Precision Tactics in HER2-Positive GI Malignancies: Capitalizing on HER2-Targeted Regimens to Improve Outcomes for Gastric/GEJ Cancers, CRC, and BTC
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Jun 19, 2024
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About This Presentation
Chair and Presenters, Yelena Y. Janjigian*, MD, Shubham Pant, MD, and John Strickler, MD, discuss HER2+ GI malignancies in this CME/MOC/NCPD/AAPA/IPCE activity titled “Precision Tactics in HER2-Positive GI Malignancies: Capitalizing on HER2-Targeted Regimens to Improve Outcomes for Gastric/GEJ Can...
Slide Content
Precision Tactics in HER2-Positive
Gl Malignancies
Capitalizing on HER2-Targeted Regimens to Improve
Outcomes for Gastric/GEJ Cancers, CRC, and BTC
Yelena Y. Janjigian", MD John Strickler, MD Shubham Pant, MD
Professor, and Chief Associate Professor of Medicine Professor
Attending, Gastrointestinal ‘Associate Director Department of Gastrointestinal
‘Oncology Service of Clinical Research - Gl Medical Oncology
Department of Medicine Duke University Department of Investigational
Memorial Sloan Kettering {8 Durham, North Carolina Y Cancer Therapeutics
Cancer Center E2 The University of Texas
New York, New York MD Anderson Cancer Center
Houston, Texas
“This actviy was developed with Yelena Y. Janigian, MO, and is not
affiated in any capacity with Memorial Sloan Kettering Cancer Center
Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Gl Malignancies
Capitalizing on HER2-Targeted Regimens to Improve
Outcomes for Gastric/GEJ Cancers, CRC, and BTC
Yelena Y. Janjigian", MD John Strickler, MD Shubham Pant, MD
Professor, and Chief Associate Professor of Medicine Professor
Attending, Gastrointestinal ‘Associate Director Department of Gastrointestinal
‘Oncology Service of Clinical Research - Gl Medical Oncology
Department of Medicine Duke University Department of Investigational
Memorial Sloan Kettering {8 Durham, North Carolina Y Cancer Therapeutics
Cancer Center E2 The University of Texas
New York, New York MD Anderson Cancer Center
Houston, Texas
“This actviy was developed with Yelena Y. Janigian, MO, and is not
affiated in any capacity with Memorial Sloan Kettering Cancer Center
Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Our Goals for Today
Improve your understanding of the biologic rationale for therapeutic
targeting of HER2 aberrations and the latest evidence supporting biomarker
testing and HER2-targeted therapies
Equip you with skills to implement personalized, team-driven treatment
plans with HER2-targeted therapies based on safety/efficacy evidence,
guideline recommendations, and patient-specific needs
Provide you with tools to address practical aspects of care when utilizing
HER2-targeted regimens, including managing adverse events, coordinating
care, and educating and engaging patients
Copyright © 2000-2024, Peerview
Improve your understanding of the biologic rationale for therapeutic
targeting of HER2 aberrations and the latest evidence supporting biomarker
testing and HER2-targeted therapies
Equip you with skills to implement personalized, team-driven treatment
plans with HER2-targeted therapies based on safety/efficacy evidence,
guideline recommendations, and patient-specific needs
Provide you with tools to address practical aspects of care when utilizing
HER2-targeted regimens, including managing adverse events, coordinating
care, and educating and engaging patients
Copyright © 2000-2024, Peerview
The Cholangiocarcinoma Foundation Is an Excellent
Resource for Professionals, Patients, and Caregivers?
The Cholangiocarcinoma Foundation’s ([email protected]) mission is to find a
cure and improve the quality of life for those affected by cholangiocarcinoma (bile duct cancer)
Visit https://cholangiocarcinoma.org/ for multiple Selected resources include
resources that patients can use to MG International Cholangiocarcinoma
Get the latest information about their disease a Patient Registry (ICPR)
Connect with other patients „rm LE
feaistry/
Participate in clinical trials,
And much more A os pe
ee Find a Specialist
h hlios/cholangiocarcinoma org/specialist map!
Find and Learn About Clinical Trials
Ichol reiner roe ie
fesearchielinical-trials/
wwebina series =
“in supa l moving patent cae is cy has bean lanes an inpamented y PU, Poe Isa Mia Education, x
and ie Cholangiocarinoma Fou PeerView.com
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Resource for Professionals, Patients, and Caregivers?
The Cholangiocarcinoma Foundation’s ([email protected]) mission is to find a
cure and improve the quality of life for those affected by cholangiocarcinoma (bile duct cancer)
Visit https://cholangiocarcinoma.org/ for multiple Selected resources include
resources that patients can use to MG International Cholangiocarcinoma
Get the latest information about their disease a Patient Registry (ICPR)
Connect with other patients „rm LE
feaistry/
Participate in clinical trials,
And much more A os pe
ee Find a Specialist
h hlios/cholangiocarcinoma org/specialist map!
Find and Learn About Clinical Trials
Ichol reiner roe ie
fesearchielinical-trials/
wwebina series =
“in supa l moving patent cae is cy has bean lanes an inpamented y PU, Poe Isa Mia Education, x
and ie Cholangiocarinoma Fou PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Colorectal Cancer Alliance Resources
to Share With Patients
colorectal
cancer
alliance
blueH@, ar RED
The Colorectal Cancer Alliance empowers a nation of passionate and determined allies to prevent, treat,
and overcome colorectal cancer in their lives and communities. Please visit the QR codes below and on
our downloadable practice aid for more information on valuable resources for patients and caregivers
’
Patient navigation/Helpline
a Clinical trials and CRC
Take our free screening quiz
PeerView.com/JPD827
PeerView.com
Copyright © 2000-2024, PeerView
to Share With Patients
colorectal
cancer
alliance
blueH@, ar RED
The Colorectal Cancer Alliance empowers a nation of passionate and determined allies to prevent, treat,
and overcome colorectal cancer in their lives and communities. Please visit the QR codes below and on
our downloadable practice aid for more information on valuable resources for patients and caregivers
’
Patient navigation/Helpline
a Clinical trials and CRC
Take our free screening quiz
PeerView.com/JPD827
PeerView.com
Copyright © 2000-2024, PeerView
Welcome and Introduction
The Critical Need for Personalized Care
in GI Cancers
Yelena Y. Janjigian*, MD
Professor, and Chief Attending, Gastrointestinal Oncology Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
fe
* This activity was developed with Yelena Y. Janjigian,
MD, and is not affiliated in any capacity with Memorial
Sloan Kettering Cancer Center.
Copyright © 2000-2024, PeerView
The Critical Need for Personalized Care
in GI Cancers
Yelena Y. Janjigian*, MD
Professor, and Chief Attending, Gastrointestinal Oncology Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
fe
* This activity was developed with Yelena Y. Janjigian,
MD, and is not affiliated in any capacity with Memorial
Sloan Kettering Cancer Center.
Copyright © 2000-2024, PeerView
HER2 Aberrations:
Clinical Role and Frequency Across Tumor Types!
+ HER2 is an established therapeutic =, =... M.
target found across a variety of
solid tumors
+ Recognized as an agnostic "zn =e ES
biomarker with pan-tumor = ESE
approvals EEE _
+ _A number of novel HER2-targeted = ==
therapies are being evaluated _ EE
in Gl cancers EEE a
— Expanding role highlights the Uterus L MS
need for broader HER2 testing E \L - HOZ
Cen prostate
En Be « <
1. Oh D-Y, Bang Y-J. Nat Rev Clin Oncol. 2020:17:33-48. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Clinical Role and Frequency Across Tumor Types!
+ HER2 is an established therapeutic =, =... M.
target found across a variety of
solid tumors
+ Recognized as an agnostic "zn =e ES
biomarker with pan-tumor = ESE
approvals EEE _
+ _A number of novel HER2-targeted = ==
therapies are being evaluated _ EE
in Gl cancers EEE a
— Expanding role highlights the Uterus L MS
need for broader HER2 testing E \L - HOZ
Cen prostate
En Be « <
1. Oh D-Y, Bang Y-J. Nat Rev Clin Oncol. 2020:17:33-48. PeerView.com
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Understanding Real-World Evidence:
Unmet Needs in HER2+ Gl Cancers Can Be Addressed’
846):
Netherlands Cancer Registry and Dutch Pathology Registry (N
HER2 Testing Has Increased Over Time
* HER? assessment increased from 10] malpeients mEsophagus =GEucaria Narcan stomach
+ Median OS increased from H 80
6.9 (2010-2013) to 7.9 months 4 70
(2014-2016) = 8
+ Overall, 77% of the HER2+ patients 3 2°
received trastuzumab E =
+ Median OS was higher in patients FA 20
with positive (8.8 months) and =
negative (7.4 months) HER2 status A
compared with untested patients 2010-2012 2013-2014 2015-2016
(5.6 months) Time Since Diagnosis, y
HERZ testing and appropriate treatment can make a difference
+ Percentages within the bars efect he proportion of patients with tumors hat showed HER? overexpression gi
1. Diksterhuis WPM et al. Gastne Cancer. 2020.23:579-590. PeerView.com
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Unmet Needs in HER2+ Gl Cancers Can Be Addressed’
846):
Netherlands Cancer Registry and Dutch Pathology Registry (N
HER2 Testing Has Increased Over Time
* HER? assessment increased from 10] malpeients mEsophagus =GEucaria Narcan stomach
+ Median OS increased from H 80
6.9 (2010-2013) to 7.9 months 4 70
(2014-2016) = 8
+ Overall, 77% of the HER2+ patients 3 2°
received trastuzumab E =
+ Median OS was higher in patients FA 20
with positive (8.8 months) and =
negative (7.4 months) HER2 status A
compared with untested patients 2010-2012 2013-2014 2015-2016
(5.6 months) Time Since Diagnosis, y
HERZ testing and appropriate treatment can make a difference
+ Percentages within the bars efect he proportion of patients with tumors hat showed HER? overexpression gi
1. Diksterhuis WPM et al. Gastne Cancer. 2020.23:579-590. PeerView.com
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ERBB Family: Targeting HER2 and HER312
+ Human epidermal growth factor
receptor (HER) family includes
— Epidermal growth factor
receptor (EGFR)
— HER2 (ERBB2)
— HER3 (ERBB3)
— HER4 (ERBB4)
+ Share common structural features
Aberrantly activated in multiple cancers
+ Serves as drug targets and biomarkers RS
for precision oncology Nucleus
1. Adapted trom Ross JS. Drug News Perspect 2009.22.93-106. 2. Adapted from Reinholz MM ot al. Lancet Oncol. 2009:10:267-277. PeerView.com
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+ Human epidermal growth factor
receptor (HER) family includes
— Epidermal growth factor
receptor (EGFR)
— HER2 (ERBB2)
— HER3 (ERBB3)
— HER4 (ERBB4)
+ Share common structural features
Aberrantly activated in multiple cancers
+ Serves as drug targets and biomarkers RS
for precision oncology Nucleus
1. Adapted trom Ross JS. Drug News Perspect 2009.22.93-106. 2. Adapted from Reinholz MM ot al. Lancet Oncol. 2009:10:267-277. PeerView.com
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Mechanisms of Action of Agents Targeting HER21
Bispecific antibodies
Single-epitope
mAbs
1. Oh DY, Bang Y3. Nat Rev Clin Oncol. 2020:17:3348. PeerView.com
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Bispecific antibodies
Single-epitope
mAbs
1. Oh DY, Bang Y3. Nat Rev Clin Oncol. 2020:17:3348. PeerView.com
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Strengthening Precision Care
in Gastric/GEJ Cancers
Modern Strategies With Targeted Therapies
in HER2+ Disease
Yelena Y. Janjigian*, MD
Professor, and Chief Attending, Gastrointestinal Oncology Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
* This activity was developed with Yelena Y. Janjigian,
MD, and is not affiliated in any capacity with Memorial
Sloan Kettering Cancer Center.
Copyright © 2000-2024, PeerView
in Gastric/GEJ Cancers
Modern Strategies With Targeted Therapies
in HER2+ Disease
Yelena Y. Janjigian*, MD
Professor, and Chief Attending, Gastrointestinal Oncology Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
* This activity was developed with Yelena Y. Janjigian,
MD, and is not affiliated in any capacity with Memorial
Sloan Kettering Cancer Center.
Copyright © 2000-2024, PeerView
Understanding Real-World Evidence (United States):
Unmet Needs in Current Practice and Focus on HER212
Electronic Health Records Data From 2011-2018
(N = 3,291 patients with advanced/metastatic gastric/GEJ adenocarcinoma)
Workup + One-third (34%) of patients were not tested for HER2 status |
First-Line
Treatment
25% of patients did not receive treatment after diagnosis
Only 58% of HER2+ patients received trastuzumab in the first line
Approximately half of patients received 2L therapy
Less than 20% of patients received 3L therapy
In the 2L, chemotherapy-based regimens remained more frequently used
Initiation of 2L targeted therapy is often delayed from the time of
progression in community oncology practices
Second-Line
Treatment
and Beyond
1. Le DT etal. Gin Colorectal Cancer. 2020:19:32:38.03.2. Bray Fetal. CA Cancer J Cn, 2018,68:394-424 PeerView.com
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Unmet Needs in Current Practice and Focus on HER212
Electronic Health Records Data From 2011-2018
(N = 3,291 patients with advanced/metastatic gastric/GEJ adenocarcinoma)
Workup + One-third (34%) of patients were not tested for HER2 status |
First-Line
Treatment
25% of patients did not receive treatment after diagnosis
Only 58% of HER2+ patients received trastuzumab in the first line
Approximately half of patients received 2L therapy
Less than 20% of patients received 3L therapy
In the 2L, chemotherapy-based regimens remained more frequently used
Initiation of 2L targeted therapy is often delayed from the time of
progression in community oncology practices
Second-Line
Treatment
and Beyond
1. Le DT etal. Gin Colorectal Cancer. 2020:19:32:38.03.2. Bray Fetal. CA Cancer J Cn, 2018,68:394-424 PeerView.com
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Assessment of HER2 Status in Gastric/GEJ Cancer!”
Compared with breast carcinomas,
in gastric/GEJ cancer Tumor heterogeneity Incomplete membrane
is more comm g C is more
+ The heterogeneity of immunostaining is greater
+ The possibility of false-negative testing is higher
— Analyzing HER2 in <6 biopsy samples
leads to a false-negative rate as high
as 9%
+ HER2 protein expression is absent in the
digestive luminal membrane > membrane
staining that is not completely circumferential
(basolateral pattern)
These differences underscore the importance of using gastric/GEJ-specific
criteria to assess HER2 expression in clinical practice
ia Ann Oncol 201324728193. 5, Abarelo L ot al. Adv Anat Pathol 2011.18:59, 6. Holmann M
Gm MA et al paid 201129 022.992 Les HE tal uJ Cone 201349. ABUS. 3 Park SR tl Eu Cane 2010514250. 4 Warne VS
ai Histopathology 2008 ñ
7. Rüschoff Jet a. Virchows Arch. 2010:457:299-307. PeerView.com
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Compared with breast carcinomas,
in gastric/GEJ cancer Tumor heterogeneity Incomplete membrane
is more comm g C is more
+ The heterogeneity of immunostaining is greater
+ The possibility of false-negative testing is higher
— Analyzing HER2 in <6 biopsy samples
leads to a false-negative rate as high
as 9%
+ HER2 protein expression is absent in the
digestive luminal membrane > membrane
staining that is not completely circumferential
(basolateral pattern)
These differences underscore the importance of using gastric/GEJ-specific
criteria to assess HER2 expression in clinical practice
ia Ann Oncol 201324728193. 5, Abarelo L ot al. Adv Anat Pathol 2011.18:59, 6. Holmann M
Gm MA et al paid 201129 022.992 Les HE tal uJ Cone 201349. ABUS. 3 Park SR tl Eu Cane 2010514250. 4 Warne VS
ai Histopathology 2008 ñ
7. Rüschoff Jet a. Virchows Arch. 2010:457:299-307. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
HER2 Testing in Gastric/GEJ Cancer
+ Who should be tested for HER2 overexpression?
+ When should HER2 testing take place?
Guideline
ESMO! Japan’ ASC NCCN*
aies À Forall patients with
— gastric/GEJ cancer at
Who? For all patients wah and potential diagnosis if metastatic
metastatic gastric/GEJ cancer candidates for y
KErotmgeied disease is documented or
‘suspected
therapy
+ Atdiagnosis
+ Repeat biomarker testing
bons may be considered at
When? At diagnosis At diagnosis ee
progression of advanced
or metastatic disease
4. Lori F et a. Ann Oncol 2022:38:1005-1020.2. Japanese Gastric Cancer Association. Gastric Cancer 2021;24:1-21. 3. Barley AN etal J Cin Oncol
2017.35.448-484. 4. Ajani JA otal. J Nol! Compr Cane Nat. 2022.20-167-192.
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+ Who should be tested for HER2 overexpression?
+ When should HER2 testing take place?
Guideline
ESMO! Japan’ ASC NCCN*
aies À Forall patients with
— gastric/GEJ cancer at
Who? For all patients wah and potential diagnosis if metastatic
metastatic gastric/GEJ cancer candidates for y
KErotmgeied disease is documented or
‘suspected
therapy
+ Atdiagnosis
+ Repeat biomarker testing
bons may be considered at
When? At diagnosis At diagnosis ee
progression of advanced
or metastatic disease
4. Lori F et a. Ann Oncol 2022:38:1005-1020.2. Japanese Gastric Cancer Association. Gastric Cancer 2021;24:1-21. 3. Barley AN etal J Cin Oncol
2017.35.448-484. 4. Ajani JA otal. J Nol! Compr Cane Nat. 2022.20-167-192.
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Current Treatment Algorithm’
+ Treatment of advanced gastroesophageal cancer
+ Molecular stratification according to HER2 status
IHC score 0/1 IHC score 2 IHC score 3
ISH test HER2
Platinum- Platinum-
fluoropyrimidine + fluoropyrimidine +
docetaxel trastuzumab
1. Adapted from LordckF. Nat Rev Clin Oncol 2016:13:248-360. PeerView.com
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+ Treatment of advanced gastroesophageal cancer
+ Molecular stratification according to HER2 status
IHC score 0/1 IHC score 2 IHC score 3
ISH test HER2
Platinum- Platinum-
fluoropyrimidine + fluoropyrimidine +
docetaxel trastuzumab
1. Adapted from LordckF. Nat Rev Clin Oncol 2016:13:248-360. PeerView.com
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Progress in Validating HER2-Directed
Agent
Trastuzumab
Trastuzumab +
pembrolizumab
Trastuzumab
deruxtecan (T-DXd)
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Regulatory Stat
Approved in the
United States and
European Union
Approved in the
United States and
European Union
Approved in the
United States, European
Union, and Japan
Therapy in Gastric/GEJ Cancers
Indicated for Patients Wi
HER2-overexpressing metastatic
gastric/GEJ cancers
PD-L1-positive HER2-expressing
gastric/GEJ cancers
Locally advanced or metastatic HER2+
gastric/GEJ adenocarcinoma who have
received a prior trastuzumab-based regimen
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Agent
Trastuzumab
Trastuzumab +
pembrolizumab
Trastuzumab
deruxtecan (T-DXd)
PeerView.com/JPD827
Regulatory Stat
Approved in the
United States and
European Union
Approved in the
United States and
European Union
Approved in the
United States, European
Union, and Japan
Therapy in Gastric/GEJ Cancers
Indicated for Patients Wi
HER2-overexpressing metastatic
gastric/GEJ cancers
PD-L1-positive HER2-expressing
gastric/GEJ cancers
Locally advanced or metastatic HER2+
gastric/GEJ adenocarcinoma who have
received a prior trastuzumab-based regimen
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Phase 3 ToGA Study: Chemotherapy + Trastuzumab
as 1L Therapy in HER2+ mGC/GEJC!
+ 594 patients randomly — Events Median OS, mo
assigned to chemotherapy Sano 2 ne
ta A motherapy alone Ë
(fluoropyrimidine + platinum) 10 x
HR (95% Cl): 0.74 (0.60-0.91)
P= .0046
with or without trastuzumab
2 08
+ Significant improvement in OS 3
in HER2+ mGC with addition 2 °°
of trastuzumab to 304 estee netas
chemotherapy led to approval E 02
in many countries m
o 13.8_ Chemotherapy alone
0 24 6 8 10 12 14 16 18 20 22 24 26 28 32 34 36
Time, mo
1. Bang YJ et al. Lancet. 2010:376:687-697. PeerView.com
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as 1L Therapy in HER2+ mGC/GEJC!
+ 594 patients randomly — Events Median OS, mo
assigned to chemotherapy Sano 2 ne
ta A motherapy alone Ë
(fluoropyrimidine + platinum) 10 x
HR (95% Cl): 0.74 (0.60-0.91)
P= .0046
with or without trastuzumab
2 08
+ Significant improvement in OS 3
in HER2+ mGC with addition 2 °°
of trastuzumab to 304 estee netas
chemotherapy led to approval E 02
in many countries m
o 13.8_ Chemotherapy alone
0 24 6 8 10 12 14 16 18 20 22 24 26 28 32 34 36
Time, mo
1. Bang YJ et al. Lancet. 2010:376:687-697. PeerView.com
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ToGA: HER2 Subgroup Analysis!
+ OS benefit of trastuzumab appeared to vary by HER2 subgroup (best for HER2
IHC 3+ and ERBB2 amplification)
Rose en Net, Media OS, on cu
All a > Gal 1 074 Te Tree uzuman
w 60-0.
Preplanned exploratory analysis Regulatory Approvals
IHC O/FISH positive HA 61 10.6 vs 7.2 0.92 (0.48-1.76) N :
IHC 1+/FISH positive HH 70 87vs102 1.24 (0.70-2.20) * United States: IHC 3+
IHC 2+/FISH positive oe 159 — 12.3vs 10.8 0.75 (0.51-1.11) and/or FISH+ tumors
IHC 3+/FISH positive ea 256 1795123 0.58(0.41-0.81) (2010)
IHC 3+/FISH negative -———}—415_47.5 vs 17.7 0.83 (0.20-3.38)
Post hoc exploratory analysis Europe: IHC 2+/FISH+
IHC 0 or 1+/FISH positive He 131 10vs87 1.07 (0.70-1.62) or IHC 3+ (2022)
IHC 2+/FISH positive or IHC 3+ Hg 446 16vs118 0.65 (0.51-0.83) AS
02 0406 1 2 345
Favors Trastuzumab + Chemotherapy Favors Chemotherapy Alone
1. Bang Y-J etal. Lancet. 2010; 76:687-697. PeerView.com
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+ OS benefit of trastuzumab appeared to vary by HER2 subgroup (best for HER2
IHC 3+ and ERBB2 amplification)
Rose en Net, Media OS, on cu
All a > Gal 1 074 Te Tree uzuman
w 60-0.
Preplanned exploratory analysis Regulatory Approvals
IHC O/FISH positive HA 61 10.6 vs 7.2 0.92 (0.48-1.76) N :
IHC 1+/FISH positive HH 70 87vs102 1.24 (0.70-2.20) * United States: IHC 3+
IHC 2+/FISH positive oe 159 — 12.3vs 10.8 0.75 (0.51-1.11) and/or FISH+ tumors
IHC 3+/FISH positive ea 256 1795123 0.58(0.41-0.81) (2010)
IHC 3+/FISH negative -———}—415_47.5 vs 17.7 0.83 (0.20-3.38)
Post hoc exploratory analysis Europe: IHC 2+/FISH+
IHC 0 or 1+/FISH positive He 131 10vs87 1.07 (0.70-1.62) or IHC 3+ (2022)
IHC 2+/FISH positive or IHC 3+ Hg 446 16vs118 0.65 (0.51-0.83) AS
02 0406 1 2 345
Favors Trastuzumab + Chemotherapy Favors Chemotherapy Alone
1. Bang Y-J etal. Lancet. 2010; 76:687-697. PeerView.com
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KEYNOTE-811: Pembrolizumab + Trastuzumab +
Chemotherapy for 1L Treatment of HER2+ mGC':2
+ Randomized, double-blind, placebo-controlled phase 3 study
Stratified by geographic region, PD-L1 CPS,
chemotherapy choice
Patients with
Pembrolizumab 200 mg IV Q3W +
HER2+ advanced trastuzumab 6 mg/kg IV Q3W + wor
gastric or GEJ FP or CAPOX® progression,
adenocarcinoma, 2
no prior therapy in Placebo | er
e trast b 6 mg/kg IV Q3W + ea
advanced setting rastuzumab 6 mg/kg ‘withdrawal
FP or CAPOX:
FP: S.fluorouracil 800 mg/m? IV days 1-5 Q3W + cisplatin 80 mg/m? IV Q3W
CAPOX: capecitabine 1,000 mg/m? BID days 1-14 Q3W + oxaliplatin 130 mg/m? IV GW
(N = 692)
+ Primary endpoints: OS and PFS per RECIST v1.1 by BICR
+ Secondary endpoints: ORR and DOR per RECIST v1.1 by BICR, safety
* Trastuzumab 8 mg/kg loading dose. ñ
1 Janjgin Y Nature 2021:600:727-730. PeerView.com
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Chemotherapy for 1L Treatment of HER2+ mGC':2
+ Randomized, double-blind, placebo-controlled phase 3 study
Stratified by geographic region, PD-L1 CPS,
chemotherapy choice
Patients with
Pembrolizumab 200 mg IV Q3W +
HER2+ advanced trastuzumab 6 mg/kg IV Q3W + wor
gastric or GEJ FP or CAPOX® progression,
adenocarcinoma, 2
no prior therapy in Placebo | er
e trast b 6 mg/kg IV Q3W + ea
advanced setting rastuzumab 6 mg/kg ‘withdrawal
FP or CAPOX:
FP: S.fluorouracil 800 mg/m? IV days 1-5 Q3W + cisplatin 80 mg/m? IV Q3W
CAPOX: capecitabine 1,000 mg/m? BID days 1-14 Q3W + oxaliplatin 130 mg/m? IV GW
(N = 692)
+ Primary endpoints: OS and PFS per RECIST v1.1 by BICR
+ Secondary endpoints: ORR and DOR per RECIST v1.1 by BICR, safety
* Trastuzumab 8 mg/kg loading dose. ñ
1 Janjgin Y Nature 2021:600:727-730. PeerView.com
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KEYNOTE-811: Pembrolizumab + Trastuzumab +
Chemotherapy for 1L Treatment of HER2+ mGC Efficacy’
Efficacy Population
Outcome: Pembrolizumab Placebo
(n= 133) (n = 131)
ORR, % (95% Cl) 74.4 (66.2-81.6) 51.9 (43.0-60.7)
ORR difference 22.7 (11.2-33.7); P = .00006
DCR, % (95% CI) 96.2 (91.4-98.8) 89.3 (82.7-94.0)
Best response, n (%)
CR 15 (11) 46)
PR 84 (63) 64 (49)
SD 29 (22) 49 (87)
PD 5(4) 76)
Not evaluable 0 2(2)
Not assessed 0 5(4)
Duration of response n=99 n=68
Median, mo (range) 10.6 (1.1+ to 16.5+) 9.5 (1.4+ to 15.4+)
26 mo duration, % 703 614
29 mo duration, % 58.4 511
| _ FDA approved May 2021 |
* Eficacy analysis: st 264 patents enroled; satty analysis: 433 paints who received 21 dose ol study medication. N
4. Janjgian Ÿ. Natur. 2021:800.727-790. PeerView.com
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Chemotherapy for 1L Treatment of HER2+ mGC Efficacy’
Efficacy Population
Outcome: Pembrolizumab Placebo
(n= 133) (n = 131)
ORR, % (95% Cl) 74.4 (66.2-81.6) 51.9 (43.0-60.7)
ORR difference 22.7 (11.2-33.7); P = .00006
DCR, % (95% CI) 96.2 (91.4-98.8) 89.3 (82.7-94.0)
Best response, n (%)
CR 15 (11) 46)
PR 84 (63) 64 (49)
SD 29 (22) 49 (87)
PD 5(4) 76)
Not evaluable 0 2(2)
Not assessed 0 5(4)
Duration of response n=99 n=68
Median, mo (range) 10.6 (1.1+ to 16.5+) 9.5 (1.4+ to 15.4+)
26 mo duration, % 703 614
29 mo duration, % 58.4 511
| _ FDA approved May 2021 |
* Eficacy analysis: st 264 patents enroled; satty analysis: 433 paints who received 21 dose ol study medication. N
4. Janjgian Ÿ. Natur. 2021:800.727-790. PeerView.com
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Key Efficacy Data From KEYNOTE-811'
All Patients PD-L1 CPS 21
ato! Pembrolitumab Placebo N Pembrolizumab Placebo
pee Modan PFS, mo 10 81 où Modan PFS, mo 108 72
(5% C1) CE) 7085) wc) (85-125) (6834)
po ee
70 70
æ 60 2 60
g 50 g 50
E 40 & 40
30 Pembrolizumab 30 Cited
20 20
10 10
o o
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 1215 18 21 24 27 30 33 36 39 42
PA Time, mo Rd Time, mo
Pembro 350 206 234 171 129 90 65 50 42 34 26 14 5 2 0 Pembro 298 250 200 150 116 84 61 48 40 33 26 14 5 2 0
Placebo 348 273 183 120 90 66 47 32 26 19 13 7 3 1 0 Placebo 296 231 150 98 76 54 38 24 20 15 12 6 3 1 0
EDA approval amended only for tumors with PD-L1 CP:
In a subgroup analysis for PD-L1 CPS <1 (N= 104), the HR for OS and PFS were
1.41 (95% Cl, 0.90-2.20) and 1.03 (95% Cl, 0.65-1.64), respectively?
1. Janjian Y ot al Lancat.2023:402:2197-2208, 2. mps ww Ida govidrugs/resources-nfrmation approved drugsda-amends-pembrokzumabs-gastc-cancet- A
indication. PeerView.com
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All Patients PD-L1 CPS 21
ato! Pembrolitumab Placebo N Pembrolizumab Placebo
pee Modan PFS, mo 10 81 où Modan PFS, mo 108 72
(5% C1) CE) 7085) wc) (85-125) (6834)
po ee
70 70
æ 60 2 60
g 50 g 50
E 40 & 40
30 Pembrolizumab 30 Cited
20 20
10 10
o o
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 1215 18 21 24 27 30 33 36 39 42
PA Time, mo Rd Time, mo
Pembro 350 206 234 171 129 90 65 50 42 34 26 14 5 2 0 Pembro 298 250 200 150 116 84 61 48 40 33 26 14 5 2 0
Placebo 348 273 183 120 90 66 47 32 26 19 13 7 3 1 0 Placebo 296 231 150 98 76 54 38 24 20 15 12 6 3 1 0
EDA approval amended only for tumors with PD-L1 CP:
In a subgroup analysis for PD-L1 CPS <1 (N= 104), the HR for OS and PFS were
1.41 (95% Cl, 0.90-2.20) and 1.03 (95% Cl, 0.65-1.64), respectively?
1. Janjian Y ot al Lancat.2023:402:2197-2208, 2. mps ww Ida govidrugs/resources-nfrmation approved drugsda-amends-pembrokzumabs-gastc-cancet- A
indication. PeerView.com
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KEYNOTE-811: Antitumor Response on Pembrolizumab +
Trastuzumab + Chemotherapy!
* 80
y
Change From Basel
8
8
1.Janigia Y et a. Lancot 2023:402:2107:2208.
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Best Response, n (%)
Pembro Placebo Pembro Placebo
(n= 350) (n= 348) ee (n=350) (n=348)
58(17) 39 (11) ORR, % (95% CI) 73 (68-77) 60 (55-65)
196 (56) 170 (49)
DCR, % (95% Cl) 92 (88-94) 87 (63-91)
67 (19) 95 (27)
19(5) 20 DOR, median 13 95
REN =) (ange), mo (144104974) — (14+10487+)
Pembro Placebo
Change From Bas
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Trastuzumab + Chemotherapy!
* 80
y
Change From Basel
8
8
1.Janigia Y et a. Lancot 2023:402:2107:2208.
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Best Response, n (%)
Pembro Placebo Pembro Placebo
(n= 350) (n= 348) ee (n=350) (n=348)
58(17) 39 (11) ORR, % (95% CI) 73 (68-77) 60 (55-65)
196 (56) 170 (49)
DCR, % (95% Cl) 92 (88-94) 87 (63-91)
67 (19) 95 (27)
19(5) 20 DOR, median 13 95
REN =) (ange), mo (144104974) — (14+10487+)
Pembro Placebo
Change From Bas
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Intrinsic Trastuzumab Resistance in ERBB2+
Gastroesophageal Cancer!
« 30% of HER2+ tumors lacked ERBB2 amplification or had comutations of the
RTK/RAS/PI3K pathway
— These patients had rapid progression on trastuzumab
P=58409
ERBB2+ top quere ot
‘expression (n= 13)
HR (CI) Longer PFS Shorter PFS P
137 (84-601 HJ er
22301140) Ha 9
020209 EH 02
0 5 10 15 2 2
1. Janjgian YY et al. Cancer Discov. 2018:8:49-58
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02 05 1 2 5 10 20 50
Time, mo
IM. ERBE2+ top quarto of expression ( = 13)
IM ERDER+/aterod RTHRASPIK (n= 9)
WERDER. (n= 4)
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Gastroesophageal Cancer!
« 30% of HER2+ tumors lacked ERBB2 amplification or had comutations of the
RTK/RAS/PI3K pathway
— These patients had rapid progression on trastuzumab
P=58409
ERBB2+ top quere ot
‘expression (n= 13)
HR (CI) Longer PFS Shorter PFS P
137 (84-601 HJ er
22301140) Ha 9
020209 EH 02
0 5 10 15 2 2
1. Janjgian YY et al. Cancer Discov. 2018:8:49-58
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02 05 1 2 5 10 20 50
Time, mo
IM. ERBE2+ top quarto of expression ( = 13)
IM ERDER+/aterod RTHRASPIK (n= 9)
WERDER. (n= 4)
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Acquired Trastuzumab Resistance’
Pretreatmert ss of ERBB2 and KRAS and PIK3CA alterations
Torreta in 20% of cases
Pre trastuzumab (HER2+)
uu
li areas’
pra
[can
eyclo
wwrrers
HER2 IHC ERBB2 FISH
1.Janjgian YY et al. Cancer Discov. 2018:8:49-58 PeerView.com
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Pretreatmert ss of ERBB2 and KRAS and PIK3CA alterations
Torreta in 20% of cases
Pre trastuzumab (HER2+)
uu
li areas’
pra
[can
eyclo
wwrrers
HER2 IHC ERBB2 FISH
1.Janjgian YY et al. Cancer Discov. 2018:8:49-58 PeerView.com
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Trastuzumab Deruxtecan Is a Novel ADC Designed
to Deliver an Antitumor Effect!
+ Antibody-drug conjugate of Hanged ard anti-HER2
trastuzumab with a
\ 4 Ces a
cleavable E
AAA et de
topoisomerase inhibitor
+ Potential advantages
— High potency payload
© cystone residuo
— High ratio of trastuzumab Dogtra
to payload molecules
Topol Pal css ‘ng?
Lu » payloa hy
Bystander’ effect (exatecan derivative) bes
Lada oa Sm ram ut ate 2370852 TOA Pam mr 20011262 PeerView.com
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to Deliver an Antitumor Effect!
+ Antibody-drug conjugate of Hanged ard anti-HER2
trastuzumab with a
\ 4 Ces a
cleavable E
AAA et de
topoisomerase inhibitor
+ Potential advantages
— High potency payload
© cystone residuo
— High ratio of trastuzumab Dogtra
to payload molecules
Topol Pal css ‘ng?
Lu » payloa hy
Bystander’ effect (exatecan derivative) bes
Lada oa Sm ram ut ate 2370852 TOA Pam mr 20011262 PeerView.com
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DESTINY-Gastric01 and 02: Improved Efficacy With 2L
T-DXd in HER2+ Advanced Gastric/GEJ Cancer
ORR, % (95% Cl)
Median DOR, mo
Median PFS, mo (95% Cl)
Median OS, mo (95% Cl)
Survival, mo
(95% CI}
125
SS (9.6-14.3)
HR for death = 0.59; P=.01
: 56
Median PFS 438g)
HR for PD or death = 0.47
1. Van Cutsom E eta. Lance. 2023:24:744:756.2. Ku G ot al. Annals of Oncol. 2022:33(suppl7):1100. 3. Shitara Ket a. N Engl Med. 2020;382:2419,
4. Yamaguch eta. JC. 2022 A0(suppl ) 242.
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E
y
$
®
E
E
in Sum of Diam
Best % Change
in Sum of Diameters
From Baseline
388580352
DESTINY-Gastric02
(United States/Europe; Progression on 1L Trastuzumab)'
Confirmed ORR: 42% (95% Cl, 30.8-53.4)
DESTINY-Gastric01
(Japan/South Korea; Progression on 22 Prior Regimens)?
Confirmed ORR: 40.5% (95% Cl, 34-52)
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T-DXd in HER2+ Advanced Gastric/GEJ Cancer
ORR, % (95% Cl)
Median DOR, mo
Median PFS, mo (95% Cl)
Median OS, mo (95% Cl)
Survival, mo
(95% CI}
125
SS (9.6-14.3)
HR for death = 0.59; P=.01
: 56
Median PFS 438g)
HR for PD or death = 0.47
1. Van Cutsom E eta. Lance. 2023:24:744:756.2. Ku G ot al. Annals of Oncol. 2022:33(suppl7):1100. 3. Shitara Ket a. N Engl Med. 2020;382:2419,
4. Yamaguch eta. JC. 2022 A0(suppl ) 242.
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E
y
$
®
E
E
in Sum of Diam
Best % Change
in Sum of Diameters
From Baseline
388580352
DESTINY-Gastric02
(United States/Europe; Progression on 1L Trastuzumab)'
Confirmed ORR: 42% (95% Cl, 30.8-53.4)
DESTINY-Gastric01
(Japan/South Korea; Progression on 22 Prior Regimens)?
Confirmed ORR: 40.5% (95% Cl, 34-52)
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Adverse Events: T-DXd in HER2+ Advanced
Gastric/GEJ Cancer After Trastuzumab
DESTINY-Gastric02
(United States/Europe; Progression on 1L Trastuzumab)*
TRAEs in 215%
of Patients, n (%)
Patients with 21 TRAES
Nausea
Fatigue
Vomiting
Diarrhea
Decreased appetite
Alopecia
Anemia
Decreased platelet count
Decreased neutrophil count
T-DXd (N= 79)
74 (93.7)
46 (58.2)
29 (36.7)
26 (32.9)
2227.8)
18 (22.8)
17 (21.5)
15 (19)
13 (16.5)
12(15.2)
Grade 23
21 (26.6)
388)
388)
143)
1013)
103)
o
676)
1013)
6176)
Nausea
{neutrophil count
L appetite
Anemia
| platelet count
| white cell count
Malaise
Diarrhea
Vomiting
Constipation
Pyrexia
Alopecia
Fatigue
| lymphocyte count
1. Van Cutsom. ESMO 2021. Abstract LBASS. 2. Shitara K etal. N Engl Y Med. 2020:3822419.
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DESTINY-Gastric01
(Japan/South Korea; Progressii
79 (63)
79 (63)
75 (60)
72 (58)
49 (39)
47 (38)
43 (34)
40 (32)
33 (26)
30 (24)
30 (24)
28 (22)
27 (22)
27 (22)
on 22 Prior Regimens)?
29 (47) 10)
22(35) 15(24)
28(45) 8(13)
19(81) 14(23)
46) 2(4)
22(85) 7m
10 (16) 0
20 (32) 10)
5(8) 0
14 (23) o
10 (16) 0
9 (15) o
15 (24) 2(3)
2(3) 1@)
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Gastric/GEJ Cancer After Trastuzumab
DESTINY-Gastric02
(United States/Europe; Progression on 1L Trastuzumab)*
TRAEs in 215%
of Patients, n (%)
Patients with 21 TRAES
Nausea
Fatigue
Vomiting
Diarrhea
Decreased appetite
Alopecia
Anemia
Decreased platelet count
Decreased neutrophil count
T-DXd (N= 79)
74 (93.7)
46 (58.2)
29 (36.7)
26 (32.9)
2227.8)
18 (22.8)
17 (21.5)
15 (19)
13 (16.5)
12(15.2)
Grade 23
21 (26.6)
388)
388)
143)
1013)
103)
o
676)
1013)
6176)
Nausea
{neutrophil count
L appetite
Anemia
| platelet count
| white cell count
Malaise
Diarrhea
Vomiting
Constipation
Pyrexia
Alopecia
Fatigue
| lymphocyte count
1. Van Cutsom. ESMO 2021. Abstract LBASS. 2. Shitara K etal. N Engl Y Med. 2020:3822419.
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DESTINY-Gastric01
(Japan/South Korea; Progressii
79 (63)
79 (63)
75 (60)
72 (58)
49 (39)
47 (38)
43 (34)
40 (32)
33 (26)
30 (24)
30 (24)
28 (22)
27 (22)
27 (22)
on 22 Prior Regimens)?
29 (47) 10)
22(35) 15(24)
28(45) 8(13)
19(81) 14(23)
46) 2(4)
22(85) 7m
10 (16) 0
20 (32) 10)
5(8) 0
14 (23) o
10 (16) 0
9 (15) o
15 (24) 2(3)
2(3) 1@)
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Current Status and Next Steps With T-DXd
+ The results of DESTINY-Gastric01 and 02 led to regulatory approvals for T-DXd
Approved September 2020 Approved January 2021 Approved December 2022
2L or later therapy after
prior trastuzumab-based regimen
3L or later therapy after
AL trastuzumab-based regimen
+ DESTINY-Gastric04: phase 3 study of second-line T-DXd versus ramucirumab + paclitaxel
(NCT04704934)
+ DESTINY-Gastric03: phase 1b/2 study of T-DXd + chemotherapy and/or immune
checkpoint inhibitors in first and second line (NCT04379596)
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+ The results of DESTINY-Gastric01 and 02 led to regulatory approvals for T-DXd
Approved September 2020 Approved January 2021 Approved December 2022
2L or later therapy after
prior trastuzumab-based regimen
3L or later therapy after
AL trastuzumab-based regimen
+ DESTINY-Gastric04: phase 3 study of second-line T-DXd versus ramucirumab + paclitaxel
(NCT04704934)
+ DESTINY-Gastric03: phase 1b/2 study of T-DXd + chemotherapy and/or immune
checkpoint inhibitors in first and second line (NCT04379596)
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Management of Nausea Associated
With Trastuzumab Deruxtecan
Proactively
manage AEs + Do not wait for patients to develop nausea
related to T-DXd
Provide the + Consider how the patient tolerated their first-
patient with line treatment (ie, if a patient previously
multipl tion experienced severe nausea, they are likely to
(5 je ayia be have a similar experience with T-DXd)
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With Trastuzumab Deruxtecan
Proactively
manage AEs + Do not wait for patients to develop nausea
related to T-DXd
Provide the + Consider how the patient tolerated their first-
patient with line treatment (ie, if a patient previously
multipl tion experienced severe nausea, they are likely to
(5 je ayia be have a similar experience with T-DXd)
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Detecting and Managing T-DXd-Related ILD:
The Five “S” Rules!
1 J E rn 4 Ç ) 5
6 à C= V4
= 7
Screen Scan Synergy Suspend Steroids
Treatment
+ Careful patient + The fundamental + Minimizing the risk + T-DXd should always ||| - The mainstay for
selection is warranted diagnostic tools for of ILD involves be interrupted if ILD is treating T-DXd-
before initiating T-DXd ILD remain teamwork, which suspected; it can only induced ILD remains
to optimize the radiological scans, includes educating be restarted in the corticosteroids, with
‘monitoring strategies with preference for Patients and all the case of asymptomatic the dose adapted to
based on baseline risk high-resolution CT care team, as well ILD that fully resolves the toxicity grade
+ Screening continues scans of the chest
during treatment, + Abaseline scan is management once
with regular clinical recommended, with ILD is suspected
assessments to repeat scans to be
exclude signs! performed
symptoms of ILD 6-12 weeks
1. Tarantino P, Tolanoy SM. JCO Oncol Prat. 2023:19:526-527.
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The Five “S” Rules!
1 J E rn 4 Ç ) 5
6 à C= V4
= 7
Screen Scan Synergy Suspend Steroids
Treatment
+ Careful patient + The fundamental + Minimizing the risk + T-DXd should always ||| - The mainstay for
selection is warranted diagnostic tools for of ILD involves be interrupted if ILD is treating T-DXd-
before initiating T-DXd ILD remain teamwork, which suspected; it can only induced ILD remains
to optimize the radiological scans, includes educating be restarted in the corticosteroids, with
‘monitoring strategies with preference for Patients and all the case of asymptomatic the dose adapted to
based on baseline risk high-resolution CT care team, as well ILD that fully resolves the toxicity grade
+ Screening continues scans of the chest
during treatment, + Abaseline scan is management once
with regular clinical recommended, with ILD is suspected
assessments to repeat scans to be
exclude signs! performed
symptoms of ILD 6-12 weeks
1. Tarantino P, Tolanoy SM. JCO Oncol Prat. 2023:19:526-527.
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Management of ILD Associated
With Trastuzumab Deruxtecan'2
Grade 1: Hold until resolved to grade 0, consider corticosteroids
(prednisolone 0.5 mg/kg/d), then
+ If resolved $28 d from onset: maintain dose
+ If resolved >28 d after onset: reduce dose by one level
+ If grade 1 ILD occurs beyond cycle day 22 and has not resolved within
49 days from last infusion: discontinue drug
Grades 2-4: Permanently discontinue treatment and promptly initiate systemic
corticosteroid treatment (eg, prednisolone 21 mg/kg/d or equivalent for 214
days followed by taper for 24 weeks)
1. Enbort (rastuzumab deruxtecan) Prosenbing Information. ps. accessdata da govidrugsatisa_docetabel2022/761 13980240 pd —
2. ModiS ot al N Engl J Med. 2020;382'610-621 PeerView.com
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With Trastuzumab Deruxtecan'2
Grade 1: Hold until resolved to grade 0, consider corticosteroids
(prednisolone 0.5 mg/kg/d), then
+ If resolved $28 d from onset: maintain dose
+ If resolved >28 d after onset: reduce dose by one level
+ If grade 1 ILD occurs beyond cycle day 22 and has not resolved within
49 days from last infusion: discontinue drug
Grades 2-4: Permanently discontinue treatment and promptly initiate systemic
corticosteroid treatment (eg, prednisolone 21 mg/kg/d or equivalent for 214
days followed by taper for 24 weeks)
1. Enbort (rastuzumab deruxtecan) Prosenbing Information. ps. accessdata da govidrugsatisa_docetabel2022/761 13980240 pd —
2. ModiS ot al N Engl J Med. 2020;382'610-621 PeerView.com
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NCCN Clinical Practice Guidelines:
HER2+ Gastric Cancer!
First Line (HER2+ Recommendations Only)»
Preferred Regimens
+ Fluoropyrimidine? + oxaliplatin + trastuzumab
+Fluoropyrimidine® + oxaliplatin + trastuzumab + pembrolizumab
+ Fluoropyrimidine® + cisplatin + trastuzumab (category 1)
*Fluoropyrimidine® + cisplatin + trastuzumab + pembrolizumab
(category 1)
Other Recommended Regimens
* Fluorouracil + irinotecan
+ Paclitaxel + carboplatin or cisplatin
+ Docetaxel + cisplatin
+ Fluoropyrimidine®
* Docetaxel + cisplatin or oxaliplatin + fluorouracil
Second or Subsequent Line of Therapy (Depeni
Preferred Regimens
+ Ramucirumab + paclitaxel (category 1)
+ T-DXd (HER2+)
+ Docetaxel (category 1)
+Paclitaxel (category 1)
+ Irinotecan (category 1)
+Fluorouracil + irinotecan
«Trifluridine + tipiracil for 23L (category 1)
dent on Prior Therapy and PS)
Other Recommended Regimens
+ Ramucirumab (category 1)
+ Irinotecan + cisplatin
+ Fluorouracil + irinotecan + ramucirumab
+ Irinotecan + ramucirumab
+ Docetaxel + irinotecan (category 28)
* Oxalilatin general preferred over cisplatin due to lower toxic.» Fluorouracil or capecitabine
1.NCEN Cinial Pracice Guidelines in Oncology. Gastric Cancer. Version 1.2024. ps www ncen org/potessionaa/physican_s/pdigastrc pal
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HER2+ Gastric Cancer!
First Line (HER2+ Recommendations Only)»
Preferred Regimens
+ Fluoropyrimidine? + oxaliplatin + trastuzumab
+Fluoropyrimidine® + oxaliplatin + trastuzumab + pembrolizumab
+ Fluoropyrimidine® + cisplatin + trastuzumab (category 1)
*Fluoropyrimidine® + cisplatin + trastuzumab + pembrolizumab
(category 1)
Other Recommended Regimens
* Fluorouracil + irinotecan
+ Paclitaxel + carboplatin or cisplatin
+ Docetaxel + cisplatin
+ Fluoropyrimidine®
* Docetaxel + cisplatin or oxaliplatin + fluorouracil
Second or Subsequent Line of Therapy (Depeni
Preferred Regimens
+ Ramucirumab + paclitaxel (category 1)
+ T-DXd (HER2+)
+ Docetaxel (category 1)
+Paclitaxel (category 1)
+ Irinotecan (category 1)
+Fluorouracil + irinotecan
«Trifluridine + tipiracil for 23L (category 1)
dent on Prior Therapy and PS)
Other Recommended Regimens
+ Ramucirumab (category 1)
+ Irinotecan + cisplatin
+ Fluorouracil + irinotecan + ramucirumab
+ Irinotecan + ramucirumab
+ Docetaxel + irinotecan (category 28)
* Oxalilatin general preferred over cisplatin due to lower toxic.» Fluorouracil or capecitabine
1.NCEN Cinial Pracice Guidelines in Oncology. Gastric Cancer. Version 1.2024. ps www ncen org/potessionaa/physican_s/pdigastrc pal
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Other New and Emerging Anti-HER2 Therapies
Zanidatamab
Bispecific antibody
Randomized phase 3
HERIZON-GEA-01 study of
zanidatamab + chemo +
tislelizumab as 1L therapy
(NCT05152147)
PRS-343
(cinrebafusp alfa;
HER2/4-1BB
bispecific)
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Newer HER2
ADCs
Evorpacept
Anti-CD47 antibody
Randomized phase 2/3
ASPEN-06 study of
trastuzumab/ramucirumab/
paclitaxel + evorpacept
(NCT05002127)
BERD HERZ cellular
therapy
bispecific
antibodies
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Copyrigh!
Zanidatamab
Bispecific antibody
Randomized phase 3
HERIZON-GEA-01 study of
zanidatamab + chemo +
tislelizumab as 1L therapy
(NCT05152147)
PRS-343
(cinrebafusp alfa;
HER2/4-1BB
bispecific)
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Newer HER2
ADCs
Evorpacept
Anti-CD47 antibody
Randomized phase 2/3
ASPEN-06 study of
trastuzumab/ramucirumab/
paclitaxel + evorpacept
(NCT05002127)
BERD HERZ cellular
therapy
bispecific
antibodies
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Copyrigh!
Practical Points: Insights on Safety Management
With Novel Options in HER2+ Disease
Patient with HER2+
gastroesophageal cancer
progressing after trastuzumab;
receiving additional HER2
therapy with T-DXd
Patient with HER2+
gastroesophageal cancer
receiving KEYNOTE-811
regimen in the frontline setting
+ Events to monitor for include
+ In KEYNOTE-811, events of
note included infusion-related ILD, neutropenia,
reactions and the classic thrombocytopenia, and left
spectrum of irAEs ventricular dysfunction
+ Standard guidelines for + Recommended strategies
managing irAEs include include dose
treatment holds, steroid modification/interruption
management, and resumption
of immunotherapy based on
grading/severity
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With Novel Options in HER2+ Disease
Patient with HER2+
gastroesophageal cancer
progressing after trastuzumab;
receiving additional HER2
therapy with T-DXd
Patient with HER2+
gastroesophageal cancer
receiving KEYNOTE-811
regimen in the frontline setting
+ Events to monitor for include
+ In KEYNOTE-811, events of
note included infusion-related ILD, neutropenia,
reactions and the classic thrombocytopenia, and left
spectrum of irAEs ventricular dysfunction
+ Standard guidelines for + Recommended strategies
managing irAEs include include dose
treatment holds, steroid modification/interruption
management, and resumption
of immunotherapy based on
grading/severity
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HER2+ Advanced/Metastatic Gastric/GEJ Cancer:
Final Thoughts
The ToGA trial established trastuzumab + chemotherapy as first-line standard of care in
HER2+ metastatic gastric cancer
Addition of pembrolizumab was approved by the FDA based on response data from KEYNOTE-811
For patients with metastatic HER2+ gastric cancer, consider
Repeat prey a Ste ctDNA to assess ERBB2 amplification
T-DXd can provide benefit in second-line or later settings, regardless of prior
ICI exposure
+ Monitoring and patient education are essential to mitigate the risk of ILD with T-DXd
+ Studies of T-DXd in combination with other agents, including ICI, are ongoing
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Final Thoughts
The ToGA trial established trastuzumab + chemotherapy as first-line standard of care in
HER2+ metastatic gastric cancer
Addition of pembrolizumab was approved by the FDA based on response data from KEYNOTE-811
For patients with metastatic HER2+ gastric cancer, consider
Repeat prey a Ste ctDNA to assess ERBB2 amplification
T-DXd can provide benefit in second-line or later settings, regardless of prior
ICI exposure
+ Monitoring and patient education are essential to mitigate the risk of ILD with T-DXd
+ Studies of T-DXd in combination with other agents, including ICI, are ongoing
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Bolstering the Treatment Arsenal
for HER2+ CRC
Innovative Targeted Strategies
and Practical Applications of Care
John Strickler, MD
Associate Professor of Medicine
Associate Director of Clinical Research — Gl
Duke University
Durham, North Carolina
> 2000-2024, PeerView
for HER2+ CRC
Innovative Targeted Strategies
and Practical Applications of Care
John Strickler, MD
Associate Professor of Medicine
Associate Director of Clinical Research — Gl
Duke University
Durham, North Carolina
> 2000-2024, PeerView
Exploring Unmet Needs for Targeted Therapy
Advanced/Metastatic CRC
Molecular Profiling! Treatment Selection
+ Up to 72% of patients with CRC are not + More than 40% of patients with mCRC are
receiving biomarker testing that completely initiated on systemic therapy before complete
adheres to published guidelines biomarker test results are available, and many
Half (52%) of US cancer centers do not have a oc no Weatmen: Dased(onitties)
: y E
standard protocol for biomarker testing for biomarker testing results:
patients with CRC Only 74% of patients with mCRC receive
second-line treatment, only 63% receive
third-line treatment, and only 45.9% receive
fourth-line treatment
Recycling of chemotherapy and biologics in the
second- and subsequent-line settings is
common and occurs more frequently than
switching to a drug regimen with an alternative
mechanism of action*
{ps in ae cancer ocre ra cancer Doman: suey summary tna) pdstranees687 02 Guterer ME tal CO Precis 7s
Oncol 2010.34: 3 Tampetin Met al Cin Colorectal Cancer 2017 8372.76. 4. loos Weta J Can One 2020 (0 4) 38. PeerView.com
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Advanced/Metastatic CRC
Molecular Profiling! Treatment Selection
+ Up to 72% of patients with CRC are not + More than 40% of patients with mCRC are
receiving biomarker testing that completely initiated on systemic therapy before complete
adheres to published guidelines biomarker test results are available, and many
Half (52%) of US cancer centers do not have a oc no Weatmen: Dased(onitties)
: y E
standard protocol for biomarker testing for biomarker testing results:
patients with CRC Only 74% of patients with mCRC receive
second-line treatment, only 63% receive
third-line treatment, and only 45.9% receive
fourth-line treatment
Recycling of chemotherapy and biologics in the
second- and subsequent-line settings is
common and occurs more frequently than
switching to a drug regimen with an alternative
mechanism of action*
{ps in ae cancer ocre ra cancer Doman: suey summary tna) pdstranees687 02 Guterer ME tal CO Precis 7s
Oncol 2010.34: 3 Tampetin Met al Cin Colorectal Cancer 2017 8372.76. 4. loos Weta J Can One 2020 (0 4) 38. PeerView.com
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Current Guidelines for Molecular Testing in mCRC!
All patients diagnosed with mCRC sh be
tested for the following
‘AS mutations
+ NRAS ERA
+ KRAS mutations
dMMR/MSI-H HER2 (ERBB2)
status amplifications
1.NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. Version 3.2024 ps cn org professional physiian_ghpdlicolon pal. PeerView.com
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All patients diagnosed with mCRC sh be
tested for the following
‘AS mutations
+ NRAS ERA
+ KRAS mutations
dMMR/MSI-H HER2 (ERBB2)
status amplifications
1.NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. Version 3.2024 ps cn org professional physiian_ghpdlicolon pal. PeerView.com
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HER2+ mCRC
+ Usually left sided Transverse colon
+ Homogeneous HER2 Ascending (eft en”
expression
+ Not mutually exclusive with tymphnove
RAS or BRAF mutations Blood —
« Associated with lung and Cecum
brain metastases Small
intestine
Sigmoid
colon
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+ Usually left sided Transverse colon
+ Homogeneous HER2 Ascending (eft en”
expression
+ Not mutually exclusive with tymphnove
RAS or BRAF mutations Blood —
« Associated with lung and Cecum
brain metastases Small
intestine
Sigmoid
colon
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HER2 Amplification in CRC
+ 5.3% HER2 amplification seen in HER2 overexpression and amplification is seen in a distinct subset of mCRC
HERACLES study (screened = 836)' Study. Pe eee FISH
ato, n (%) Concordance
— Long-term clinical outcomes of a
trastuzumab + lapatinib: ORR: 28%; aL td 139 fest ae 2 3 K=085
mPFS 4.7 mo; mOS: 10 mo ee aS
ae . Ooietal. Mod 244 IHC: 8 (3) 6 ® TOR
+ HER2 amplification enriched in KRAS, Pathol. 2004 FISH: 8 (3)
NRAS, BRAF, and PIK3CA WT tumors? — warcetal a
Human Path 1489s 36) 2 2 100%
HE HER? amplification Summary IHC 1822 16 36 9604
Quadruple
Unselected KRASWT Negative 4 =11)
(n= 2,349) (n=44) (Xenopatients) ERBB2 4% ||||]
KRAS 41%) mm
p == om a
NRAS 9% m som
27% 136%
En en as PIKSCA 20% mn mann mo ma
Partenón à ton
1. Siena S et al. ASCO GI 2015. Abstract 865.2. Berto A et al. Cancer Disco. 2011:1:508-523. PeerView.com
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+ 5.3% HER2 amplification seen in HER2 overexpression and amplification is seen in a distinct subset of mCRC
HERACLES study (screened = 836)' Study. Pe eee FISH
ato, n (%) Concordance
— Long-term clinical outcomes of a
trastuzumab + lapatinib: ORR: 28%; aL td 139 fest ae 2 3 K=085
mPFS 4.7 mo; mOS: 10 mo ee aS
ae . Ooietal. Mod 244 IHC: 8 (3) 6 ® TOR
+ HER2 amplification enriched in KRAS, Pathol. 2004 FISH: 8 (3)
NRAS, BRAF, and PIK3CA WT tumors? — warcetal a
Human Path 1489s 36) 2 2 100%
HE HER? amplification Summary IHC 1822 16 36 9604
Quadruple
Unselected KRASWT Negative 4 =11)
(n= 2,349) (n=44) (Xenopatients) ERBB2 4% ||||]
KRAS 41%) mm
p == om a
NRAS 9% m som
27% 136%
En en as PIKSCA 20% mn mann mo ma
Partenón à ton
1. Siena S et al. ASCO GI 2015. Abstract 865.2. Berto A et al. Cancer Disco. 2011:1:508-523. PeerView.com
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HER2 as a Target in Colorectal Cancer?
IHC 3+ or ISH+ means HER2 is amplified/overexpressed (ERBB2+)*
Identifying ERBB2+: specific criteria for mCRC
Phenotype
+ ERBB2+ <5%19
+ Enriched in RAS WT
+ No evidence about differences
in sex 3 |
[ y + Rectal and left-sided tumors
+ CNS M1 avidity 3 E E A THC 2+ or 10%-
faint segmental 150% cells IHC 3+
or granular; any | circumferential | SIsH (it
‘cellularity
Biomarker role of HER2
+ I
Fee HER2+ mCRC is a challenging and heterogeneous disease
+ Low prevalence of disease limits phase 3 trials
. : controversial?
Ecole CT + Patients with HER2-low mCRC do not respond to targeted therapy (in contrast to other tumors)?
+ Negative predictive: anti-
EGER? (controversia, lack of + Sequencing anti-HER2 therapies in the treatment algorithm of mCRC is not clear
prospective data)‘ + Role ofliquid biopsy in detecting ERBB2+
+ Positive predictive: dual anti- + Resistance after targeted therapy
HERZ treatment + Role of HER2 mutations"?
* Tissue images: Li Fe al Vrchows Arch. 2020:476:391-398, Body image: BoRender.
1 Mece-Bomstam F ea. Cin Cancer Ros 201925:2033-2041.2. Seo AN et al PLOS One. 20169098528, 3. Nam SK et al. PLOS One. 2016:11:00151865,
4 Laurent Puig P et al. Ann Oncol 2016.27 vi. 5, Satore-BianchiA etal. Oncologist. 2019:24:1305-1402. 6. Raghav Ket al. J Cin Oncol 2016:34:3517.
7. Berto A et al. Cancer Disco, 2011:1508-523. 8, Valora E ot a. Mod Pathol. 2015:281481-1491. 9, Kavun SM e el. Cancer Discov. 2015:5832-41 N
40. Siena S e al. Lancot Oncol 202122.779.189. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
IHC 3+ or ISH+ means HER2 is amplified/overexpressed (ERBB2+)*
Identifying ERBB2+: specific criteria for mCRC
Phenotype
+ ERBB2+ <5%19
+ Enriched in RAS WT
+ No evidence about differences
in sex 3 |
[ y + Rectal and left-sided tumors
+ CNS M1 avidity 3 E E A THC 2+ or 10%-
faint segmental 150% cells IHC 3+
or granular; any | circumferential | SIsH (it
‘cellularity
Biomarker role of HER2
+ I
Fee HER2+ mCRC is a challenging and heterogeneous disease
+ Low prevalence of disease limits phase 3 trials
. : controversial?
Ecole CT + Patients with HER2-low mCRC do not respond to targeted therapy (in contrast to other tumors)?
+ Negative predictive: anti-
EGER? (controversia, lack of + Sequencing anti-HER2 therapies in the treatment algorithm of mCRC is not clear
prospective data)‘ + Role ofliquid biopsy in detecting ERBB2+
+ Positive predictive: dual anti- + Resistance after targeted therapy
HERZ treatment + Role of HER2 mutations"?
* Tissue images: Li Fe al Vrchows Arch. 2020:476:391-398, Body image: BoRender.
1 Mece-Bomstam F ea. Cin Cancer Ros 201925:2033-2041.2. Seo AN et al PLOS One. 20169098528, 3. Nam SK et al. PLOS One. 2016:11:00151865,
4 Laurent Puig P et al. Ann Oncol 2016.27 vi. 5, Satore-BianchiA etal. Oncologist. 2019:24:1305-1402. 6. Raghav Ket al. J Cin Oncol 2016:34:3517.
7. Berto A et al. Cancer Disco, 2011:1508-523. 8, Valora E ot a. Mod Pathol. 2015:281481-1491. 9, Kavun SM e el. Cancer Discov. 2015:5832-41 N
40. Siena S e al. Lancot Oncol 202122.779.189. PeerView.com
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HER2 Testing in mCRC: When and How!
+ ERBB2 positivity in
breast and gastric
cancers was modified
for CRC tumors
+ HERACLES diagnostic
criteria: archival test
validation, n = 256;
clinical validation,
n= 830
+ Staining scale 0 to 3
but modified degrees
of cutoffs appropriate
for CRC tumor tissue
features
1. Vahoa E otal. Mod Pathol 2015:28:1481-1491.
PeerView.com/JPD827
He 3+
He 2+
Inc 1+
Heo
HERACLES Diagnostic Criteria
Intense circumferential, basolateral,
or lateral staining in 250% of cells
Intense circumferential, basolateral,
‘oF lateral staining in >10% and <50%
of cols
Intense circumferential, basolateral,
or lateral staining in 510% of cells
‘Moderate circumferential,
basolateral, or lateral staining in
250% of cell
‘Any type of moderate staining in
<50% of cells
Faint segmental or granular staining
with any cellularity
No staining
Positive
Negative
Equivocal
Negative
Negative
Negative
NA
Mandatory HC retest; SHconeidred
710% collar it ERBB2 CENT rai
confirmed, perform ISH il
a NA
Mandatory IHC reten SH considered,
coasts esla ERBBZICENTT rato
med. pa se
NA NA
NA NA
NA NA
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Copyright © 2000-2024, PeerView
+ ERBB2 positivity in
breast and gastric
cancers was modified
for CRC tumors
+ HERACLES diagnostic
criteria: archival test
validation, n = 256;
clinical validation,
n= 830
+ Staining scale 0 to 3
but modified degrees
of cutoffs appropriate
for CRC tumor tissue
features
1. Vahoa E otal. Mod Pathol 2015:28:1481-1491.
PeerView.com/JPD827
He 3+
He 2+
Inc 1+
Heo
HERACLES Diagnostic Criteria
Intense circumferential, basolateral,
or lateral staining in 250% of cells
Intense circumferential, basolateral,
‘oF lateral staining in >10% and <50%
of cols
Intense circumferential, basolateral,
or lateral staining in 510% of cells
‘Moderate circumferential,
basolateral, or lateral staining in
250% of cell
‘Any type of moderate staining in
<50% of cells
Faint segmental or granular staining
with any cellularity
No staining
Positive
Negative
Equivocal
Negative
Negative
Negative
NA
Mandatory HC retest; SHconeidred
710% collar it ERBB2 CENT rai
confirmed, perform ISH il
a NA
Mandatory IHC reten SH considered,
coasts esla ERBBZICENTT rato
med. pa se
NA NA
NA NA
NA NA
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Copyright © 2000-2024, PeerView
MOUNTAINEER: Agreement Varies
Among HER2 Testing Platforms’
Pairwise Percent Agreement Among Three Central HER2 Testing Modalities
Blood NGS vs IHC/FISH vs IHC/FISH vs
issue NGS Blood NGS
n/N 47/58 63/68 66/83
% 81 92. 79.
90% Cl 68.6-90.1 83.7-97.6 69.2-87.6
+ Samples submitted for central testing for patients treated with tucatinib and trastuzumab (cohorts A and B)
+ Evaluable results
— 70 per IHC/FISH
— 50 per tissue NGS
- 71 per blood NGS
1. Sticker JH et a. ASCO 2023. Abstract 3528. PeerView.com
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Among HER2 Testing Platforms’
Pairwise Percent Agreement Among Three Central HER2 Testing Modalities
Blood NGS vs IHC/FISH vs IHC/FISH vs
issue NGS Blood NGS
n/N 47/58 63/68 66/83
% 81 92. 79.
90% Cl 68.6-90.1 83.7-97.6 69.2-87.6
+ Samples submitted for central testing for patients treated with tucatinib and trastuzumab (cohorts A and B)
+ Evaluable results
— 70 per IHC/FISH
— 50 per tissue NGS
- 71 per blood NGS
1. Sticker JH et a. ASCO 2023. Abstract 3528. PeerView.com
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MOUNTAINEER: Global, Open-Label, Phase 2 Trial!
22L mCRC Cohort A (n= 45) Cohort B (n= 41)
HER2+ per local 3 >
: Tucatinib 300 mg PO BID + trastuzumab Tucatinib 300 mg PO BID +
IHCISHINGS testing 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) trastuzumab 6 mg/kg Q
RAS WT (loading dose: 8 mg/kg C1D1)
Measurable disease per
RECIST 1.1
Prior fluoropyrimidines, Cohort C (n= 31)
oxaliplatin, irinotecan, Tucatinib
and anti-VEGF mAb
MOUNTAINEER began as a US investigator-sponsored trial and initially consisted of a single cohort (cohort A) and was expanded
globally to include patients randomized to receive tucatinib + trastuzumab (cohort B) or tucatinib monotherapy (cohort C)
Efficacy endpoints: assessed in patients who received any amount of study treatment and had HER2+ tumors
Primary endpoints: confirmed ORR in cohorts A + B (RECIST 1.1 per BICR)
‘Secondary endpoints
= Cohorts A + B: DOR per BICR, PFS per BICR, and OS
— Cohort C: ORR by 12 weeks of treatment (RECIST 1.1 per BICR)
Safety presented in cohorts A + B who received any amount of study treatment
1. Sticker JH et al. Lancet, 2023:24:496-508 PeerView.com
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22L mCRC Cohort A (n= 45) Cohort B (n= 41)
HER2+ per local 3 >
: Tucatinib 300 mg PO BID + trastuzumab Tucatinib 300 mg PO BID +
IHCISHINGS testing 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) trastuzumab 6 mg/kg Q
RAS WT (loading dose: 8 mg/kg C1D1)
Measurable disease per
RECIST 1.1
Prior fluoropyrimidines, Cohort C (n= 31)
oxaliplatin, irinotecan, Tucatinib
and anti-VEGF mAb
MOUNTAINEER began as a US investigator-sponsored trial and initially consisted of a single cohort (cohort A) and was expanded
globally to include patients randomized to receive tucatinib + trastuzumab (cohort B) or tucatinib monotherapy (cohort C)
Efficacy endpoints: assessed in patients who received any amount of study treatment and had HER2+ tumors
Primary endpoints: confirmed ORR in cohorts A + B (RECIST 1.1 per BICR)
‘Secondary endpoints
= Cohorts A + B: DOR per BICR, PFS per BICR, and OS
— Cohort C: ORR by 12 weeks of treatment (RECIST 1.1 per BICR)
Safety presented in cohorts A + B who received any amount of study treatment
1. Sticker JH et al. Lancet, 2023:24:496-508 PeerView.com
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MOUNTAINEER: Summary of Efficacy
and Safety (Primary Analysis)
Efficacy Overview of Tucatinib + Safety Overview of Tucatinib +
Trastuzumab Cohorts A + B (N = 84)! Trastuzumab Cohorts A + B (N = 86)?
Tucatinib +
Confirmed ORR, % TEAES, n (%)
38.1 (27.7-49.3) Trastuzumab
(Cone) Any-grade AEs 82 (95.3)
Tucatinib related 63 (73.3)
mDOR, mo (95% Cl) 12.4 (8.5-25.5) aa 58 (67.4)
Grade 23 AEs 33 (38.4)
DCR, n (%) 60 (71) Tucatinib related 8(9.3)
Trastuzumab related 6(7)
PFS, mo (95% Cl) 8.2 (4.2-10.3) SAES: 19 (22.1)
Tucatinib related 3 (3.5)
Trastuzumab related 2(23)
Osiimo (95% Cl) er) RES leading to study treatment 568)
discontinuation**
ASCO 2024 AEs leading to tucatinib dose modification 22 (25.6)
create RASWT HER En Deaths due to AEs o
TERES leading lo discontinuaton ol tucaini included alanine aminotransterase increase (2.3%). COVID-19 pneumnia (12%). cholangs (1.2%) and fatigue
(12%) TEAES leading to discontinuation of tasturumal included alanine amineranlerase nerase (2.3%) and GOVID-10 pnoumona (12%) =
1. Sticker JH etal. Lancet Oncol. 2023:24:496-508, 2. Sticker JH et al. 2022 ESMO GI Congress. Abstract LBA-2. 3. Sticker JH et al ASCO 2024. Abstract 3500. PeerView.com
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and Safety (Primary Analysis)
Efficacy Overview of Tucatinib + Safety Overview of Tucatinib +
Trastuzumab Cohorts A + B (N = 84)! Trastuzumab Cohorts A + B (N = 86)?
Tucatinib +
Confirmed ORR, % TEAES, n (%)
38.1 (27.7-49.3) Trastuzumab
(Cone) Any-grade AEs 82 (95.3)
Tucatinib related 63 (73.3)
mDOR, mo (95% Cl) 12.4 (8.5-25.5) aa 58 (67.4)
Grade 23 AEs 33 (38.4)
DCR, n (%) 60 (71) Tucatinib related 8(9.3)
Trastuzumab related 6(7)
PFS, mo (95% Cl) 8.2 (4.2-10.3) SAES: 19 (22.1)
Tucatinib related 3 (3.5)
Trastuzumab related 2(23)
Osiimo (95% Cl) er) RES leading to study treatment 568)
discontinuation**
ASCO 2024 AEs leading to tucatinib dose modification 22 (25.6)
create RASWT HER En Deaths due to AEs o
TERES leading lo discontinuaton ol tucaini included alanine aminotransterase increase (2.3%). COVID-19 pneumnia (12%). cholangs (1.2%) and fatigue
(12%) TEAES leading to discontinuation of tasturumal included alanine amineranlerase nerase (2.3%) and GOVID-10 pnoumona (12%) =
1. Sticker JH etal. Lancet Oncol. 2023:24:496-508, 2. Sticker JH et al. 2022 ESMO GI Congress. Abstract LBA-2. 3. Sticker JH et al ASCO 2024. Abstract 3500. PeerView.com
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Most Common TEAEs (210%) for Tucatinib + Trastuzumab??
12 LESS
so M Grace 2 + Most common tucatinib-related AEs (210%): diarrh
80 I Grade 1 (52.3%), fatigue (29.1%), nausea (18.6%), and dermatitis
acneiform (17.4%)
Grade 23 tucatinib-related AEs (22%): alanine
aminotransferase increase (2.3%) and diarrhea
Frequency, %
8
o
‘a ESS FECES SET SENSE
# Cs LÉ Se EE e SES [E 3 e
Ca e o
e <
1. Sticker JH et al. Lancot Oncol. 2023/24:496-508. 2. Sticker JH et al. 2022 ESMO GI Congress. Abstract LBA 2. PeerView.com
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12 LESS
so M Grace 2 + Most common tucatinib-related AEs (210%): diarrh
80 I Grade 1 (52.3%), fatigue (29.1%), nausea (18.6%), and dermatitis
acneiform (17.4%)
Grade 23 tucatinib-related AEs (22%): alanine
aminotransferase increase (2.3%) and diarrhea
Frequency, %
8
o
‘a ESS FECES SET SENSE
# Cs LÉ Se EE e SES [E 3 e
Ca e o
e <
1. Sticker JH et al. Lancot Oncol. 2023/24:496-508. 2. Sticker JH et al. 2022 ESMO GI Congress. Abstract LBA 2. PeerView.com
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Tucatinib + Trastuzumab: Confirmed ORR per BICR
in Prespe
ied Subgroups’?
CORR, %
Subsroupe (95% Cl)
38.1 (27.7-49.3)
Overall
Age
<65y 72 36.1 (25.1-48.3)
265 y 12 50 (21.1-78.9)
ECOG PS at baseline
0 50 44 (30.0-58.7)
12 34 29.4 (15.1-47.5)
Primary site of disease
Left-sided primary 71 42.3 (30.6-54.6)
All other primaries 13 15.4 (1.9-45.4)
Geographic region
North America 39.1 (27.6-51.6)
Europe
33.3 (11.8-61.6)
0 > 2
Confirmed ORR, %
1. Sticker JH ot al Lancot Oncol 2023/24:496-508.2. Sticker JH ot al 2022 ESMO GI Congress. Abstract LBA 2.
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in Prespe
ied Subgroups’?
CORR, %
Subsroupe (95% Cl)
38.1 (27.7-49.3)
Overall
Age
<65y 72 36.1 (25.1-48.3)
265 y 12 50 (21.1-78.9)
ECOG PS at baseline
0 50 44 (30.0-58.7)
12 34 29.4 (15.1-47.5)
Primary site of disease
Left-sided primary 71 42.3 (30.6-54.6)
All other primaries 13 15.4 (1.9-45.4)
Geographic region
North America 39.1 (27.6-51.6)
Europe
33.3 (11.8-61.6)
0 > 2
Confirmed ORR, %
1. Sticker JH ot al Lancot Oncol 2023/24:496-508.2. Sticker JH ot al 2022 ESMO GI Congress. Abstract LBA 2.
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MOUNTAINEER: Results by Testing Modality’
Central IHC/FISH Tissue NGS (PGDX) Blood NGS (G360)
Primary
Analysis*
PFS, mo 82 10.1 28 10.9 24 8.1 109
(95% Cl) (42403) (42152) (1263) | (70207) (13NR) (31402) (20-184)
ORR, % 38.4 40 10 477 o 414 20
(5% Cl) (77-493) (NR) (0.344) (82-63) (045.9) (8.155) (43-481)
Duration of
124 16.4 153 124
(5% CD MO (85255) (10.6-25.5) - (8.9-25.5) = (6.2-38.3) -
* Tainted paint wth HERZ+ resul rom any sue based assay (HC, FISH, NGS) .
1. Sticker JH et al ASCO 2023. Abstract 3528. PeerView.com
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Central IHC/FISH Tissue NGS (PGDX) Blood NGS (G360)
Primary
Analysis*
PFS, mo 82 10.1 28 10.9 24 8.1 109
(95% Cl) (42403) (42152) (1263) | (70207) (13NR) (31402) (20-184)
ORR, % 38.4 40 10 477 o 414 20
(5% Cl) (77-493) (NR) (0.344) (82-63) (045.9) (8.155) (43-481)
Duration of
124 16.4 153 124
(5% CD MO (85255) (10.6-25.5) - (8.9-25.5) = (6.2-38.3) -
* Tainted paint wth HERZ+ resul rom any sue based assay (HC, FISH, NGS) .
1. Sticker JH et al ASCO 2023. Abstract 3528. PeerView.com
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Studies of Trastuzumab + Pertuzumab for HER2+ mCRC
ORR, % (95% Cl) Median PFS, mo Median OS, mo
(95% Cl) (95% Cl)
86 (all RAS} 28 (19-39) 2.9 (1.4-5.3) 11.5 (7.7-NE)
MyPathway'® 69 (RAS WT) 32 (21-44) 4.1 (2.7-5.6) 15.5 (10.3-20.9)
16 (RAS mut) 12 (2-38) 1.4 (1.2-2.8)° NIA
27 tissue+ 30 (14-50) 4 (1.4-5.6) 10.1 (4.5-16.5)
TRIOMEEE 25 ctDNA+ 28 (12-49) 3.1 (1.4-5.6) 8.8 (4.3-12.9)
SWOG-16135 26 31 44 NR
TAPUR® 28 25 (11-45) 4 (2.6-6.4) 14 (7.5-23.9)
One patient had unknown HER status. » For est 13 patients env,
1. Mere-Bemstam F tal. Lance Oncol. 2019:20'518-530.2. Manc-Bemstam Feta. J Cin Oncol 2021:0(supl 18) Abstract 3004.3. Sweeney Cet J Cin
Oncol 2024:42:256-265 4 Nakamura Yet al. Not Med. 202%;27 1699-1003. 5. Raghav KPS etal. J Cn Oncol 2023:41(supp 4) Abstract 140.8, Gupta Ret al JCO AN
‘Precis Oncol 2022602200308 PeerView.com
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ORR, % (95% Cl) Median PFS, mo Median OS, mo
(95% Cl) (95% Cl)
86 (all RAS} 28 (19-39) 2.9 (1.4-5.3) 11.5 (7.7-NE)
MyPathway'® 69 (RAS WT) 32 (21-44) 4.1 (2.7-5.6) 15.5 (10.3-20.9)
16 (RAS mut) 12 (2-38) 1.4 (1.2-2.8)° NIA
27 tissue+ 30 (14-50) 4 (1.4-5.6) 10.1 (4.5-16.5)
TRIOMEEE 25 ctDNA+ 28 (12-49) 3.1 (1.4-5.6) 8.8 (4.3-12.9)
SWOG-16135 26 31 44 NR
TAPUR® 28 25 (11-45) 4 (2.6-6.4) 14 (7.5-23.9)
One patient had unknown HER status. » For est 13 patients env,
1. Mere-Bemstam F tal. Lance Oncol. 2019:20'518-530.2. Manc-Bemstam Feta. J Cin Oncol 2021:0(supl 18) Abstract 3004.3. Sweeney Cet J Cin
Oncol 2024:42:256-265 4 Nakamura Yet al. Not Med. 202%;27 1699-1003. 5. Raghav KPS etal. J Cn Oncol 2023:41(supp 4) Abstract 140.8, Gupta Ret al JCO AN
‘Precis Oncol 2022602200308 PeerView.com
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DESTINY-CRC01 Assessed T-DXd in Patients
With Previously Treated HER2-Expressing CRC!
+ Open-label, multicenter phase 2 study (NCT03384940)
T-DXd 6.4 mg/kg Q3W
Unresectable and/or metastatic CRC
HER2 expressing (central confirmation)
RAS/BRAF WT
22 prior regimens
Prior anti-HER2 treatment allowed
Futility monitoring was done after 220 patients in
cohort A had 12 weeks of follow-up to inform opening
of cohorts B and C
Excluded patients with a history of or
current/suspected ILD
+ Primary endpoint: confirmed ORR by ICR in cohort A
Cohort C (n = 18)
+ Data cutoff: August 9, 2019 HER2 IHC 1+
- 38.5% (30/78) remained on treatment
— 61.5% discontinued, primarily for progressive disease (41%) and clinical progression (9%)
1. Siena S et al ASCO 2020, Abstract 4000
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With Previously Treated HER2-Expressing CRC!
+ Open-label, multicenter phase 2 study (NCT03384940)
T-DXd 6.4 mg/kg Q3W
Unresectable and/or metastatic CRC
HER2 expressing (central confirmation)
RAS/BRAF WT
22 prior regimens
Prior anti-HER2 treatment allowed
Futility monitoring was done after 220 patients in
cohort A had 12 weeks of follow-up to inform opening
of cohorts B and C
Excluded patients with a history of or
current/suspected ILD
+ Primary endpoint: confirmed ORR by ICR in cohort A
Cohort C (n = 18)
+ Data cutoff: August 9, 2019 HER2 IHC 1+
- 38.5% (30/78) remained on treatment
— 61.5% discontinued, primarily for progressive disease (41%) and clinical progression (9%)
1. Siena S et al ASCO 2020, Abstract 4000
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DESTINY-CRC01: T-DXd Shows Durable Activity
in HER2+ mCRC Refractory to Standard Treatment!
DESTINY-CRC01 Efficacy: Response Rate in Cohort A and Subgroup Analysis
Cohort A: Best Percentage
Change In Tumor Size Cohort A: ORR by Subgroup
Ego
FH
po T RR BE
ge Bat de —= 453 ness
E Fr + ao 0308
65 =— 280749
sl sur == 20 uses
HE == 8er
E Region =-— 23 18016
35 I 9 am
ERES == wu 275001
55 006 PS Das + ai ons
6% 10:9) —E => 128
EE HERZ stats Inc 3+ (n= 40) — ss 409730
5a eos | Fr tae
5% Pro HER2 veses Yon n= 1) = ae em
5 EE == do ass
SE A | EE ERE TE LT]
EC EE mn
1. Yoshino Tet al. Nat Commun. 2023:14:3332. PeerView.com
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in HER2+ mCRC Refractory to Standard Treatment!
DESTINY-CRC01 Efficacy: Response Rate in Cohort A and Subgroup Analysis
Cohort A: Best Percentage
Change In Tumor Size Cohort A: ORR by Subgroup
Ego
FH
po T RR BE
ge Bat de —= 453 ness
E Fr + ao 0308
65 =— 280749
sl sur == 20 uses
HE == 8er
E Region =-— 23 18016
35 I 9 am
ERES == wu 275001
55 006 PS Das + ai ons
6% 10:9) —E => 128
EE HERZ stats Inc 3+ (n= 40) — ss 409730
5a eos | Fr tae
5% Pro HER2 veses Yon n= 1) = ae em
5 EE == do ass
SE A | EE ERE TE LT]
EC EE mn
1. Yoshino Tet al. Nat Commun. 2023:14:3332. PeerView.com
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DESTINY-CRC01: T-DXd Shows Durable Activity
in HER2+ mCRC Refractory to Standard Treatment!
DESTINY-CRC01 Efficacy: PFS and OS
PFS
HER HG Je or MC 26nSH cohort A
HER IMC 2414: or 8
A E E E
sora Tine, mo
ass 44 36 99 27 22 18 18 10 9 7 5 3 1 0
Sono da a 6 1 0 8 0 0 0 5 0 8 0 0 0
cme 18 4 1 0 0 0 0 0 0 9 0 0 0 0 8
HERZ IMG 30 FIG MER NC 278
cn here MERE te coher ©
Megan PFS couse 210440 140320
1. Yoshino Teta Nat Commun. 2023:14:3352,
PeerView.com/JPD827
os
100
»
ze ERA IG + or WNC 2418 hota
o verano
Her
» ER cote
of
ae ar E UE TE UE UE E VETE TEE ES
ir Timo, mo
Cha st 44 08 a5 32012825 2 18 1 6 1
Corn 15 14
6 oo
10 8654000000000
Goo G 18 15 8 8 6 6 4 3 3 2 0 0 0 oo
HERZINC 20 or NC HERZIHC 2vnsH-
msn Coben Cohen HERZINC 1 Cohort
$i ig 0
(och. mo 15508208 7360N€) 110209)
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in HER2+ mCRC Refractory to Standard Treatment!
DESTINY-CRC01 Efficacy: PFS and OS
PFS
HER HG Je or MC 26nSH cohort A
HER IMC 2414: or 8
A E E E
sora Tine, mo
ass 44 36 99 27 22 18 18 10 9 7 5 3 1 0
Sono da a 6 1 0 8 0 0 0 5 0 8 0 0 0
cme 18 4 1 0 0 0 0 0 0 9 0 0 0 0 8
HERZ IMG 30 FIG MER NC 278
cn here MERE te coher ©
Megan PFS couse 210440 140320
1. Yoshino Teta Nat Commun. 2023:14:3352,
PeerView.com/JPD827
os
100
»
ze ERA IG + or WNC 2418 hota
o verano
Her
» ER cote
of
ae ar E UE TE UE UE E VETE TEE ES
ir Timo, mo
Cha st 44 08 a5 32012825 2 18 1 6 1
Corn 15 14
6 oo
10 8654000000000
Goo G 18 15 8 8 6 6 4 3 3 2 0 0 0 oo
HERZINC 20 or NC HERZIHC 2vnsH-
msn Coben Cohen HERZINC 1 Cohort
$i ig 0
(och. mo 15508208 7360N€) 110209)
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Safety Consistent With Prior T-DXd Trials: ILD, Pneumonitis
Require Careful Monitoring, Prompt Intervention!
hort A: HERZ IHC 3+ or
TH 2+1SH+ (a= 53)
DESTINY-CRCO1 Results: Safety
Cohort 8:
HER2 INC 2¥/ISH- (n = 15)
Any Grade, Any Grade, Any Grade Any Grade Grade 23
tients with any TEAE 53 (100) 15 (100) 18 (100) 86 (100) 56 (65.1)
Nausea 37 698) sw 7089) 5361) 569)
Anomia 21 (096) 40267) 6633) 31.06) 12014)
Fatigue 21098) 7487) 3167) 3100) 102)
Decreased appetite we 533) 789) 30 (49) o
Decreased platelet count 17624) 487) 789) 28 (26) eos
Vomiting 2384) 3020) 168) 27314) 102)
Decreased neutrophil count 2671) 2093) 4022) 20002) 19.224)
Drache 19958) o 4022) 2387) 102)
Adjudicated Drug-Related ILD/Pneumonitis in All Cohorts Median time to onset: 61 (9-165) d
Grade 1
1%)
o
sun
de? Grades
102)
1.Yoshino Teta. Nat Commun. 2023:14:3352,
PeerView.com/JPD827
Grade 4
o
8/8 patients received corticosteroids
4 patients with grade 2 cases recovered; 1 with a grade 3 case did not
recover (later died: PD)
3.5 (0-50) d
+ Median time from onset to initiation of steroid treatment in all cases:
In the 3 fatal cases, onset was 9-120 (median, 22) d
Death occurred 6-19 (median, 6) d after diagnosis PeerView.com
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Require Careful Monitoring, Prompt Intervention!
hort A: HERZ IHC 3+ or
TH 2+1SH+ (a= 53)
DESTINY-CRCO1 Results: Safety
Cohort 8:
HER2 INC 2¥/ISH- (n = 15)
Any Grade, Any Grade, Any Grade Any Grade Grade 23
tients with any TEAE 53 (100) 15 (100) 18 (100) 86 (100) 56 (65.1)
Nausea 37 698) sw 7089) 5361) 569)
Anomia 21 (096) 40267) 6633) 31.06) 12014)
Fatigue 21098) 7487) 3167) 3100) 102)
Decreased appetite we 533) 789) 30 (49) o
Decreased platelet count 17624) 487) 789) 28 (26) eos
Vomiting 2384) 3020) 168) 27314) 102)
Decreased neutrophil count 2671) 2093) 4022) 20002) 19.224)
Drache 19958) o 4022) 2387) 102)
Adjudicated Drug-Related ILD/Pneumonitis in All Cohorts Median time to onset: 61 (9-165) d
Grade 1
1%)
o
sun
de? Grades
102)
1.Yoshino Teta. Nat Commun. 2023:14:3352,
PeerView.com/JPD827
Grade 4
o
8/8 patients received corticosteroids
4 patients with grade 2 cases recovered; 1 with a grade 3 case did not
recover (later died: PD)
3.5 (0-50) d
+ Median time from onset to initiation of steroid treatment in all cases:
In the 3 fatal cases, onset was 9-120 (median, 22) d
Death occurred 6-19 (median, 6) d after diagnosis PeerView.com
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DESTINY-CRC02 Is Assessing Different Doses of T-DXd!
STAGE 2
STAGE 1°
Arm 1
T-DXd 5.4 mg/kg
Patients with
HER2- Stratification factors
overexpressing ECOG PS: 0 or 1
(IHC 3+ or IHC HER? status: IHC 3+
2+/ISH+)? or IHC 2+/1SH+
unresectable, RAS status (WT vs
recurrent, mutant)
or metastatic CRC
T-DXd 5.4 mg/kg Q3W
+ Primary objective: assess efficacy of T-DXd at the 5.4 mg/kg and 6.4 mg/kg doses
+ Primary endpoint: confirmed ORR by blinded ICR
* Enrollment wil not be interrupted beton stages 1 and 2; is not the intent to modify the study design based onthe Interim analysis resus. Study is binded to
im and ants. Mase number plan wih HERZ IC 20+ 0 Manu and minimum nun of urs wih PAS man Sat
12 30 andn = 20, respective) A
1 ps calais gov show NCTO4T 4481 PeerView.com
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STAGE 2
STAGE 1°
Arm 1
T-DXd 5.4 mg/kg
Patients with
HER2- Stratification factors
overexpressing ECOG PS: 0 or 1
(IHC 3+ or IHC HER? status: IHC 3+
2+/ISH+)? or IHC 2+/1SH+
unresectable, RAS status (WT vs
recurrent, mutant)
or metastatic CRC
T-DXd 5.4 mg/kg Q3W
+ Primary objective: assess efficacy of T-DXd at the 5.4 mg/kg and 6.4 mg/kg doses
+ Primary endpoint: confirmed ORR by blinded ICR
* Enrollment wil not be interrupted beton stages 1 and 2; is not the intent to modify the study design based onthe Interim analysis resus. Study is binded to
im and ants. Mase number plan wih HERZ IC 20+ 0 Manu and minimum nun of urs wih PAS man Sat
12 30 andn = 20, respective) A
1 ps calais gov show NCTO4T 4481 PeerView.com
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DESTINY-CRCO2: Efficacy Outcomes’
5.4 mg/kg Q3W
(n =82)
6.4 mg/kg Q3W
(n= 40)
Confirmed ORR, % (95% Cl) 37.8 (27.3-49.2) 27.5 (14.6-43.9)
mDOR, mo (95% CI) 5.5 (4.2-8.1) 5.5 (3.7-NE)
Disease control rate, % (95% Cl) | 86.6 (77.3-93.1) 85 (70.2-94.3)
PFS, mo (95% Cl) 5.8 (4.6-7.0) 5.5 (4.2-7.0)
OS, mo (95% Cl) 13.4 (12.5-16.8) NE (9.9-NE)
1. Raghav K otal ASCO 2023. Abstract 3501 PeerView.com
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5.4 mg/kg Q3W
(n =82)
6.4 mg/kg Q3W
(n= 40)
Confirmed ORR, % (95% Cl) 37.8 (27.3-49.2) 27.5 (14.6-43.9)
mDOR, mo (95% CI) 5.5 (4.2-8.1) 5.5 (3.7-NE)
Disease control rate, % (95% Cl) | 86.6 (77.3-93.1) 85 (70.2-94.3)
PFS, mo (95% Cl) 5.8 (4.6-7.0) 5.5 (4.2-7.0)
OS, mo (95% Cl) 13.4 (12.5-16.8) NE (9.9-NE)
1. Raghav K otal ASCO 2023. Abstract 3501 PeerView.com
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DESTINY-CRC-02: Best ORR (BICR)
by T-DXd 5.4 mg/kg Subgroup’
Subgroups (N = 82) ORR, nN ORR, % (95% CI)
‘All patients, 5.4 mg/kg — —— 31/82 37.8 (27.3492)
HERZ status H
IHC 3+ os 30164 46.9 (34.3-59.8)
IHC 2eISH+ = H 1118 5.6 (0.1-27.3)
RAS status 1
WT —— 27168 39,7 (28.0-52.3)
Mutant et 4/14 28.6 (8.4-58.1)
ECOG PS {
0 — 18146 39.1 (25.1-54.6)
1 —— 13/36 36.1 (20.8-53.8)
Primary tumor site
Left colon? 24/61 39.3 (27.1-52.7)
Right colon? 721 33.3 (14.6-57.0)
Prior anti-HER2 treatment
No 24/65 36.9 (25.3-49.8)
Yes TAT 41.2 (18.4-67.1)
EE soon ©
ORR, %
Based on no exact Copper-Pearson mathod or binomial dstrbuton.* Al RAS muated responders wre IHC 3, Includes rectum, sigmoid, and descending
ncudos cecum, ascending, and vansvese. e
1. Raghav K et al. ASCO 2023, Abstract 3501. PeerView.com
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by T-DXd 5.4 mg/kg Subgroup’
Subgroups (N = 82) ORR, nN ORR, % (95% CI)
‘All patients, 5.4 mg/kg — —— 31/82 37.8 (27.3492)
HERZ status H
IHC 3+ os 30164 46.9 (34.3-59.8)
IHC 2eISH+ = H 1118 5.6 (0.1-27.3)
RAS status 1
WT —— 27168 39,7 (28.0-52.3)
Mutant et 4/14 28.6 (8.4-58.1)
ECOG PS {
0 — 18146 39.1 (25.1-54.6)
1 —— 13/36 36.1 (20.8-53.8)
Primary tumor site
Left colon? 24/61 39.3 (27.1-52.7)
Right colon? 721 33.3 (14.6-57.0)
Prior anti-HER2 treatment
No 24/65 36.9 (25.3-49.8)
Yes TAT 41.2 (18.4-67.1)
EE soon ©
ORR, %
Based on no exact Copper-Pearson mathod or binomial dstrbuton.* Al RAS muated responders wre IHC 3, Includes rectum, sigmoid, and descending
ncudos cecum, ascending, and vansvese. e
1. Raghav K et al. ASCO 2023, Abstract 3501. PeerView.com
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Case Discussion: A Female Pati
Aged 60 years
No allergies
Former smoker
No other underlying illnesses
Father (smoker) had lung cancer at 75 years
Exons 2,3,4 KRAS WT
Exons 2,3,4 NRAS WT
Exon 15 BRAF WT
pMMR/MSS
Images courtesy of Elena Elez, MD, PAO.
PeerView.com/JPD827
ent Presenting With mCRC?
December 2018: weight loss and asthenia
Endoscopy PET-CT scan
Low-grade sigmoid adenocarcinoma Possible bone lesion (L4)
CT scan
‘Sigmoid tumor + liver metastasis.
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Aged 60 years
No allergies
Former smoker
No other underlying illnesses
Father (smoker) had lung cancer at 75 years
Exons 2,3,4 KRAS WT
Exons 2,3,4 NRAS WT
Exon 15 BRAF WT
pMMR/MSS
Images courtesy of Elena Elez, MD, PAO.
PeerView.com/JPD827
ent Presenting With mCRC?
December 2018: weight loss and asthenia
Endoscopy PET-CT scan
Low-grade sigmoid adenocarcinoma Possible bone lesion (L4)
CT scan
‘Sigmoid tumor + liver metastasis.
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Progression After Upfront Therapy—What’s Next?
+ Aged 60 years
+ Exons 2,3,4 KRAS WT
+ Exons 2,3,4 NRAS WT
Exon 15 BRAF WT
pMMR/MSS
+ Diagnosis: stage IV sigmoid colon
adenocarcinoma (liver metastasis)
+ Multidisciplinary team assessment:
nonresectable/1L FOLFOX + panitumumab
(C1: January 2, 2019)
Images courtesy of Elena Elez, MD, PhD.
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4 cycles
+ Partial response
10 cycles
+ Confirmed partial response
July 2019 December 2019
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+ Aged 60 years
+ Exons 2,3,4 KRAS WT
+ Exons 2,3,4 NRAS WT
Exon 15 BRAF WT
pMMR/MSS
+ Diagnosis: stage IV sigmoid colon
adenocarcinoma (liver metastasis)
+ Multidisciplinary team assessment:
nonresectable/1L FOLFOX + panitumumab
(C1: January 2, 2019)
Images courtesy of Elena Elez, MD, PhD.
PeerView.com/JPD827
4 cycles
+ Partial response
10 cycles
+ Confirmed partial response
July 2019 December 2019
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Surgery With Additional Follow-Up Recommended
November 2019: sigmoidectomy
Aged 60 years + Pathology report: pT4a pNia G2
Exons 2,3,4 KRAS WT (1/28) IL+IV+ IP+, RO
Exons ZI NRASWT December 2019: liver
Exon 15 BRAF WT bisegmentectomy
PMMR/MSS + Pathology report: adenocarcinoma,
New multidisciplinary team RO, RAS/BRAF WT
assessment: patient is suitable for
surgery FOLLOW-UP
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November 2019: sigmoidectomy
Aged 60 years + Pathology report: pT4a pNia G2
Exons 2,3,4 KRAS WT (1/28) IL+IV+ IP+, RO
Exons ZI NRASWT December 2019: liver
Exon 15 BRAF WT bisegmentectomy
PMMR/MSS + Pathology report: adenocarcinoma,
New multidisciplinary team RO, RAS/BRAF WT
assessment: patient is suitable for
surgery FOLLOW-UP
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HER2+ Status Confirmed After Additional Therapy
and Another Progression—What Are the Options?
+ Tissue sample
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Liver sample 2019: IHC HER2+++
NGS (liquid biopsy): TP53, APC, and
PTEN mutations
ERBB2 amplified +++ (CN 5.7)
MSS
May 2020: liver, peritoneal, and bone
progression (progression-free interval: 6 mo)
+ 5 cycles FOLFIRI + bevacizumab
(C1: May 2020)
PROGRESSION OF DISEASE
liver, lung, and bone)
« Palliative radiotherapy (L4)
October 2020: liver and peritoneal
progression
+ Clinical trial: dual-HER2 blockade
(C1: November 2020, 3 cycles total)
Partial response
* 6cycles
PROGRESSION OF DISEASE (July 2021)
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and Another Progression—What Are the Options?
+ Tissue sample
PeerView.com/JPD827
Liver sample 2019: IHC HER2+++
NGS (liquid biopsy): TP53, APC, and
PTEN mutations
ERBB2 amplified +++ (CN 5.7)
MSS
May 2020: liver, peritoneal, and bone
progression (progression-free interval: 6 mo)
+ 5 cycles FOLFIRI + bevacizumab
(C1: May 2020)
PROGRESSION OF DISEASE
liver, lung, and bone)
« Palliative radiotherapy (L4)
October 2020: liver and peritoneal
progression
+ Clinical trial: dual-HER2 blockade
(C1: November 2020, 3 cycles total)
Partial response
* 6cycles
PROGRESSION OF DISEASE (July 2021)
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Three Key Take-Homes From This Case
For this patient with CRC, earlier HER2 testing would have
been optimal
Early confirmation of HER amplification would have supported
earlier use of HER2-directed therapy
Clinical trials testing trastuzumab or T-DXd—based options
could have been considered, allowing for earlier use of
HER2-directed therapy
PeerView.com
PeerView.com/JPD827
For this patient with CRC, earlier HER2 testing would have
been optimal
Early confirmation of HER amplification would have supported
earlier use of HER2-directed therapy
Clinical trials testing trastuzumab or T-DXd—based options
could have been considered, allowing for earlier use of
HER2-directed therapy
PeerView.com
PeerView.com/JPD827
HER2 in mCRC:
HER2 amplification/overexpression is an actionable target in refractory HER2+ mCRC
HER2 should be tested in all patients with mCRC (NGS testing and/or IHC/FISH)
Anti-HER2 therapies demonstrate greatest efficacy
in biomarker-selected HER2+ mCRC patient populations
IHC 3+ High gene copy number KRAS, NRAS, PIK3CA, and BRAF WT
Several anti-HER2 therapies have demonstrated efficacy
+ Trastuzumab + tucatinib has high ORR and DOR with favorable tolerability
+ Trastuzumab deruxtecan has activity in RAS-mutated HER2+ disease and retains activity after
progression on prior anti-HER2 therapies
Key considerations: clinical/genomic characteristics, efficacy, and AE profile
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inal Thoughts
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HER2 amplification/overexpression is an actionable target in refractory HER2+ mCRC
HER2 should be tested in all patients with mCRC (NGS testing and/or IHC/FISH)
Anti-HER2 therapies demonstrate greatest efficacy
in biomarker-selected HER2+ mCRC patient populations
IHC 3+ High gene copy number KRAS, NRAS, PIK3CA, and BRAF WT
Several anti-HER2 therapies have demonstrated efficacy
+ Trastuzumab + tucatinib has high ORR and DOR with favorable tolerability
+ Trastuzumab deruxtecan has activity in RAS-mutated HER2+ disease and retains activity after
progression on prior anti-HER2 therapies
Key considerations: clinical/genomic characteristics, efficacy, and AE profile
PeerView.com
inal Thoughts
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Wielding New Therapeutic Tools
to Manage HER2-Amplified BTC
Modern and Emerging Targeted Approaches
to Improve Patient Survival
Shubham Pant, MD
Professor
Department of Gastrointestinal Medical Oncology
Department of Investigational Cancer Therapeutics
The University of Texas MD Anderson Cancer Center
Houston, Texas
2000-2024, PeerView
to Manage HER2-Amplified BTC
Modern and Emerging Targeted Approaches
to Improve Patient Survival
Shubham Pant, MD
Professor
Department of Gastrointestinal Medical Oncology
Department of Investigational Cancer Therapeutics
The University of Texas MD Anderson Cancer Center
Houston, Texas
2000-2024, PeerView
The Cholangiocarcinoma Foundation Is an Excellent
Resource for Professionals, Patients, and Caregivers?
The Cholangiocarcinoma Foundation’s ([email protected]) mission is to find a
cure and improve the quality of life for those affected by cholangiocarcinoma (bile duct cancer)
Visit https://cholangiocarcinoma.org/ for multiple Selected resources include
resources that patients can use to [ga] International Cholangiocarcinoma
Get the latest information about their disease a Patient Registry (ICPR)
Connect with other patients —— ss
Participate in clinical trials, A
And much more # un ===]
ee WU Find a Specialist
a hlios/cholangiocarcinoma org/specialistmap/
Find and Learn About Clinical Trials
I x
Https://cholangiocarcinoma.org/professionals!
fesearchiclinical-trials/ S
Behinarseries
“in supa l moving patent cae is cy has bean lanes an inpamented y PU, Poe Isa Mia Education, x
and ie Cholangiocarinoma Fou PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Resource for Professionals, Patients, and Caregivers?
The Cholangiocarcinoma Foundation’s ([email protected]) mission is to find a
cure and improve the quality of life for those affected by cholangiocarcinoma (bile duct cancer)
Visit https://cholangiocarcinoma.org/ for multiple Selected resources include
resources that patients can use to [ga] International Cholangiocarcinoma
Get the latest information about their disease a Patient Registry (ICPR)
Connect with other patients —— ss
Participate in clinical trials, A
And much more # un ===]
ee WU Find a Specialist
a hlios/cholangiocarcinoma org/specialistmap/
Find and Learn About Clinical Trials
I x
Https://cholangiocarcinoma.org/professionals!
fesearchiclinical-trials/ S
Behinarseries
“in supa l moving patent cae is cy has bean lanes an inpamented y PU, Poe Isa Mia Education, x
and ie Cholangiocarinoma Fou PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Right hepatic duct
PeerView.com/JPD827
Cystic duct
Distal common
bile duct
Biliary Cancers
Left hepatic duct
Common
hepatic duct
Common
bile duct
I intrahepatic—in the liver
I Pertilar—near the hilum
(where the bile ducts exit the liver)
[M Distal extrahepatic—outside the liver
PeerView.com
Copyright © 2000-2024, PeerView
PeerView.com/JPD827
Cystic duct
Distal common
bile duct
Biliary Cancers
Left hepatic duct
Common
hepatic duct
Common
bile duct
I intrahepatic—in the liver
I Pertilar—near the hilum
(where the bile ducts exit the liver)
[M Distal extrahepatic—outside the liver
PeerView.com
Copyright © 2000-2024, PeerView
Current Shortcomings in the Management
of Advanced Biliary Cancers’
of 1,009 oncology pro
rs found that 81% were not confident in their ability
to use targeted therapies in patients with advanced CCA
Moreover...
meas
First Line Second Line
|
een coma |
er
ser
==
sms |
=
—
Third Line
|
en
nt chem =
oer
1. Parikh K ta, ASCO GI 2021. Abstract 347.2. Valderrama A at a, ASCO GI 2022. Abstract 398.
PeerView.com/JPD827
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 the third line
of treatment
Median time on treatment in the first line was
3.2 months; in both the second and third lines,
median time was 2.7 months
PeerView.com
Copyright O 2000-2024, Peerview
of Advanced Biliary Cancers’
of 1,009 oncology pro
rs found that 81% were not confident in their ability
to use targeted therapies in patients with advanced CCA
Moreover...
meas
First Line Second Line
|
een coma |
er
ser
==
sms |
=
—
Third Line
|
en
nt chem =
oer
1. Parikh K ta, ASCO GI 2021. Abstract 347.2. Valderrama A at a, ASCO GI 2022. Abstract 398.
PeerView.com/JPD827
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 the third line
of treatment
Median time on treatment in the first line was
3.2 months; in both the second and third lines,
median time was 2.7 months
PeerView.com
Copyright O 2000-2024, Peerview
Biliary Tract Cancers: Genomic Differences
Based on Tumor Location!
Biomarker-driven management to
improve outcomes.
Biospecimen sampling
(tumor, blood, urine) __A
Gallbladder carcinoma
UL Eco
“GBC ana EOS
AS muta
(OO 10 48%)
Lo equ ot
Large duct 60 a
KR mios || sor ee
Grow || “aseo =
FPR re
(Gon 020%)
tr
1. Seott Ad et al. J Cin Oncol. 2022:40:2716:27%4. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Based on Tumor Location!
Biomarker-driven management to
improve outcomes.
Biospecimen sampling
(tumor, blood, urine) __A
Gallbladder carcinoma
UL Eco
“GBC ana EOS
AS muta
(OO 10 48%)
Lo equ ot
Large duct 60 a
KR mios || sor ee
Grow || “aseo =
FPR re
(Gon 020%)
tr
1. Seott Ad et al. J Cin Oncol. 2022:40:2716:27%4. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Phase 3 ABC-06: Second-Line FOLFOX Chemotherapy vs
Active Symptom Control for Advanced BTC’
Best Response Rate
(RECIST v1.1)
CR
PR
so
Response rate
—— (CR+PR)
Disease control rate
(CR + PR + SD)
Progressive disease
Death
Not evaluable
(nonmeasurable
disease)
1. Lamarca et al. Lancet Oncol. 2021:22:690-701.
PeerView.com/JPD827
23
27
23
‘Arm B (ASC + FOLFOX),
28
33
37
3
Ito
2:
24 0
33 190+ Faro
HE
28
“ ‘oy
EN a
o
man
ASC*FOUFOK 81 54 20 16 8
x
2
ASC + mFOLFOX
Radiological PFS.
16 mo
133m Yen
184m
Median PFS: 4 months
(95% Cl, 32-5.0)
PAC
EE)
o
OS by Trial Arm
o
‘Time From Randomization, mo
0
o
ArmA AmBiasc+
(ASC Alone) _"MEOLEOX
Sm
Adjusted HR
53 62
0.69 95% cl,0.50.097)
Pe ot
os, eo TE TE TE TE ETE
cual Time From Randomization, mo
Mouse 8 @ 20 1 0
ASCemrourox 81 Gt 41 20 21
9
A
$
3
4
2
¿ PeerView.com
Copyright © 2000-2024, PeerView
Active Symptom Control for Advanced BTC’
Best Response Rate
(RECIST v1.1)
CR
PR
so
Response rate
—— (CR+PR)
Disease control rate
(CR + PR + SD)
Progressive disease
Death
Not evaluable
(nonmeasurable
disease)
1. Lamarca et al. Lancet Oncol. 2021:22:690-701.
PeerView.com/JPD827
23
27
23
‘Arm B (ASC + FOLFOX),
28
33
37
3
Ito
2:
24 0
33 190+ Faro
HE
28
“ ‘oy
EN a
o
man
ASC*FOUFOK 81 54 20 16 8
x
2
ASC + mFOLFOX
Radiological PFS.
16 mo
133m Yen
184m
Median PFS: 4 months
(95% Cl, 32-5.0)
PAC
EE)
o
OS by Trial Arm
o
‘Time From Randomization, mo
0
o
ArmA AmBiasc+
(ASC Alone) _"MEOLEOX
Sm
Adjusted HR
53 62
0.69 95% cl,0.50.097)
Pe ot
os, eo TE TE TE TE ETE
cual Time From Randomization, mo
Mouse 8 @ 20 1 0
ASCemrourox 81 Gt 41 20 21
9
A
$
3
4
2
¿ PeerView.com
Copyright © 2000-2024, PeerView
HER2 Overexpression and Prognosis’
100 Disease-Free Survival 100 Overall Survival
80 80
&
$
2
Eso 60
3
2
£ 40 40
©
8 HER2- HER2-
© 20 20
HER2+ HER2+
0 0
O 12 24 36 48 60 72 84 96 108 120 O 12 24 36 48 60 72 84 96 108120132
Time, mo Time, mo
DFS according to HER2 status OS curves according to HERZ status
Median DFS: 10.1 vs 17.8 months, P =.04 Median OS: 23.5 vs 36.1 months, P = 241
1. Vivaldi © et al. The Oncologist 2020;25:886-893. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
100 Disease-Free Survival 100 Overall Survival
80 80
&
$
2
Eso 60
3
2
£ 40 40
©
8 HER2- HER2-
© 20 20
HER2+ HER2+
0 0
O 12 24 36 48 60 72 84 96 108 120 O 12 24 36 48 60 72 84 96 108120132
Time, mo Time, mo
DFS according to HER2 status OS curves according to HERZ status
Median DFS: 10.1 vs 17.8 months, P =.04 Median OS: 23.5 vs 36.1 months, P = 241
1. Vivaldi © et al. The Oncologist 2020;25:886-893. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
MyPathway Trial: Pertuzumab and Trastuzumab
for HER2+ Metastatic BTC’
661 patients enrolled in MyPathway
39 with HER2+ metastatic BTC
39 treated and eligible for efficacy analysis
36 discontinued from study
3 still on treatment treatment (35 PD, 1 death)
HA
32 discontinued from study
treatment (28 deaths:
1 completed study;
2 patient withdrawals;
1 lost to follow-up)
4 still in follow-up
1.Jave M ot al Lancot Oncol. 2021:22:1290-1300.
PeerView.com/JPD827
ORR 29%
Be
Es
ö
5°
38
38
BE | ost overt response
& a Partial response
Sule casa
100 LM Progressive disease
THAW WTOTNNTHAMS CANON ENS EU TIT ETES
Patient
PeerView.com
Copyright © 2000-2024, Peerview
for HER2+ Metastatic BTC’
661 patients enrolled in MyPathway
39 with HER2+ metastatic BTC
39 treated and eligible for efficacy analysis
36 discontinued from study
3 still on treatment treatment (35 PD, 1 death)
HA
32 discontinued from study
treatment (28 deaths:
1 completed study;
2 patient withdrawals;
1 lost to follow-up)
4 still in follow-up
1.Jave M ot al Lancot Oncol. 2021:22:1290-1300.
PeerView.com/JPD827
ORR 29%
Be
Es
ö
5°
38
38
BE | ost overt response
& a Partial response
Sule casa
100 LM Progressive disease
THAW WTOTNNTHAMS CANON ENS EU TIT ETES
Patient
PeerView.com
Copyright © 2000-2024, Peerview
HERB Trial: T-DXd Shows Activity in Patients
1. Ohba A et a. ASCO 2022. Abstract 4006
PeerView.com/JPD827
Maximum Tumor Shrinkage
From Baseline, %
With HER2-Expressing BTCs!
Key inclusion criteria
+ Histologically confirmed
‘unresectable or recurrent BTC
+Centraly confirmed HER2-
‘expressing status
expressing | +Retractory or intolerant to
treatment, including gemcitabine
«ECOGPS 0 or t
7 7 Noireienes 16 inal sites’
ORR (HER2+): 36.4%
HERZ»
HER? low oxpressng
8858.83888
Patients
SCRUM-Japan registry study
PeerView.com
Copyright © 2000-2024, PeerView
1. Ohba A et a. ASCO 2022. Abstract 4006
PeerView.com/JPD827
Maximum Tumor Shrinkage
From Baseline, %
With HER2-Expressing BTCs!
Key inclusion criteria
+ Histologically confirmed
‘unresectable or recurrent BTC
+Centraly confirmed HER2-
‘expressing status
expressing | +Retractory or intolerant to
treatment, including gemcitabine
«ECOGPS 0 or t
7 7 Noireienes 16 inal sites’
ORR (HER2+): 36.4%
HERZ»
HER? low oxpressng
8858.83888
Patients
SCRUM-Japan registry study
PeerView.com
Copyright © 2000-2024, PeerView
DESTINY-PanTumor02: T-DXd Has Broad Activity,
Including for HER2+ BTC’
846
5
57.5 ] se 56.3
147.1 0) 40 45 I u
Endometrial____Cervical Ovarian Bladder Pancreatic
NR (9.9-NR)
Objective Response and Duration of Response
MAIL mIHC 3+ mIHC 2+
Confirmed ORR
by Investigator, %
0383888338388
Median DOR,
mo (95% Cl 142(4.1-NR) 113(41221) 87(43118) 221(41-NR) | 86(21-NR) 5.7 (NR-NR)
All Patients ) IHC 3+ (n= 75) 25)
‘ORR, % (05% CI) 37.1 (31.3-43.2) 61.3 (49.4-72.4) 27.2 (19.6-35.9)
Median DOR, mo (95% Cl) 11.3 (06-178) 22.1 (9.6-NR) 98 (4.3-12.6)
1. Mere Borstam F ota
:SMO 2023. Abstract LBA. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Including for HER2+ BTC’
846
5
57.5 ] se 56.3
147.1 0) 40 45 I u
Endometrial____Cervical Ovarian Bladder Pancreatic
NR (9.9-NR)
Objective Response and Duration of Response
MAIL mIHC 3+ mIHC 2+
Confirmed ORR
by Investigator, %
0383888338388
Median DOR,
mo (95% Cl 142(4.1-NR) 113(41221) 87(43118) 221(41-NR) | 86(21-NR) 5.7 (NR-NR)
All Patients ) IHC 3+ (n= 75) 25)
‘ORR, % (05% CI) 37.1 (31.3-43.2) 61.3 (49.4-72.4) 27.2 (19.6-35.9)
Median DOR, mo (95% Cl) 11.3 (06-178) 22.1 (9.6-NR) 98 (4.3-12.6)
1. Mere Borstam F ota
:SMO 2023. Abstract LBA. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Tumor-Agnostic FDA Approval for T-DXd
Updated NCCN Guidelines for Biliary Cancer!
Second- or subsequent-line therapy: T-DXd added for HER2+ tumors (IHC 3+)
Useful in certain circumstances
Accelerated FDA Approval?
For adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors who have
received prior systemic treatment and have no satisfactory alternative treatment options
ASCO 2024
T-DXd showed clinically meaningful benefit in patients with BTC across primary tumor
locations, and data support further exploration of T-DXd in this population?
1. NCCN Cinical Practice Guidelines in Oncology. Bilary Tract Cancers. Version 2.2024. 2. ht
rugsia.grant- accelerated approval lam-vastusumab-deruxtocar-naki-unresectabe-oF met
vs da. goviéregsesourcos-informas
ener. 3 Oh D-Y etal, ASCO 2024. A
PeerView.com
PeerView.com/JPD827 Copyrigh!
Updated NCCN Guidelines for Biliary Cancer!
Second- or subsequent-line therapy: T-DXd added for HER2+ tumors (IHC 3+)
Useful in certain circumstances
Accelerated FDA Approval?
For adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors who have
received prior systemic treatment and have no satisfactory alternative treatment options
ASCO 2024
T-DXd showed clinically meaningful benefit in patients with BTC across primary tumor
locations, and data support further exploration of T-DXd in this population?
1. NCCN Cinical Practice Guidelines in Oncology. Bilary Tract Cancers. Version 2.2024. 2. ht
rugsia.grant- accelerated approval lam-vastusumab-deruxtocar-naki-unresectabe-oF met
vs da. goviéregsesourcos-informas
ener. 3 Oh D-Y etal, ASCO 2024. A
PeerView.com
PeerView.com/JPD827 Copyrigh!
Tucatinib and Trastuzumab Efficacy and Safety’
Change From Baseline in Each Patient
Change From Baseline, % _
os eas s
ees 8
Median DOR: 6 mo
Individual Patients (N = 29)*
' Percentages may not add upto a total due to rounding,
4. Nakamura Y at al ASCO 2023. Abstract 4007.
PeerView.com/JPD827
Most Common TEAEs (210%)
y Grace 12
Grade 23
Frequency, %.
A +
Most common grade 23 TEAEs were nausea, decreased
appetite, and cholangitis, each in 3 patients (10%
ll Utd "GPL. Yl Cle
rd
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Copyright © 2000-2024, PeerView
Change From Baseline in Each Patient
Change From Baseline, % _
os eas s
ees 8
Median DOR: 6 mo
Individual Patients (N = 29)*
' Percentages may not add upto a total due to rounding,
4. Nakamura Y at al ASCO 2023. Abstract 4007.
PeerView.com/JPD827
Most Common TEAEs (210%)
y Grace 12
Grade 23
Frequency, %.
A +
Most common grade 23 TEAEs were nausea, decreased
appetite, and cholangitis, each in 3 patients (10%
ll Utd "GPL. Yl Cle
rd
PeerView.com
Copyright © 2000-2024, PeerView
Phase 1 Trial of Zanidatamab in Patients With Locally
Advanced/Metastatic HER2-Expressing Cancers!
rt 1 Dose Escalation
{N = 46)
Cat ny conc
cones 1 amy concer Gras Cate 56: GEA cohen 7.86
A IN O CS)
ow caw caw am
Smoke tong 15m conato nota mato sonoro
Part 2 Dose Expansion
(N= 86)
‘Cohort: any cancers other than BC or GEA
IHC 3e or IHC 2+/FISHe
20 mg Qu
BTC cre Other
n=22 8. n=36
2 ncudes BC (n= 8) gastri cancr (= 5), CRC (n = 1) skin cancer (= 1) an osophageal cancer (n = 1) * Includes BC (n = 3). ceria cancer ( 1). esophageal
cancer (n= 1), GE (n= 1 and gaste cancer (n= 1). One patent wth CRC recewed 10 mghg QW and was pooled wit th 20 mag Q2W dose for analyses A
1. Merc Berstam F cet Oncol, 2022:23:1858-1570. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
Advanced/Metastatic HER2-Expressing Cancers!
rt 1 Dose Escalation
{N = 46)
Cat ny conc
cones 1 amy concer Gras Cate 56: GEA cohen 7.86
A IN O CS)
ow caw caw am
Smoke tong 15m conato nota mato sonoro
Part 2 Dose Expansion
(N= 86)
‘Cohort: any cancers other than BC or GEA
IHC 3e or IHC 2+/FISHe
20 mg Qu
BTC cre Other
n=22 8. n=36
2 ncudes BC (n= 8) gastri cancr (= 5), CRC (n = 1) skin cancer (= 1) an osophageal cancer (n = 1) * Includes BC (n = 3). ceria cancer ( 1). esophageal
cancer (n= 1), GE (n= 1 and gaste cancer (n= 1). One patent wth CRC recewed 10 mghg QW and was pooled wit th 20 mag Q2W dose for analyses A
1. Merc Berstam F cet Oncol, 2022:23:1858-1570. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
Antitumor Activity in Patients With HER2-Expressing BTC
Treated With Zanidatamab in Part 2 of Study’
Phase 1 Study:
Patients With Biliary Cancers
3 8
8 à
o
Median DOR:
Median PFS;
ORR 40% DCR 65% DOR 7.4 mo
* Doted Ines represent 20% increase or 30% decrease in tumor size. Watrtal lt of greatest percentage change inthe sum ol th longest diameter of measurable
tumors in palta wth Dry tract cane. 7
1. Mare Bornstam Fetal, Lancet Oncol 2022.23:1558-1570. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
Treated With Zanidatamab in Part 2 of Study’
Phase 1 Study:
Patients With Biliary Cancers
3 8
8 à
o
Median DOR:
Median PFS;
ORR 40% DCR 65% DOR 7.4 mo
* Doted Ines represent 20% increase or 30% decrease in tumor size. Watrtal lt of greatest percentage change inthe sum ol th longest diameter of measurable
tumors in palta wth Dry tract cane. 7
1. Mare Bornstam Fetal, Lancet Oncol 2022.23:1558-1570. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
HERIZON-BTC-01 Trial: A Global Phase 2b Study
of Zanidatamab Monotherapy in HER2-Amplified BTC1
Repeating every month + Primary endpoint: ORR
+ Key secondary endpoints:
DOR, DCR, PFS, OS,
frequency and severity of
AEs, and frequency of SAES
and deaths
Every 8 weeks:
CTMRI
Patients with Day 1 Day 15
HER2-amplified BTC
(N = 100)
Zanidatamab
By Investigator Assessment
(0 = 80)
‘Confirmed ORR, % (95% CI) 41.3 (804-528) 413 004-528)
Confirmed BOR, n (%)
CR 103 46) 16 patients had
PR 32.0) 20639)
u Es a ongoing responses at the time
Po 24 (80) 25 (51.3) of data cutoff
NE 1113) 143)
DCR (CR + PR + SD), % (95% CI) 688 (574787) 675 (561-776)
CBR (CR + PR + [SD 26 mo} %
ce 475 (862500) 475 (862-500)
1. Pant 8 et al ASCO 2029. Abstract 4008. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
of Zanidatamab Monotherapy in HER2-Amplified BTC1
Repeating every month + Primary endpoint: ORR
+ Key secondary endpoints:
DOR, DCR, PFS, OS,
frequency and severity of
AEs, and frequency of SAES
and deaths
Every 8 weeks:
CTMRI
Patients with Day 1 Day 15
HER2-amplified BTC
(N = 100)
Zanidatamab
By Investigator Assessment
(0 = 80)
‘Confirmed ORR, % (95% CI) 41.3 (804-528) 413 004-528)
Confirmed BOR, n (%)
CR 103 46) 16 patients had
PR 32.0) 20639)
u Es a ongoing responses at the time
Po 24 (80) 25 (51.3) of data cutoff
NE 1113) 143)
DCR (CR + PR + SD), % (95% CI) 688 (574787) 675 (561-776)
CBR (CR + PR + [SD 26 mo} %
ce 475 (862500) 475 (862-500)
1. Pant 8 et al ASCO 2029. Abstract 4008. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
Treatment Duration for Patients With Response (CR or PR)
or Stable Disease per RECIST v1.1 by ICR (Cohort 1)!
N=80
12.9 (1.5-16.9+)
Median DOR, mo (range)
2 Median time to first response, mo (range) 1.8 (1.655)
= Median duration of follow-up, mo (range) 124 (7-24)
a ‘Median duration of treatment, mo (range) 56 (0.5-19.84)
© Tumor response
M Disease progression
> Treatment ongoing
21
18
9 12 15
Time From Treatment Start, mo
Time to tumor response or treatment duration end Time from tumor response to treatment duration end
PeerView.com
o 3 6
1. Harding et al. Lancet Oncol 2029,24:772:782.
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
or Stable Disease per RECIST v1.1 by ICR (Cohort 1)!
N=80
12.9 (1.5-16.9+)
Median DOR, mo (range)
2 Median time to first response, mo (range) 1.8 (1.655)
= Median duration of follow-up, mo (range) 124 (7-24)
a ‘Median duration of treatment, mo (range) 56 (0.5-19.84)
© Tumor response
M Disease progression
> Treatment ongoing
21
18
9 12 15
Time From Treatment Start, mo
Time to tumor response or treatment duration end Time from tumor response to treatment duration end
PeerView.com
o 3 6
1. Harding et al. Lancet Oncol 2029,24:772:782.
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Adverse Events of Special Interest!
Cohort 1 (N = 80) Total (N = 87)
Any Grade Grade 23 Any Grade Grade 23
AESI, n (%)
IRR
Confirmed cardiac events ree 4 Gn 4 oy 3 en
Noninfecious pulmonary 1(13) 113) 1(11) 111)
- 675) 38 (43.7) 6 (69)
+ IRR events: all events resolved, generally within 1 day; most occurred with the first cycle of treatment
(26/29); most had no recurrence (26/29)
+ Confirmed cardiac events: decreased LVEF in 5 patients (5.7%); patients were clinically asymptomatic,
and the events were confounded by pre-existing or concurrent conditions
+ Diarrhea: all but two events (both grade 3) were managed in the outpatient setting, typically with
loperamide; most events (87/99) were resolved at the time of data cutoff; median time to resolution of 2
days (range, 1-267)
AESis that occured in 21 patient. N
1. Harding 3 et al Lancot Oncol. 2029,24:772:782 PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, Peerview
Cohort 1 (N = 80) Total (N = 87)
Any Grade Grade 23 Any Grade Grade 23
AESI, n (%)
IRR
Confirmed cardiac events ree 4 Gn 4 oy 3 en
Noninfecious pulmonary 1(13) 113) 1(11) 111)
- 675) 38 (43.7) 6 (69)
+ IRR events: all events resolved, generally within 1 day; most occurred with the first cycle of treatment
(26/29); most had no recurrence (26/29)
+ Confirmed cardiac events: decreased LVEF in 5 patients (5.7%); patients were clinically asymptomatic,
and the events were confounded by pre-existing or concurrent conditions
+ Diarrhea: all but two events (both grade 3) were managed in the outpatient setting, typically with
loperamide; most events (87/99) were resolved at the time of data cutoff; median time to resolution of 2
days (range, 1-267)
AESis that occured in 21 patient. N
1. Harding 3 et al Lancot Oncol. 2029,24:772:782 PeerView.com
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Quality of Life Outcomes With Zanidatamab*
EQ-5D-5L QoL Outcomes in Patients With HER2+ BTC by Tumor Response
Best Confirmed Overall Tumor Response
cR so
BL & eL | sont | eL | sont | eL | Bont
(a=) | m=n | m=3n | (n=32) | (0=20 | (n=22) | (n= 24 | (n= 19)
Median VAS score o 09 0 8 0 8 © 7
Median VAS change from basaline® = = 40 == 5 - +0
Least severe response level (no problem), n (%)
Mobility o O 23(74) 30(94) 16T) 19(86) 15) 12(63)
Self-care o © 28(90) 31(97) 18(86) 19(86) 23) 1618)
Usual activities o 0 23(74) 29(91) 11(52) 158) 16(67) 100)
Pain/discomtort O 10100) 15(48) 28(88) TO) 130) 10) 7(37)
Anxiety/depression o O 18(58) 28(88) 12(57) 14(64) 13(54) 14(74)
aan aa ESO 203 Anne IR PeerView.com
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EQ-5D-5L QoL Outcomes in Patients With HER2+ BTC by Tumor Response
Best Confirmed Overall Tumor Response
cR so
BL & eL | sont | eL | sont | eL | Bont
(a=) | m=n | m=3n | (n=32) | (0=20 | (n=22) | (n= 24 | (n= 19)
Median VAS score o 09 0 8 0 8 © 7
Median VAS change from basaline® = = 40 == 5 - +0
Least severe response level (no problem), n (%)
Mobility o O 23(74) 30(94) 16T) 19(86) 15) 12(63)
Self-care o © 28(90) 31(97) 18(86) 19(86) 23) 1618)
Usual activities o 0 23(74) 29(91) 11(52) 158) 16(67) 100)
Pain/discomtort O 10100) 15(48) 28(88) TO) 130) 10) 7(37)
Anxiety/depression o O 18(58) 28(88) 12(57) 14(64) 13(54) 14(74)
aan aa ESO 203 Anne IR PeerView.com
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TAB Study: Trastuzumab + Gemcitabine/Cisplatin
for Treatment-Naive HER2+ BTC’
Consort Diagram
876 patients were screened for HER2 status
118 (13.4%) patients were HER2 positive
90 patients enrolled in a single-arm trial
28 were excluded
+ 23 did not meet inclusion criteria
+ 5 declined to participate
18 patients with ongoing treatment,
72 patients discontinued intervention
+ 70 had dise
1.Ostwal VS et al. JCO, 2023:41:4089-4089. PeerView.com
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for Treatment-Naive HER2+ BTC’
Consort Diagram
876 patients were screened for HER2 status
118 (13.4%) patients were HER2 positive
90 patients enrolled in a single-arm trial
28 were excluded
+ 23 did not meet inclusion criteria
+ 5 declined to participate
18 patients with ongoing treatment,
72 patients discontinued intervention
+ 70 had dise
1.Ostwal VS et al. JCO, 2023:41:4089-4089. PeerView.com
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TAB Results!
Overall Survival Progression-Free Survival
6-month OS: 81.1% (95% CI, 72.9-90.3) 10
6-month PFS: 75.6% (95% Cl, 66.6-84.6)
12monh OS: 29.1% (25% Cl 273509) a 12:monih PFS: 17.6% (95% Cl, 167-185)
2 \_, Median OS:8.95 months 05% Cl 9201056) à Medion PFS: 7 months (5% Ci, 6278)
3 " 3
on 075
i i
3 3
dos Eos
a a
8 ¿
dos os
E E
3 3
o o
° y y = à y y y = 2
Time, mo Time, mo
No. at Rak No. at Rsk
so 1 2 D 2 so se 6 4 1
1. Ostwal VS etal..CO. 2023:41:4089-408. PeerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Overall Survival Progression-Free Survival
6-month OS: 81.1% (95% CI, 72.9-90.3) 10
6-month PFS: 75.6% (95% Cl, 66.6-84.6)
12monh OS: 29.1% (25% Cl 273509) a 12:monih PFS: 17.6% (95% Cl, 167-185)
2 \_, Median OS:8.95 months 05% Cl 9201056) à Medion PFS: 7 months (5% Ci, 6278)
3 " 3
on 075
i i
3 3
dos Eos
a a
8 ¿
dos os
E E
3 3
o o
° y y = à y y y = 2
Time, mo Time, mo
No. at Rak No. at Rsk
so 1 2 D 2 so se 6 4 1
1. Ostwal VS etal..CO. 2023:41:4089-408. PeerView.com
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A Phase 2 Multi-Institutional Trial Evaluating Trastuzumab +
FOLFOX for HER2+ BTC Refractory to Gem/Cis!
Treatment-Related Adverse Events
N=34 D oc ne ve om
ORR: 29.4% Es 00 sm a
A Median PFS: 5.1 mo Ft rt deed 9 er)
3. ‘een
35 m) Personen coat wm am o
¿E cer ventes wo
Es Dies rey 20 o
ez pa O
53 Fave 2 10 o
ze
E mans CT
ee nt cet rey oo
Ez Pe 0 0.
r= 50 o. e
tii i mi oO
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> zu 4 mm,
PeerView.
1. Choong-Kun L. Lancet Gastroenterol. 2023:8:56-65. ‘eerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
FOLFOX for HER2+ BTC Refractory to Gem/Cis!
Treatment-Related Adverse Events
N=34 D oc ne ve om
ORR: 29.4% Es 00 sm a
A Median PFS: 5.1 mo Ft rt deed 9 er)
3. ‘een
35 m) Personen coat wm am o
¿E cer ventes wo
Es Dies rey 20 o
ez pa O
53 Fave 2 10 o
ze
E mans CT
ee nt cet rey oo
Ez Pe 0 0.
r= 50 o. e
tii i mi oO
eon 40m er)
> zu 4 mm,
PeerView.
1. Choong-Kun L. Lancet Gastroenterol. 2023:8:56-65. ‘eerView.com
PeerView.com/JPD827 Copyright © 2000-2024, PeerView
Audience Q&A
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