023;41.4003.4008. PeerView.com
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KEYNOTE-966 HR-QOL:
EORTC QLQ-C30 Functional and Symptom Domains!
QLQ-C30 Functional Domains QLQ-C30 Symptom Domains
Le M Pembro +gemicis | 1 Pembro + gemicis
Placebo + gemicis | E E Placebo + gemicis | e
8 3
É á
LS Mean Score Change From BL.
Decline
LS Mean Score Change From BL
Improvement
prising RO. 8 5 soc
a ce natn ars, Se
1. Yoa G etal. J Gin Oncol. 2028:41:4003-4003 PeerView.com
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EORTC QLQ-C30 Functional and Symptom Domains!
QLQ-C30 Functional Domains QLQ-C30 Symptom Domains
Le M Pembro +gemicis | 1 Pembro + gemicis
Placebo + gemicis | E E Placebo + gemicis | e
8 3
É á
LS Mean Score Change From BL.
Decline
LS Mean Score Change From BL
Improvement
prising RO. 8 5 soc
a ce natn ars, Se
1. Yoa G etal. J Gin Oncol. 2028:41:4003-4003 PeerView.com
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KEYNOTE-966 HR-QOL: EORTC QLQ-BIL21
Longitudinal Change in Jaundice and Pain Domains!
Jaundice Pain
3 9] m Pembro + gemicis a
E *] Mm Placebo + gemicis g®
Es É 64 Difference in LS Mean (95% Cl): 2
Da $4 -1.87 (-4.26 to 0.53); P=.13 3
Be Be
$ $
gs eo x
a 3. E
& 1 Difference in LS Mean (95% Ci}; go 3
es 0.26 (-1.35 to 1.87); P = .75 na 3
E 2 E
10 “0
AEREO LIC RAI
Pembrolzumab + genvcis NR (16:26:08) ie NR (NAAR)
Placobo + gemica NR (NENA) ARMAR)
1. Yoa G etal. J Gin Oncol. 2023:41:4003-4003. PeerView.com
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Longitudinal Change in Jaundice and Pain Domains!
Jaundice Pain
3 9] m Pembro + gemicis a
E *] Mm Placebo + gemicis g®
Es É 64 Difference in LS Mean (95% Cl): 2
Da $4 -1.87 (-4.26 to 0.53); P=.13 3
Be Be
$ $
gs eo x
a 3. E
& 1 Difference in LS Mean (95% Ci}; go 3
es 0.26 (-1.35 to 1.87); P = .75 na 3
E 2 E
10 “0
AEREO LIC RAI
Pembrolzumab + genvcis NR (16:26:08) ie NR (NAAR)
Placobo + gemica NR (NENA) ARMAR)
1. Yoa G etal. J Gin Oncol. 2023:41:4003-4003. PeerView.com
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Phase 2 IMbrave151 Trial: Emerging Evidence
for Frontline Chemoimmunotherapy for Advanced CCA!
Key eli
lity criteria
Aged 218 years
Histologically confirmed metastatic or advanced
unresectable CCA
ECOG PS 0 or 1
No prior systemic therapy for advanced BTC
Measurable lesion, as defined by RECIST v1.1
Adequate hematologic, hepatic, and renal
function
Primary outcome measure: PFS
Atezolizumab + bevacizumab +
gemcitabine/cisplatin
N=162
Atezolizumab +
gemcitabine/cisplatin
Secondary outcome measures: OS, ORR, DOR, DCR, and TTCD
1. Elkhouciy À ASCO GI 2023. Abstract 401
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for Frontline Chemoimmunotherapy for Advanced CCA!
Key eli
lity criteria
Aged 218 years
Histologically confirmed metastatic or advanced
unresectable CCA
ECOG PS 0 or 1
No prior systemic therapy for advanced BTC
Measurable lesion, as defined by RECIST v1.1
Adequate hematologic, hepatic, and renal
function
Primary outcome measure: PFS
Atezolizumab + bevacizumab +
gemcitabine/cisplatin
N=162
Atezolizumab +
gemcitabine/cisplatin
Secondary outcome measures: OS, ORR, DOR, DCR, and TTCD
1. Elkhouciy À ASCO GI 2023. Abstract 401
PeerView.com/HFK827
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Copyright © 2000-2024, PeerView
IMbrave151 Primary Endpoint: Progression-Free Survival!
100
Events, n 0%), 4557) 58 (69.9)
Median PFS, mo (95% C1) 836840) 796234)
Sraited HR (95% CI) 0.76 (051-114)
80
(Sm PFS rato, % (5% GI) 782 (68.8877) 031626730)
60
PFS, %
40
Atezo + bev + gemícis (n = 79)
20
Atezo + placebo + gemicis (n = 83)
ot a + + —
9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
No. at Risk Time, mo
Alozo + bov+gemids 72 75 73 67 Gf 87 56 41 3% 18 15 5 OS 1 1 NE
‘iezo + placebo +
gomicis 8 78 72 65 62 OS Si 3 m 18 4 3 NE NE NE
1. Elkhouciy À ASCO GI 2023. Abstract 401 PeerView.com
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100
Events, n 0%), 4557) 58 (69.9)
Median PFS, mo (95% C1) 836840) 796234)
Sraited HR (95% CI) 0.76 (051-114)
80
(Sm PFS rato, % (5% GI) 782 (68.8877) 031626730)
60
PFS, %
40
Atezo + bev + gemícis (n = 79)
20
Atezo + placebo + gemicis (n = 83)
ot a + + —
9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
No. at Risk Time, mo
Alozo + bov+gemids 72 75 73 67 Gf 87 56 41 3% 18 15 5 OS 1 1 NE
‘iezo + placebo +
gomicis 8 78 72 65 62 OS Si 3 m 18 4 3 NE NE NE
1. Elkhouciy À ASCO GI 2023. Abstract 401 PeerView.com
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Case Discussion: Frontline Treatment
Selection for Advanced BTC
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
itial workup revealed CA 19-9 of 20; albumin: 4.0; total bilirubin: 0.5; BUN: 22; creatinine: 0.72;
WBC 3.5; Hg/Hct: 11.8/36.4; platelets: 170,000
+ CT scan showed multiple liver masses, with the largest measuring 7 x 6.4 cm in the right hepatic
lobe, and multiple enlarged periaortic lymph nodes
+ Ultrasound-guided liver mass biopsy showed poorly differentiated adenocarcinoma
IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
NGS: TP53, CDKN2A
ECOG PS 1
Discussion
Is this patient a candidate for standard cytotoxic therapy or a chemoimmunotherapy regimen?
Which ICI-based regimens would you consider, and how would you select among validated strategies?
‘What factors for maintenance therapy would you consider?
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Selection for Advanced BTC
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
itial workup revealed CA 19-9 of 20; albumin: 4.0; total bilirubin: 0.5; BUN: 22; creatinine: 0.72;
WBC 3.5; Hg/Hct: 11.8/36.4; platelets: 170,000
+ CT scan showed multiple liver masses, with the largest measuring 7 x 6.4 cm in the right hepatic
lobe, and multiple enlarged periaortic lymph nodes
+ Ultrasound-guided liver mass biopsy showed poorly differentiated adenocarcinoma
IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
NGS: TP53, CDKN2A
ECOG PS 1
Discussion
Is this patient a candidate for standard cytotoxic therapy or a chemoimmunotherapy regimen?
Which ICI-based regimens would you consider, and how would you select among validated strategies?
‘What factors for maintenance therapy would you consider?
PeerView.com
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Immunotherapy in
Subsequent Lines of Treatment
Subsequent Lines of Treatment
Introduction to Margery, a 60-Year-Old Female Patient
Progressing on First-Line Chemotherapy
Margery presented with a history of abdominal pain, fatigue, and unintentional
weight loss
+ Initial workup revealed total bilirubin: 1.2 mg/dL; AST: 56 units/mL; ALT: 67 units/mL;
platelets: 105,000/mcL
+ Imaging confirmed bilobar hepatic disease with pulmonary metastases; histopathologic
examination is consistent with cholangiocarcinoma
+ ECOG PS1
Patient treated with upfront gemcitabine/cisplatin; progression after 4 months
How should this patient be sequenced? What are some important factors to
consider when selecting IO in subsequent lines of therapy?
Let's review the evidence
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Progressing on First-Line Chemotherapy
Margery presented with a history of abdominal pain, fatigue, and unintentional
weight loss
+ Initial workup revealed total bilirubin: 1.2 mg/dL; AST: 56 units/mL; ALT: 67 units/mL;
platelets: 105,000/mcL
+ Imaging confirmed bilobar hepatic disease with pulmonary metastases; histopathologic
examination is consistent with cholangiocarcinoma
+ ECOG PS1
Patient treated with upfront gemcitabine/cisplatin; progression after 4 months
How should this patient be sequenced? What are some important factors to
consider when selecting IO in subsequent lines of therapy?
Let's review the evidence
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Second-Line Experience With Pembrolizumab for Biliary Cancer!
+ KEYNOTE-028: phase 1b biomarker-selected basket
+ KEYNOTE-158: phase 2 unselected multicohort study
+ Most heavily pretreated patients
+ Pembrolizumab was well tolerated
— 18% had immune-related AES
— 6% were grade 3; no grade 4/5 AES
+ Caveats: location of biliary cancer was
not collected
+ Atleast 1 patient in KEYNOTE-028 was MSI-H;
others were missing MSI status
+ Assays for PD-L1 differed between the two trials
= KEYNOTE-028: prototype assay
- KEYNOTE-158: CPS >1 using IHC 2203
1. Pina-Paul SA ota. nt J Concor.2020;147:2190-2198,
PeerView.com/HFK827
Change From Baseline, %
in Target Lesions by RECIST 1.1, %
1m PD-L1 positive (KEYNOTE-158)
1m PD-L1 negative (KEYNOTE-158)
1m PD-L1 NE (KEYNOTE-158)
1m PD-L1 positive (KEYNOTE-026)
100
80
oo
40
20% tu
20
o
20
e 30% tumor reduction
£0
ORR KN-028: 13 (2.8-33.6); DOR >24 mo: 66.7
hi ORR KN-158: 5.8 (2.1-12.1), DOR >24 mo: 50
400
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+ KEYNOTE-028: phase 1b biomarker-selected basket
+ KEYNOTE-158: phase 2 unselected multicohort study
+ Most heavily pretreated patients
+ Pembrolizumab was well tolerated
— 18% had immune-related AES
— 6% were grade 3; no grade 4/5 AES
+ Caveats: location of biliary cancer was
not collected
+ Atleast 1 patient in KEYNOTE-028 was MSI-H;
others were missing MSI status
+ Assays for PD-L1 differed between the two trials
= KEYNOTE-028: prototype assay
- KEYNOTE-158: CPS >1 using IHC 2203
1. Pina-Paul SA ota. nt J Concor.2020;147:2190-2198,
PeerView.com/HFK827
Change From Baseline, %
in Target Lesions by RECIST 1.1, %
1m PD-L1 positive (KEYNOTE-158)
1m PD-L1 negative (KEYNOTE-158)
1m PD-L1 NE (KEYNOTE-158)
1m PD-L1 positive (KEYNOTE-026)
100
80
oo
40
20% tu
20
o
20
e 30% tumor reduction
£0
ORR KN-028: 13 (2.8-33.6); DOR >24 mo: 66.7
hi ORR KN-158: 5.8 (2.1-12.1), DOR >24 mo: 50
400
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KEYNOTE-158: Updated Analysis Showed Meaningful Activity
and Durable Responses for Pretreated MSI-H/dMMR BTC’
“
a smal g con |,
zo inuntine OMS gry Tract Panerestie
& o (0-25) ) 2)
3 «0
Er ‘ORR, % 485 a 42 EN 102
rl fone (962610) (BATA) reden (156553) (2403)
En Bost objective
Fon Tesponse.n 09)
8% E wan «es a gra) | a | 14m
is PR Bm 914 8307 500 | sera | 3689
3 so Ben 70n Tes 203 | sm) | 309
hi Patients Po 19(279) — 15(357) 5.20) 12 (50) 8(364) 8 (36.4)
‘mDOR, mo NR Na na ne aos Ne
100 ange) (291047.+) (631051.19 (21+1041.39) (42104354) (62-405+) |(6-11024.34)
» mes mo Er 22 er 22 42 21
m trs asus ares usa 2052 | ero | us
7
zo Ep me ms wi æe | m | m
pa
af mos,mo NR " Ne ER 194 ar
>|; ee Gone u er Gen ion | os | ete)
Median DOR, mo rango)
6 CEE oer cat = eee ln co lle
RREPITETEZETETTIT
Time, mo
1.Naio M tal. Ann Oncol 2022:39:929:98. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
and Durable Responses for Pretreated MSI-H/dMMR BTC’
“
a smal g con |,
zo inuntine OMS gry Tract Panerestie
& o (0-25) ) 2)
3 «0
Er ‘ORR, % 485 a 42 EN 102
rl fone (962610) (BATA) reden (156553) (2403)
En Bost objective
Fon Tesponse.n 09)
8% E wan «es a gra) | a | 14m
is PR Bm 914 8307 500 | sera | 3689
3 so Ben 70n Tes 203 | sm) | 309
hi Patients Po 19(279) — 15(357) 5.20) 12 (50) 8(364) 8 (36.4)
‘mDOR, mo NR Na na ne aos Ne
100 ange) (291047.+) (631051.19 (21+1041.39) (42104354) (62-405+) |(6-11024.34)
» mes mo Er 22 er 22 42 21
m trs asus ares usa 2052 | ero | us
7
zo Ep me ms wi æe | m | m
pa
af mos,mo NR " Ne ER 194 ar
>|; ee Gone u er Gen ion | os | ete)
Median DOR, mo rango)
6 CEE oer cat = eee ln co lle
RREPITETEZETETTIT
Time, mo
1.Naio M tal. Ann Oncol 2022:39:929:98. PeerView.com
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Phase 2 LEAP-005: Lenvatinib + Pembrolizumab
for Previously Treated Biliary Cancers!
N=31 Percentage Change From Baseline in Target Lesion Size" Progression Free Surat
ORR, % (95%C!) 10(220) = men
DCR", % (95% CI) 68(49-83) 5 ES
22
= Om "Bl mamgen or |
PR 3 (10) E |
so 18 (58) we == E
PD 7 (23) ao mern “St E a R
Nonevaluable® 2(6)
No assessment” 1(3) Overall Survival
Median DOR, mo 53 = Ps
(range) (21-62) E H
In patients with advance: ncers who did not respond al |
to one prior line of therapy, lenvatinib + pembrolizumab -
demonstrated encouraging efficacy and manageable t
xicity
* Defined as best overall response of CR, PR. or SO. All rospondors had a PO-L1 CPS 21. « Patent had postoaseline imaging. and the best overall response was.
determined tobe nonevaluable per REGIST vi 1. * Paten! had no postoaseline imaging.» Paion with treatment ongong." PFS por RECIST vi. by BICR.
4. Vilanueva Letal. ASCO 2021. Abstract 4080.
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Copyright © 2000-2024, Peerview
for Previously Treated Biliary Cancers!
N=31 Percentage Change From Baseline in Target Lesion Size" Progression Free Surat
ORR, % (95%C!) 10(220) = men
DCR", % (95% CI) 68(49-83) 5 ES
22
= Om "Bl mamgen or |
PR 3 (10) E |
so 18 (58) we == E
PD 7 (23) ao mern “St E a R
Nonevaluable® 2(6)
No assessment” 1(3) Overall Survival
Median DOR, mo 53 = Ps
(range) (21-62) E H
In patients with advance: ncers who did not respond al |
to one prior line of therapy, lenvatinib + pembrolizumab -
demonstrated encouraging efficacy and manageable t
xicity
* Defined as best overall response of CR, PR. or SO. All rospondors had a PO-L1 CPS 21. « Patent had postoaseline imaging. and the best overall response was.
determined tobe nonevaluable per REGIST vi 1. * Paten! had no postoaseline imaging.» Paion with treatment ongong." PFS por RECIST vi. by BICR.
4. Vilanueva Letal. ASCO 2021. Abstract 4080.
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Phase 2 BTC-BGB: Sitravatinib + Tislelizumab
in Previously Treated Advanced BTC‘
+ Locally advanced or metastatic BTC
(IHCC, EHCC, GBC, AoV cancer)
+ Prior 1 palliative chemotherapy
Sitravatinib 120 mg PO QD +
tislelizumab 200 mg IV D1
asw
î î
(ED ED ED Lo 5
+ Atleast 1 measurable lesion
+ ECOG PS 0or 1
+ Primary objective: DCR Screening After 6 weeks At progression
+ Secondary objective: ORR, PFS, OS, DOR, and safety
1. Yoon J etl. ASCO 2024. Abstract 4018. PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
in Previously Treated Advanced BTC‘
+ Locally advanced or metastatic BTC
(IHCC, EHCC, GBC, AoV cancer)
+ Prior 1 palliative chemotherapy
Sitravatinib 120 mg PO QD +
tislelizumab 200 mg IV D1
asw
î î
(ED ED ED Lo 5
+ Atleast 1 measurable lesion
+ ECOG PS 0or 1
+ Primary objective: DCR Screening After 6 weeks At progression
+ Secondary objective: ORR, PFS, OS, DOR, and safety
1. Yoon J etl. ASCO 2024. Abstract 4018. PeerView.com
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Efficacy Results: Sitravatinib + Tislelizumab
in Previously Treated Advanced BTC‘
+ Median follow-up duration: 10.5 months (95% Cl, 7.03-15.6); death: 32 (74.4%)
+ Median cycle: 4 (range, 1-29)
ICIN:
je,n(%) ICI Treated,
= Vicios.
CR o 0 o Ken Bost response
PR 6(17.6) 2(222) 8 (18.6) x
so 167.4) 4444) 20065 É
PD 11 (624) 113) ne E
Unevaluable 1629) 222) 3m €
ITT population n=34 n=9 N=43 É
ORR (95% CI) 176(77-328) — 22249544) 18662321 $
DCR (95% Cl) TROT TEA) 6160370 E
Per-protocol population n=32 n=7 N=39
ORR (95% Cl) 188(82346) 286 (65-658) 20.5 (102-350)
DCR (95% Cl) 65.6 (51.6-82.7) 85.7(49.9-98.4) 69.2 (56.5-84.0)
1. Yoon Jet a ASCO 2024, Abstract 4018. PeerView.com
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in Previously Treated Advanced BTC‘
+ Median follow-up duration: 10.5 months (95% Cl, 7.03-15.6); death: 32 (74.4%)
+ Median cycle: 4 (range, 1-29)
ICIN:
je,n(%) ICI Treated,
= Vicios.
CR o 0 o Ken Bost response
PR 6(17.6) 2(222) 8 (18.6) x
so 167.4) 4444) 20065 É
PD 11 (624) 113) ne E
Unevaluable 1629) 222) 3m €
ITT population n=34 n=9 N=43 É
ORR (95% CI) 176(77-328) — 22249544) 18662321 $
DCR (95% Cl) TROT TEA) 6160370 E
Per-protocol population n=32 n=7 N=39
ORR (95% Cl) 188(82346) 286 (65-658) 20.5 (102-350)
DCR (95% Cl) 65.6 (51.6-82.7) 85.7(49.9-98.4) 69.2 (56.5-84.0)
1. Yoon Jet a ASCO 2024, Abstract 4018. PeerView.com
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Efficacy Results: Sitravatinib + Tislelizumab
in Previously Treated Advanced BTC’ (Cont'd)
PFS
100
Log-rank test P = 14
ICI treated: 5.83 mo
(95% CI, 4.67-N/A)
ICI naive: 4.76 mo
(95% Cl, 3.03-7.4)
o 6 12 18 24 30
Time Since Start of Treatment, mo
No. at Risk
ICinaive 34 4 5 1 o o
ICitreated 9 4 3 3 1 0
1. Yoon J etl. ASCO 2024. Abstract 401.
PeerView.com/HFK827
os
100
75
Log-rank test P= 48
=
ej 5 ICI treated: 11.9 mo
° (95% CI, 5.50-N/A)
25
ICI naive: 10.2 mo
(85% Cl, 6.87-14.7)
o
o 6 12 18 24 30
Time Since Start of Treatment, mo
No, at Risk
ICinaive 34 25 12 5 o o
ICitreated 9 6 4 4 1 o
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Copyright © 2000-2024, Peerview
in Previously Treated Advanced BTC’ (Cont'd)
PFS
100
Log-rank test P = 14
ICI treated: 5.83 mo
(95% CI, 4.67-N/A)
ICI naive: 4.76 mo
(95% Cl, 3.03-7.4)
o 6 12 18 24 30
Time Since Start of Treatment, mo
No. at Risk
ICinaive 34 4 5 1 o o
ICitreated 9 4 3 3 1 0
1. Yoon J etl. ASCO 2024. Abstract 401.
PeerView.com/HFK827
os
100
75
Log-rank test P= 48
=
ej 5 ICI treated: 11.9 mo
° (95% CI, 5.50-N/A)
25
ICI naive: 10.2 mo
(85% Cl, 6.87-14.7)
o
o 6 12 18 24 30
Time Since Start of Treatment, mo
No, at Risk
ICinaive 34 25 12 5 o o
ICitreated 9 6 4 4 1 o
PeerView.com
Copyright © 2000-2024, Peerview
Biomarker Analysis: Is There A Role for
Immunotherapy for Germline Mutations ?12
+ Definition of HRDness
ATM, ATR, BAP1 BARD1, BRCA1, BROA2, BRIP1, CDK12,
CHEK1, CHEK2, FANCL, MRE11, NBN, PALB2, RADS1,
RADS1B, RADS1C, RADS1D, RADS4L, XRCC2 r patients with a family history suggestive of BRCA1/2 mutations, consider
= ‘Dolelion, famechit; nonseneo, méfie missones raion germiine testing andlor referral to a genetic counselor
+ Sout of 27 patients (18.5%) were identified as having HRD PFS os
ORR wo 100 HR dehnt 21.13 mo
ee (95% Cl 21.1-N/A)
HR dent NR. 8
HR profeient= 8:57 mo
(95% C1, 1397-NA)
SR Cl 5. AA)
= Pa
go Log-rank est P= 018 ÿ ©
E $
Haprotient 4.67 mo
immo ‘© 188% CI. 327-723) =
spender Log rank test p= 018
o o N
o y y y à ° y y = à
usa Time Since Start of Treatment, mo nu Time Since Start of Treatment, mo
Ron 2 7 4 a 1 Mo 2 “ 7 s 1
a u: 5 4 1 De s 5 2 o
HR Dofilont HR Protect
Tissue NGS. o
PeerView.com
1. Yoon J et al ASCO 2024. Abstract 4018. 2. Samadder NJ eta. JAMA Oncol. 2021 Feb 17(2)230-237.
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Immunotherapy for Germline Mutations ?12
+ Definition of HRDness
ATM, ATR, BAP1 BARD1, BRCA1, BROA2, BRIP1, CDK12,
CHEK1, CHEK2, FANCL, MRE11, NBN, PALB2, RADS1,
RADS1B, RADS1C, RADS1D, RADS4L, XRCC2 r patients with a family history suggestive of BRCA1/2 mutations, consider
= ‘Dolelion, famechit; nonseneo, méfie missones raion germiine testing andlor referral to a genetic counselor
+ Sout of 27 patients (18.5%) were identified as having HRD PFS os
ORR wo 100 HR dehnt 21.13 mo
ee (95% Cl 21.1-N/A)
HR dent NR. 8
HR profeient= 8:57 mo
(95% C1, 1397-NA)
SR Cl 5. AA)
= Pa
go Log-rank est P= 018 ÿ ©
E $
Haprotient 4.67 mo
immo ‘© 188% CI. 327-723) =
spender Log rank test p= 018
o o N
o y y y à ° y y = à
usa Time Since Start of Treatment, mo nu Time Since Start of Treatment, mo
Ron 2 7 4 a 1 Mo 2 “ 7 s 1
a u: 5 4 1 De s 5 2 o
HR Dofilont HR Protect
Tissue NGS. o
PeerView.com
1. Yoon J et al ASCO 2024. Abstract 4018. 2. Samadder NJ eta. JAMA Oncol. 2021 Feb 17(2)230-237.
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Other Ongoing Trials With Immunotherapy’
Drug Phase NCT
Nivolumab monotherapy in the second-line setting à NCT02829918
Durvalumab + SNDX-6532 2 NCT04301778
Bispecific antibodies + standard agents 2 NCTO5775159
Durvalumab + tremelimumab + RT in the second-line setting = NCT03482102
Nivolumab + rucaparib in the second-line setting 2 NCT03639935
Durvalumab + tremelimumab + paclitaxel (IMMUNO-BIL) 2 NCT03704480
Nal-irinotecan + nivolumab in the second-line setting 1/2 NCT03785873
1. htpsinicatals. gov. PeerView.com
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Drug Phase NCT
Nivolumab monotherapy in the second-line setting à NCT02829918
Durvalumab + SNDX-6532 2 NCT04301778
Bispecific antibodies + standard agents 2 NCTO5775159
Durvalumab + tremelimumab + RT in the second-line setting = NCT03482102
Nivolumab + rucaparib in the second-line setting 2 NCT03639935
Durvalumab + tremelimumab + paclitaxel (IMMUNO-BIL) 2 NCT03704480
Nal-irinotecan + nivolumab in the second-line setting 1/2 NCT03785873
1. htpsinicatals. gov. PeerView.com
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Case Discussion: Second-Line Treatment Selection
for MSI-H/dMMR BTC
Margery presented with a history of abdominal pain, fatigue, and unintentional
weight loss
Initial workup revealed total bilirubin: 1.2 mg/dL; AST: 56 units/mL; ALT: 67 units/mL;
platelets: 105,000/meL
Imaging confirmed bilobar hepatic disease with pulmonary metastases; histopathologic
examination is consistent with cholangiocarcinoma
ECOG PS 1
Patient treated with upfront gemcitabine/cisplatin; progression after 4 months
Further evaluation reveals MSI-H/dMMR status
Given baseline testing is incomplete, what additional testing would you order?
How would you approach second-line treatment selection for this patient?
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om/HF
Copyright © 2000-2024, PeerView
for MSI-H/dMMR BTC
Margery presented with a history of abdominal pain, fatigue, and unintentional
weight loss
Initial workup revealed total bilirubin: 1.2 mg/dL; AST: 56 units/mL; ALT: 67 units/mL;
platelets: 105,000/meL
Imaging confirmed bilobar hepatic disease with pulmonary metastases; histopathologic
examination is consistent with cholangiocarcinoma
ECOG PS 1
Patient treated with upfront gemcitabine/cisplatin; progression after 4 months
Further evaluation reveals MSI-H/dMMR status
Given baseline testing is incomplete, what additional testing would you order?
How would you approach second-line treatment selection for this patient?
PeerView.com
om/HF
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Practical Strategies
When Implementing Immunotherapies
in Real-World BTC Management
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
When Implementing Immunotherapies
in Real-World BTC Management
Arndt Vogel, MD, PhD
Professor of Medicine, University of Toronto
Longo Family Chair in Liver Cancer Research
Toronto, Canada
Go online to access full CME/MOC information, including faculty disclosures.
Back to Jonathan’s Case: Toxicity Management
Considerations for Immunotherapy Regimens
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
+ IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
+ NGS: TP53, CDKN2A
+ ECOG PS 1
The patient is started on a pembrolizumab + gemcitabine/cisplatin regimen
at potential toxicities would you be preparing for with tl
Let's review the evidence
iew.com
Copyright © 2000-2024, PeerView
Considerations for Immunotherapy Regimens
Jonathan, aged 67 years, presents with a history of abdominal pain, nausea, and itchy skin
+ IHC stain was positive for CK7 and negative for CDX-2, CK20, p63, TTF-1, and NKX3.1,
favoring intrahepatic ICC
+ NGS: TP53, CDKN2A
+ ECOG PS 1
The patient is started on a pembrolizumab + gemcitabine/cisplatin regimen
at potential toxicities would you be preparing for with tl
Let's review the evidence
iew.com
Copyright © 2000-2024, PeerView
What Are the Most Common AEs of PD-1/PD-L1 Therapy?!
Encephalitis, asept meningitis.
Hypophysis.
Thyroidis, hypothyroidism,
hypentyroida
Trombocyiopenia
‘anaemia
Any organ can be affe
1. Postow MA etal N Engl J Mod, 2018:378:158-168,
PeerView.com/HFK827
dues
=D mouth, mucositis
a Ay
Lamosa
]
| Pancreatts
U autoimmune diabetes
therapy
Adverse Event
Skin changes
(eg, redness, itching)
Hypothyroidism
Hyperthyroidism
Colit
Hepatitis
Nephritis
Pneumonitis
Hypophysitis
Type 1 diabetes mellitus
Pancreatitis
Myositis
Myocarditis,
Encephalitis
ated Frequenc:
40-50
20-30
5-10
10-30
5-10
5-10
5-10
1-3
13
1-3
1-3
1-3
1-2
PeerView.com
Copyright © 2000-2024, PeerView
Encephalitis, asept meningitis.
Hypophysis.
Thyroidis, hypothyroidism,
hypentyroida
Trombocyiopenia
‘anaemia
Any organ can be affe
1. Postow MA etal N Engl J Mod, 2018:378:158-168,
PeerView.com/HFK827
dues
=D mouth, mucositis
a Ay
Lamosa
]
| Pancreatts
U autoimmune diabetes
therapy
Adverse Event
Skin changes
(eg, redness, itching)
Hypothyroidism
Hyperthyroidism
Colit
Hepatitis
Nephritis
Pneumonitis
Hypophysitis
Type 1 diabetes mellitus
Pancreatitis
Myositis
Myocarditis,
Encephalitis
ated Frequenc:
40-50
20-30
5-10
10-30
5-10
5-10
5-10
1-3
13
1-3
1-3
1-3
1-2
PeerView.com
Copyright © 2000-2024, PeerView
Patterns and Duration of Common Immune-Related AEs"
CTLA-4 Inhibitors PD-1/PD-L1 Inhibitors
3 3
8 a
3 3
Ê É
of 68 SE Dr u 50 9 4 6 8 0 2 E
Treatment Duration, wk
Treatment Duration, wk
PD-1/PD-L1 + CTLA-4 Inhibitors
Endocrinopathy
Toxicity Grade
5 on wm E
4. Mating ot al. Nat Rov Cin Oncol 2019,16:563-580. Tesatmest Duration, we
PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
CTLA-4 Inhibitors PD-1/PD-L1 Inhibitors
3 3
8 a
3 3
Ê É
of 68 SE Dr u 50 9 4 6 8 0 2 E
Treatment Duration, wk
Treatment Duration, wk
PD-1/PD-L1 + CTLA-4 Inhibitors
Endocrinopathy
Toxicity Grade
5 on wm E
4. Mating ot al. Nat Rov Cin Oncol 2019,16:563-580. Tesatmest Duration, we
PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
irAE Grading and Management!
Grade 1: minimal or no symptoms;
iagnostic changes only
+ In general, checkpoint inhibitor therapy should be
continued with close monitoring, with the exception of
some neurologic, hematologic, and cardiac toxicities
Grade 2: mild to moderate symptoms
+ Hold checkpoint inhibitor therapy for most
grade 2 toxicities
+ Consider resuming immunotherapy when symptoms
and/or laboratory values revert to grade 1 or lower
+ Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone
or equivalent) may be administered
1. NCCN Ginical Practice Guidelines in Oncology. Management of Inmunctherapy-Related Toxicies. Version 1.2024. Itpswwnccn org!
Potessionalsiphysician_glsipdtimmunotherapy pl.
PeerView.com/HFK827
Grades 3/4: severe or life-threatening symptoms
+ Grade 3 toxicities
= Hold checkpoint inhibitor therapy
= Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d
or methylprednisolone IV 1-2 mg/kg/d)
— If symptoms do not improve with 48-72 hours of
high-dose corticosteroids, infliximab may be offered for
some toxicities
— Taper corticosteroids over the course of at least
4-6 weeks
— When symptoms and/or laboratory values revert to
grade 1 or lower, rechallenging with immunotherapy may
be offered; however, caution is advised, especially in
those patients with early-onset irAEs; dose adjustments
are not recommended
+ Grade 4 toxicities
= In general, permanent discontinuation of checkpoint
inhibitor therapy is warranted, with the exception of
endocrinopathies that have been controlled by hormone
replacement
PeerView.com
Copyright © 2000-2024, PeerView
Grade 1: minimal or no symptoms;
iagnostic changes only
+ In general, checkpoint inhibitor therapy should be
continued with close monitoring, with the exception of
some neurologic, hematologic, and cardiac toxicities
Grade 2: mild to moderate symptoms
+ Hold checkpoint inhibitor therapy for most
grade 2 toxicities
+ Consider resuming immunotherapy when symptoms
and/or laboratory values revert to grade 1 or lower
+ Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone
or equivalent) may be administered
1. NCCN Ginical Practice Guidelines in Oncology. Management of Inmunctherapy-Related Toxicies. Version 1.2024. Itpswwnccn org!
Potessionalsiphysician_glsipdtimmunotherapy pl.
PeerView.com/HFK827
Grades 3/4: severe or life-threatening symptoms
+ Grade 3 toxicities
= Hold checkpoint inhibitor therapy
= Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d
or methylprednisolone IV 1-2 mg/kg/d)
— If symptoms do not improve with 48-72 hours of
high-dose corticosteroids, infliximab may be offered for
some toxicities
— Taper corticosteroids over the course of at least
4-6 weeks
— When symptoms and/or laboratory values revert to
grade 1 or lower, rechallenging with immunotherapy may
be offered; however, caution is advised, especially in
those patients with early-onset irAEs; dose adjustments
are not recommended
+ Grade 4 toxicities
= In general, permanent discontinuation of checkpoint
inhibitor therapy is warranted, with the exception of
endocrinopathies that have been controlled by hormone
replacement
PeerView.com
Copyright © 2000-2024, PeerView
Case Discussion: Toxicity Management
Considerations for Immunotherapy Regimens
Jonathan, aged 67 years, presents with a history of abdominal pain, iscussi
nausea, and itchy skin
How should the care team manage the
diarrhea in this patient?
Initial workup revealed CA 19-9 of 20; albumin: 4.0; total bilirubin: 0.5; BUN
creatinine: 0.72; WBC 3.5; Hg/Hct: 11.8/36.4; platelets: 170,000
CT scan showed multiple liver masses, with the largest measuring 7 x 6.4 WhatotnarwAEeshound the eae tear
em in the right hepatic lobe, and multiple enlarged periaortic Iympt be prepared lo snonkoriiianage Wen
Ultrasound-quided liver mass biopsy showed poorly differentiated integrating immunotherapy regimens?
isplatin
tient is started on a pembrolizumab + gemcitabine
regimen
PeerView.com
Copyright © 2000-2024, PeerView
PeerView.com/HFK827
Considerations for Immunotherapy Regimens
Jonathan, aged 67 years, presents with a history of abdominal pain, iscussi
nausea, and itchy skin
How should the care team manage the
diarrhea in this patient?
Initial workup revealed CA 19-9 of 20; albumin: 4.0; total bilirubin: 0.5; BUN
creatinine: 0.72; WBC 3.5; Hg/Hct: 11.8/36.4; platelets: 170,000
CT scan showed multiple liver masses, with the largest measuring 7 x 6.4 WhatotnarwAEeshound the eae tear
em in the right hepatic lobe, and multiple enlarged periaortic Iympt be prepared lo snonkoriiianage Wen
Ultrasound-quided liver mass biopsy showed poorly differentiated integrating immunotherapy regimens?
isplatin
tient is started on a pembrolizumab + gemcitabine
regimen
PeerView.com
Copyright © 2000-2024, PeerView
PeerView.com/HFK827
Conclusions
+ Immune checkpoint inhibitors have shown promising activity as monotherapy or
in combinations, which are being validated in additional clinical studies
+ Chemoimmunotherapy is the preferred primary treatment choice for unresectable and
metastatic BTCs, as supported by the phase 3 TOPAZ-1 and KEYNOTE-966 trials
+ Biliary cancers are genetically heterogeneous, with many potentially targetable
genetic alterations
+ Immune-based therapy remains investigational in the 2L setting (with the exception of
pembrolizumab for MSI-H/dMMR tumors)
+ Participating in a clinical trial is highly encouraged to identify effective treatment
for patients with biliary cancers
+ The next cohort of trials will include bispecific antibodies and CAR-T therapies as new
potential treatment options
PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
+ Immune checkpoint inhibitors have shown promising activity as monotherapy or
in combinations, which are being validated in additional clinical studies
+ Chemoimmunotherapy is the preferred primary treatment choice for unresectable and
metastatic BTCs, as supported by the phase 3 TOPAZ-1 and KEYNOTE-966 trials
+ Biliary cancers are genetically heterogeneous, with many potentially targetable
genetic alterations
+ Immune-based therapy remains investigational in the 2L setting (with the exception of
pembrolizumab for MSI-H/dMMR tumors)
+ Participating in a clinical trial is highly encouraged to identify effective treatment
for patients with biliary cancers
+ The next cohort of trials will include bispecific antibodies and CAR-T therapies as new
potential treatment options
PeerView.com
PeerView.com/HFK827 Copyright © 2000-2024, PeerView
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