Accelerating Therapeutic Progress in HER2+ and HER2-Low Breast Cancer: State of the Science and Guidance for Individualized Clinical Decisions

Chair and Presenters, Komal Jhaveri, MD, FACP, Javier Cortes, MD, PhD, Prof. Giuseppe Curigliano, MD, PhD, and Ian Krop, MD, PhD, discuss breast cancer in this CME/MOC/NCPD/AAPA/IPCE activity titled “Accelerating Therapeutic Progress in HER2+ and HER2-Low Breast Cancer: State of the Science and Guidance for Individualized Clinical Decisions.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/42EzL7g. CME/MOC/NCPD/AAPA/IPCE credit will be available until June 30, 2025.

1. Accelerating Therapeutic Progress in
HER2-Positive and HER2-Low Breast Cancer

State of the Science and Guidance for Individualized Clinical Decisions

RQ Komal Jhaveri, MD, FACP Javier Cortes, MD, PhD
Patricia and James Cayne Chair for Junior Faculty Head
Associate Attending = International Breast Cancer Center (IBCC)
Breast Medicine Service and Early Drug Development Service Barcelona, Spain
Section Head, Endocrine Therapy Research Program.

Clinical Director, Early Drug Development Service

Department of Medicine

Memorial Sloan Kettering Cancer Center/Evelyn H. Lauder Breast and Imaging Center
New York, New York

Prof. Giuseppe Curigliano, MD, PhD lan Krop, MD, PhD.

Full Professor of Medical Oncology Professor of Internal Medicine
Department of Oncology and Hemato-Oncology Associate Director, Clinical Sciences
University of Milano Yale Cancer Center

Director New Haven, Connecticut

Division of Early Drug Development for Innovative Therapies

European Institute of Oncology, IRCCS

Milano, Italy

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

Copyright © 2000-2024, Peerview

2. Our Goals for Today

Augment your knowledge of the approved and emerging
therapies in HER2+ and HER2-low breast cancer

Equip you with skills to integrate novel therapies into
treatment plans throughout the disease continuum

Provide you with insights into emerging options and future
directions in HER2+ and HER2-low breast cancer

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3. We have partnered with GRASP and LBBC in this program

LIVING BEYOND
BREAST CANCER”

Please review and download the supplemental resource compendium,
which includes information and educational materials for your patients to
help them become better informed and engaged participants in their care

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4. Case to Consider

+ 57-year-old woman with HER2+ MBC

History and Presentation

+ Diagnosed with 2.2-cm breast tumor and two clinically positive lymph nodes

+ Biopsy confirms ER+, PgR+, HER2+ breast cancer

+ Staging workup reveals 18-cm liver with multiple solid metastases

+ Liver enzymes mildly elevated (3X ULN), but function is normal

+ Biopsy demonstrates metastatic breast cancer, ER+, PgR+, HER2+, high grade
+ No baseline brain metastases

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5. Case Continues

History and Presentation

+ She initiates first-line therapy with THP

+ After two cycles, her symptoms have improved; after four cycles, she has a 70%
reduction in tumor burden; after 6 cycles, she has a CR in the liver

+ She develops moderate neuropathy as well as edema related to the taxane; drops the
taxane but continues HP

+ She initiates an aromatase inhibitor concurrently with the HP

20 Months Later

+ She has progression in the liver, with a new 1.5-cm metastasis, as well as new lung
metastases

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6. Current Therapeutic Options
and Standards of Care in
HER2+ Breast Cancer

lan Krop, MD, PhD

Professor of Internal Medicine
Associate Director, Clinical Sciences
Yale Cancer Center

New Haven, Connecticut

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7. The Expanding Armamentarium of Agents
for HER2+ Breast Cancer!

gore? | Bispecific antibodies
+ was
“woe + BTRCAOITA
© GeR-1302
rastuzumab el + PRES
siens HER? vaccines
HE: HERA + AGO
Fes)

+ initie

es

‘Antibody-drug conjugates
> Adotrastuzumab emtansine (T-DM1)

+ ARXTOS

+ ALTO

+ Trastuzumab derurtecan (T-DX 4)

1. Mer Berstam F et al, Cin Cancer Res, 2019:25 2033-2041 PeerView.com

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8. First-Line Therapy

for Metastatic Breast Cancer

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9. CLEOPATRA End-of-Study Results: Adding Pertuzumab
to Taxane + Trastuzumab Improves PFS and OS!

m . P0001
so Median PFS: 18.7 mo
xo
gs
+ ano PES 0 ess: 16%. 308 events 76%)
‘so FT D OO 0 © E wo Ww %
Ben Tine
ES" io mu IaH mon BUN zum wm BE |e neo AEH cm con
ESE Bey Sun Bee Ben Hee won tom oon
Ps Median OS: 57.1 mo P< 0001
ze Landmark 08 at years: 37% 23 events (58%)
PE
8
3 Landmat OS a 8 years: 23%, 280 evens (0%)
FER Timo, mo
MS une way may man muy mue Mo toco wen mem nam mu acen

O Toren) tates) ES SON win men aan MOMO, VU o
1. Swain Set al. Lancet Oncol 2020:21:519-520. PeerView.com

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10. Second-Line Therapy

for Metastatic Breast Cancer

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11. Trastuzumab Deruxtecan (T-DXd):
A Novel HER2 Antibody-Drug Conjugate (ADC)'*

Characteristic Differences Between T-DXd and T-DM1

HER2-Targeting ADCs With a Sir

ilar mAb Backbone

d DM1
Trastuzumab Topoisomerase | 7 Trastuzumab
deruxtecan inhibitor Payload Moh Ani mierutubule emtansine
(T-Dxa) (T-DM1)

cleavable linker?

Evidence of bystander No k
__ CC atitumor effect? RU nN effect?

-8:1 Drug-to-antibody ratio =3.5:1 NS #
Sa Yes Tumor-selective No ar Y if

4. Cortes J etal ESMO 2021. Abstract LBA-1. 2. Nakada T et al. Chem Pharm Bul (Tokyo). 2019:87-173-185. 3. Ogtani Y et al. Ci Cancer Res. 2016:22:5087-5108, en
4. Tra PA et al, Pharmacol Ther. 2018:181:126-142. 5. Ogtan Y et a. Cancer Sei 2016:107:1030-1046, 6, LoRusso PM et al, Cin Cancer Res.2011:17:8437.6447. Peer VIE W.com

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12. DESTINY-Breast03: Study Design’

Randomized, Open-Label, Multicenter Study (NCT03529110)

T-DXd

Unresectable or metastatic
HER2+* breast cancer

RATS 5.4 mg/kg Q3W
Stratification EM

HR status

Previously treated with
trastuzumab and taxane in

i + Prior treatment with 11
advanced/metastatic setting or pertuzumab
(neo)adjuvant setting with + History of visceral

recurrence within 6 mo of

disease
therapy?

+ Primary endpoint: PFS (BICR)
+ Key secondary endpoint: OS:
+ Secondary endpoints: ORR (BICR and investigator), DOR (BICR), and safety

The prespecified OS interim analysis was planned with 153 events”;
at the time of data cutoff (July 25, 2022), 169 OS events were observed
and the P-value to achieve statistical significance was .013

HERZ INC 3+ or IHC 2+/SH+ based on central confirmation Progression during or <8 months after completing aduvant therapy involving rasuzumab and taxane

«80% powered at 2-sided significance level of 5%. Information ración of 61%, with a salue boundary to reach statistical significance of 008. The P-value was

recalcuated based on he actual OS events atthe data cto m

Y HurvteS ef a SABCS 2022. Abstract 69202. PeerView.com

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13. DESTINY-Breast03: PFS and OS!

Trtuzumab Trastuzumab.
Derunecan _Emtansine

100
RTE EEE
so mesa) 0330026043)
> on
Roo
2
Eso Trastuzumab deruxtecen (n= 261)
204 + censor
Trastuzumab emtansine (n= 263)
19 mm nn nn
01234 5.8 7 8 0 1011121914 1910 17 181020212229 242920 27 29200 1 23934353637 38304081 42434445
Time, mo
100
e
ze Trastuzumab deruxtecan (n= 261)
g Tratuzumab _ Trastuzumab ‘Trastuzumab emtansine (n = 263)
8 « Deruxecan _ Emtanaine
Tada, ma WERE) NR @DSNE) _NR(SAONE)
20 | mes cn 084 047087)
13 0057
A A nn
01234 58 7 8 8 1011121314181617181020212229262526272820303132993436363730304041424344454047
Time, mo View.
1.HurvizSA etal. Lancet, 2023:401:105-117. PeerView.com

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14. Evolution of PFS After Trastuzumab/Taxane

Median PFS, mo
383888

ou

RS

fo Pa
1.Geyer tat Eng Med. 2000358.2738.2143.2.Von Mick O tl Clin Onol.200027.1006.2006 ya
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3! Verma Set al. N Engl Y Med. 2012.367.1783-1701.4. u B et al Lancet Oncol 2021:22:351-360. 5. Hurviz SA et al. Lancet. 2025:401:105-117.

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15. DESTINY-Breast03: Updated Survival Results’

Median duration of follow-up was 43.0 mo (range, 0.0-62.9) for T-DXd
and 35.4 mo (range, 0.0-60.9) for T-DM1

Efficacy 261) (n= 263) HR (95% Cl)

526 (48.7-NE) — 427(35:4-NE) 0.73 (0.56-0.94)
290(237-400) _7.2(68-8.3) _0.30(0.24-0.38)
mPFS2, mo (95% CI) 45.2(39.3-NE) 231(178297) 0.53 (0.41-0.68)

Confirmed ORR, %
(95% cl) 78.9 (73.5-83.7) 36.9 (31.0-43.0)

Q
MOS, mo (95% Cl)

+ OS rate at 36 mo was 67.6% (95% Cl, 61.3%-73.0%)
MPFS, mo (95% CI)

for T-DXd vs 55.7% (95% Cl, 49.2%-61.7%) for T-DM1

+ PFS rate at 24 mo was 55.8% (95% Cl, 49.1%-62.0%)
for T-DXd vs 20.6% (95% Cl, 15.4%-26.4%) for T-DM1

MDOR, mo (95% Cl) 305(230-NE) —17.0(14:1-237)

+ Adjudicated drug-related interstitial lung
disease/pneumonitis occurred in 16.7% of patients

Any-grade TEAES 256 (99.6) 249 (95.4) with T-DXd (4 new events [all grade 2] since prior
Grade 23 TEAES 149 (68.0) 136 (62.1) DCO) vs 3.4% with T-DM1 (1 new event [grade 1])
Serious TEAEs 74 (27.6) 59 (22.6) + Neither arm had grade 4 or 5 events

1. Hamiton E et a, ASCO 2024. Abstract 1025. PeerView.com

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DESTINY-Breast03:
Most Common TEAEs in 220% of Patients!

System Organ Cla:
Preferred Term, n (%)

Any Grade
Blood and lymphatic system disorders
‘Anemia IT 1A) 2) 51 (19.5) 1765)

Platelet count decreased 64 (249) 20(78)
White blood cell count decreased 16.61) 208)

Gastrointestinal disorders

Nausea 1881770) 870 79 (30.3) 104)
Vomiting 133 (51.8) 45 28 (10.7) 208)
Constipation 96 (37.4) 0 51 (19.5) o
Diarrhea 83 (32.3) 3(12) 2180) 2(08)

General disorders,

Fatigue 79 (30.7) 1568) 53 (20.3) 2(08)
Headache 61 (23.7) 104) 40 (15.3) o

Investigations
Neutrophil count decreased 79 (30.7) 41 (16.0) 30 (119 EICH)
‘Aspartate aminotransferase increased 72 (28.0) 2(08) 08 ( 14.64)
‘Alanine aminotransferase increased 59 (23.0) 4(16) 83 (318) 1246)

Metabolism and nutrition disorders

Decreased appetite 46 (17.6) 104)
Weight decreased 2388) 2(08)
‘Skin and subcutaneous tissue disorders
Alopecia 984) o
TEs were managed secado 1 Te POCO
"Cases of alopecia reported during the study were graded based on the cinial judgement of the investigator. One case of alopecia was categorized as grade 3 by the investigator despite

grade 3 alopecia not being recognized bythe NCI Common Terminology crier. The event outcome was reported a recovered by the investigator. :
1" Huviz Set al. SABCS 2022 Abstract 65202. PeerView.com

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17. DESTINY-Breast03:
Adjudicated Drug-Related ILD/Pneumonitis'

Grade 1 Grade 2 Grade 3 Grade 4 Grade5 Any Gra

T-DXd (n= 257),n(%) 11(43) 26(10.1) 2(08) 0 o 39 (15.2)

T-DM1 (n= 261),n(%) 4(1.5) 3 (1.1) 1 (0.4) 0 0 8(3.1)

+ Adjudicated drug-related ILD/pneumonitis rates were similar to other MBC trials with T-DXd2*

+ With longer treatment exposure and follow-up, the ILD/pneumonitis rate increased from 10.5% in the PFS
interim analysis? to 15.2%

— There were 4 additional grade 1, 8 additional grade 2, and no additional grade 3 events
+ The overall incidence of grade 3 events (0.8%) was the same as in the PFS interim analysis*
+ There were no adjudicated drug-related grade 4 or 5 events

1. Hurt 5 tal. SABCS 2022. Abstract GS2-02. 2. Modi S et al. N Engl J Med, 2020:382 610-821. na
3.Powell CA et al, ESMO Open. 2022.7:100564, 4. Corts Jet al. N Engl J Med, 2022.306:1143-1154. PeerView.com

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18. Strategies for Managing AEs of Interest With T-DXd!

Nausea and oo
vomiting + Prophylactic treatment wth a roe-dug regimen (o. 9. DEX + S-HT, receptor antagonist + NIK receptor antago)
+ Escalate or taper regimen based on indwdualtoorances.

Loy Mrs Grade 1
pnoumonitis + Proactive montonng ó a,
+ Regular CT chest scans only esse lo grado 0
+ Advis patients of ik + Consider steroids in casos

and adicto on ‘with extensive ng
Sonelsymetoms ‘cement oceans

A patients LVEF decrease Congestive heart failure

+ Assess LVEF before treatment + Hold or dsconinue T-OXa + Pormanenty discontinuo T-OX4
and every 34 mans 03 per Label mstrucions

1. Gurigiano Get a. ESMO Open. 2024:9:102080 PeerView.com

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19. Detecting and Managing T-DXd-Related ILD:
The Five S Rules!

at

Screen

=

C=

Scan

Synergy

©

Suspend
Treatment

Steroids

+ Careful patent selection
is warranted before
initiating T-X¢ to
‘optimize the monitoring
strategies based on
the baseline risk

+ Sereening continues
‘during treatment,
‘with regular cnica!
‘assessments to exclude
‘igns/symptoms of ILO

+ The fundamental

diagnostic tools for ILD
remain radiological
scans, with preference
for high-resolution CT
‘scans of the chest

+ Abaseline scan is

recommended, with
repeat scans to be
performed every 6-12
weeks

1. Tarantino P, Tolaney SM. JCO Oncol Pract. 2023:0P2300007,

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+ Minimizing the risk
Of ILD involves.
teamwork, which
includes educating
Patients and the entire
‘care team, as well

as mutidiscipinary
management once
ILD is suspected

+ T-DXd should always
be interrupted i ILD is
‘suspected: it can only
be restarted in the
‘case of asymptomatic
ILO that fuly resolves

+ The mainstay
for treating T-DXd-
induced ILD remains.
corticosteroids, with
the dose to be adapted
to the toxicty grade

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20. Later-Line Therapy and

Management of Brain Metastases

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21. Brain Metastases in HER2+ Breast Cancer’

+ Breast cancer is one of the most common causes of BM and LMC
+ The incidence in HER2+ tumors is 20%-30% and is associated with better prognosis than in other

subtypes of breast cancer
+ There are different options to treat BM depending on several factors

100
= =
P< 001

7 125%
Lung Breast Melanoma
Colorectal Renal = CUP.

o
en: 1986-1999 2000-2009 2010-2020

13%
20%
20%

2

o.

8

8

Clinical Characteristics, %

1. Kukss M tal. Neuro Oncol 202123:894-904. 2. Ramakrishna N et a. J Gin Oncol 2018:36:2804-2807. Pe
PeerView.com

3. Hurviz SA etal. Clin Cancer Res. 2019:25.2433-2441. 4. Steindl A etal. Eur Cancer. 2022:162:170-181

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22. Local Therapies!

+ Surgery in case of very limited number of lesions and no evidence
of systemic disease (mass effect, pathology needed)

Combination

+ Local interventions with radiation therapy remain the indicated therapy
for patients with BMs (SRS for up to 10 lesions, WBRT...)

Avoid WBRT (if possible)

1. Baieux Cet a. Br J Cancer 2021:124:142-155, 2. Mahajan A etal. Lancet Oncol. 2017;18:1040-1048 PeerView.com

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23. Systemic Therapies’

New era of treatment of HER2+ tumors
+ TKls (tucatinib, and others under development...)
+ ADCs (trastuzumab deruxtecan)

Is systemic treatment the best option for patients
with BM and HER2+ breast cancer?

1. Baieux Get al. Br J Cancer 2021:124:142:15S. PeerView.com

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24. CLEOPATRA: Study Design!

Pertuzumab + trastuzumab + docetaxel
2 (n= 406)
Patients with HER2+ MBC

centrally confirmed
(N = 808)

Placebo + trastuzumab + docetaxel
in = 402)

Patients with known BM excluded

Exploratory analysis?
+ The incidence of BM did not differ between the groups (13.7% pertuzumab, 12.6% placebo)
+ Pertuzumab significantly increased time to development of BM (15 vs 11.9 mo; HR, 0.58, P = .0049)

1. Baselga Jet al. N Engl J Med. 2012:366:109-119, 2, Swain SM et a. Ann Oncol. 2014:25:1116-1121. PeerView.com

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25. Pooled Analysis of T-DXd in HER2+ MBC With Brain
Metastases From DESTINY-Breast01, 02, and 03!

DESTINY -Breast0t (N = 253)

+ Phase 2 study

+ Patients previously treated with T-OMt

+ Patients with asymptomatic and previously local treated
BM eligible

+ Prior BM therapy within 60 days prohibited

DESTINY-Breast02 (N = 608)*«

+ Phase 3 study

+ Patents previously treated with T-OMt

+ Patients win asymptomatic and previously
‘weatedlunteated BM eigbie

+ Prior BM therapy within 14 days of randomization
prohibited

Endpoints
+ ICORR(CR + PR

in brain) per BICR per
RECIST 1.1
+ 1C-DOR per BICR
+ CNS-PFS per BICR
© Safety and tolerabity

(DESTINY-Broast03 (N= 52474

- Phase 3 study

+ Patents previously eated with trastuzumab and a taxane
in metastate or (neo)aguvant seting with recurence within
8 months of therapy

+ Patents vit asymptomatic and previously
lweatedlunreated EM eigbie

K_ Prior BM therapy within 14 days of randomization prohibited

‘The BM and non-BM pools were determined by BICR at baseline among all patients based on mandatory brain CT/MRI screening

Data for patients inthe 54-MPRG T-OXd arms were pooled ram the DB-01, 8-02, and 08-03 tals. Comparator data were pooled from the 08-02 and DB-03 tías. AN vee studies were
Conducted in unresectable BC. HERZ status was confirmed centaly, and a documented radiograph progression afer most recent treatment was required

The presence of BMs was of a sraifieaton factor. Data cua: March 26, 2021. Data cutof June 30, 2022. Data cto: May 21, 2021. « Samoa OW.

138 mang am. a
{Hurt 8 etal ESMO 2023, Abstract 3770, PeerView.com

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26. Pooled Analysis of DESTINY-Breast01, 02, and 03:
Exploratory Best IC Response, ORR, and DOR per BICR!

Intracranial ORR?
T-DXd BM Pool ‘Comparator BM Pool

= 5
É 40 163 159
5 ee

Complete response 30

= Partal response 20

Treated/Stable BI Untreated/Ac
(n= 104) 4)

Best overall IC response, n (%)

Stable dsease 48462) 15641) 22.483) 1560)
Progressive disease, 309) 123) 7(121) 50)
Not evaluabe!mising 868) 8082) 702 206)

16-DOR, median, mo (95% CI) 12341179) 1750136318) 116846) Nat

+ T-DXd consistently demonstrated superior rates of IC responses over comparator in patients with treated/stable and untreated/active BMs
+ Atrend in prolonged median IC-DOR was most pronounced in the untreated/active BMs subgroup

“The table considers both Large and nontarget lesions at baselne. Lesions in previously radiated areas were not considered measurable target sions unless there was demonstrated

progresión in the lesion.

FIC-ORR was assessed per RECIST v1.1." DalC-OoR NA due o small number of responders (9 <10)

1. Hurvkz Set al ESMO 2029. Abstract 3770, PeerView.com

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27. PFS, %
o3885833888

No at Rsk
TON tected
oe ion)

(ness

Pooled Analysis of DESTINY-Breast01, 02, and 03:
Exploratory CNS-PFS per BICR!

Treated/Stable BMs
TOXA Comparator
Mean, mo 123
He) (63118)
HR (95% Ch 0.5005 (03921-0.8805)

T-0Xa treated {n = 104)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time, mo
104 100 89 83 72 68 46 02 2 2 18 12 4 4 2 0 0 0

susmauus ss 3 10 00000

Untreated/Active BMs
T.0Kd Compartor
100 Wedonmo 188 30
20 (we) (mean 2757)
2 HR (SN CH 0.1010 0.1000.03473)
60
2 50
E
Eos DX woated (n= 4)
20
2 Comparator rated (n= 25)
o
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
tisk Time, mo
Tame aaa wane 6 4420
E)

T-DXd demonstrated a trend toward prolonged CNS-PFS over comparator,
with a noticeably greater advantage for patients with untreated/active BMs

1. Hunt $ tal. ESMO 2023. Abstract 3770.

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28. DESTINY-Breast07: Efficacy of T-DXd Monotherapy in
Patients With HER2+ MBC and Active Brain Metastases’

DESTINY-Breast07 (module 7): Safety and tolerability of T-DXd monotherapy in patients
with HER2+ MBC and active BMs in the first- or second-line setting

Best Percent Change in Targeted Lesion Size Best Percent Change in IC Targeted Lesion Size
With T-DXd Monotherapy per RECIST 1.1 With T-DXd Monotherapy per RANO-BM Criteria
so Confirmed ORR, % (80% Cl): so Confirmed IC ORR, % (80% Ci):
. seras . ee
ji 2 EN 25] raton vano novo ea.
7 i.
És 55
a 33 *
LE ¿e
E gf #
400 ™
Dated err ne 30% neste etl pal Dated een ne 20% dees thereto pal
mens ae
en ae PeerViewcom

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29. T-DXd for BM

Study Type Active BM RR
Des Phase 3 No 67.4%
Liberata dienes Phase 2 Yes 73% (11/15; RANO-BM)
Kabraji S et al. 20228 Retrospective Yes 70% (7/10; RANO-BM)
ee et al. 2022 Retrospective Yes 54% (20/37; RECIST)
E Eo Phase 2 Yes 46% (6/13; RANO-BM)

Pérez-García JM et al. 2022

1.Hurviz SA et al. ESMO Open. 2024; 9:102924. 2. Bartsch R et al. Nature Med 2022:28:1840-1847. 3. Kabraj Seta. Cin Cancer Ros. 2023:29:174-182, a
4. Yamanaka T et al SABCS 2022. Abstract PO7-01. 5. Vaz Batista M etal SABCS 2021. Abstract PO4-06. 6, Pérez-Garcia JM et al. Neuro Oncol. 2023:25:157-168. Peer Vie:

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30. HER2-Targeted Tyrosine Kinase Inhibitors’?

HERI/EGFR HER2 HERS HERS

Tucatinib (HER2)
Lapatinib (HER1, HER2)

Neratinib (HER1, HER2, HER4)

1. Dent SF et a. Curr Oncol Rep, 2021:23:128, 2. Murthy Rta. Lancet Oncol, 2018;19:880-88. PeerView.com

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31. HER2CLIMB Study Design: Tucatinib + Trastuzumab
+ Capecitabine vs Placebo + Trastuzumab + Capecitabine!

HER2+ metastatic breast cancer Tucatinib + trastuzumab
+ capecitabine

Prior treatment with trastuzumab,
pertuzumab, and T-DM1 (21-day
ECOG 0-1
Brain MRI at baseline
— No evidence of brain metastases,
or
Untreated, previously treated
stable, or previously treated Placebo + trastuzumab
progressing, brain metastases not + capecitabine
needing immediate local therapy 2

Stratification variables Endpoints
+ Presence of brain metastases (yes or no) + Primary: PFS (first 480 patients randomized)
+ ECOG status (0 or 1) + Secondary: OS (total population), PFS among patients
+ Region of the world (US or Canada or rest of world) with brain metastases, ORR
Notable baseline characteri 48% of patients had CNS metastases
1. Murthy Ret al. N Engl J Med. 2020:382 507-606. PeerView.com

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32. HER2CLIMB: PFS and OS!

PFS os

tn
oS SUMED H MT DD Sw a oF eT REMAN A HHS DESO
Time, mo Time, mo
hos O
1.Curiglano G et al. Ann Oncol. 2022:33:321-329 PeerView.com

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33. HER2CLIMB: Updated OS in Patients
With Active Brain Metastases’

10

os

os

04

OS, Probability

02 TUC + tas + cape

Placebo + tres + cape

E % % 4 4 4
No. at Risk

TUC+kas scape 118 111 102 92 Bt 73 67 56 42 33 27 16 9 6 5 5 41
Placebo + vas + cape 56 54 46 39 28 22 18 12 9 6 4 3 2 1 0 0 0

+ OS benefit with tucatinib was improved with additional follow-up: median OS was 9.1 mo longer in the tucatinib arm compared
with the control arm in all patients with brain metastases

- Median OS was 9.6 mo longer in the tucatinib arm compared with control in patients with active brain metastases
- Median OS was 5.2 mo longer in the tucatinib arm compared with control in patients with treated stable brain metastases

4. Lin N et a. JAMA Oncol. 2023:9:197-205. PeerView.com

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34. HER2CLIMB-02: Study Design!

Randomized, Double-Blind, Phase 3 Study of Tucatinib or Placebo
With T-DM1 for Metastatic HER2+ Breast Cancer

Tucatinib
300 mg PO BID

Unresectable locally advanced/metastatic
HER2+ breast cancer with progression
after trastuzumab and taxane

+ ECOG PS <1

+ Previously treated stable, progressing, or
untreated BM not requiring immediate local
therapy were allowed on study

+
T-DM1
3.6 mg/kg Q21D

Placebo

P ID
N = 460 +
T-DM1
3.6 mg/kg Q21D
+ Primary endpoint: PFS by investigator assessment per RECIST v1.1
+ Key secondary endpoints: OS, PFS in patients with brain metastases, ORR by investigator
assessment per RECIST v1.1, OS in patients with brain metastases
1. Hunitz SA etal, SABCS 2023. Abstract GS01-10, PeerView.com

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35. HER2CLIMB-02: PFS'

T-DM1 + Tucatinib T-DM1 + Placebo

10 (n= 228) {n = 235)
09 Events, n 151 182
68 Median PFS (95% Cl),mo 9.5(74-10.) 746681)
2 or HR (95% CI) 076 (061-095)
ae TOM +tucatinib à Me
3
2 05
5
£ os
02
01
o
o 3 6 9 2 15 8 A 2% 27 0 3 % %
Time From Randomization, mo
No, at Risk
TOM! + tucatinD 228 1656 126 96 62 7 40 22.14 10 5 4 14 0
T-DM1 + placebo 235 177 120 9 58 4 40 2 19 10 8 5 3 0
1. Hurt SA etal, SABCS 2023, Abstract GS01-10, PeerView.com

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36. HER2CLIMB-02: OS'

10
09
08
2
go T-DM1 + tucatinib
2 os
E TOM Tue TOM + Paebo
= 04 Leal rhein T-DMt + placebo
034 Fawn 7 ©
0.2 | Median OS (95% Ch,mo —— NR(NRAR) EV)
014 HR (05% cr 123 (087474)
0
0 3 6 8 2 8 16 A A A 3 3% % 39 42
Time From Randomization, mo
No. at Risk
TOMI +tucatnd 229 225 217 209 202 199 180 132 09 56 30 16 7 3 0
TOMI + placebo 206 227 22 212 20% 191 180 135 90 58 32 16 10 4 0

Median follow-up was 24.4 mo. As of data cutoff, 134 out of 253 (53%) prespecified events for the OS final
analysis were observed. Interim OS results did not meet the prespecified crossing boundary of P s .0041.

The proportional hazard assumption was not maintaine post 18 months, with extensive censoring on both :
‘Hui SA aa ADOS 2009 Arne ODIO PeerView.com

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37. HER2CLIMB-02: PFS in Patients With Brain Metastases’

T-DM1+Tucatinib — T-DM1 + Placebo

10 (n= 99) (n= 105)
09 Events, n 70 85
08 Median PFS (95% Cl), mo 7.8 (6.7-10.0) 5.7 (4.6-7.5)
= 7 TOM +tucatinib HR (95% CI» 0.64 (0.46-089)
æ 06
3
© 05
= 04
e
E 03
02 T-DMI + placebo
01
0
0 3 6 8 2 15 8 À A 7 9 3 % 9
Time From Randomization, mo
No. at Risk

T-DM1+tucatinib 99 76 57 40
T-DMi+placebo 105 75 46 30

* The outcome was not formally tested
4 Han SA et at SABCS 2023, Abstract 6501-10.

PeerView.com/SBE827

25 2 15 6 4 4 3 2 1 o
18 12. 10 6 3 2 1 0 o 0

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38. PeerView.com/SBE827

NALA Trial: A Phase 3 Trial of Neratinib + Capecitabine
vs Lapatinib + Capecitabine!

Centrally Confirmed PFS os

19
09
os
o7
os
os
gos
Fos
02
or
o

24 mo vs 22.2 mo
A1.8 mo
P=NS

8.8 mo vs 6.6 mo os

Neratinib + cape

os 6 8 À 6 w À À 7 0 à» 36 co. eC RE MHMT HHH O Oe
une Tme,mo ig Trine, mo

+ 1-y PFS: 29% vs 15%
+ ORR: 33% vs 27% (P= .1201)
+ Median DOR: 8.5 mo vs 5.6 mo (HR, 0.50; 95% Cl, 0.33-0.74; P=.0004)
+ Fewer interventions for CNS disease occurred with N + C vs L + C (22.8% VS 29.2%; P= .043)
1. Saura Cet al J Gin Oncol, 2020:36:3138:3140, PeerView.com

Copyright © 2000-2024, Peerview

39. Other Drugs and Combos in BM

Study Type IC-ORR
N Phase 2 Yes 8%
Nora + capectabine Phase 2 ves 33% (patin treated)
a + capecitabine IS no Cx
KA URN Phase 3B No 21%
en ESP iS an
DESTINY Breasts: Phase 3 No T-DM1 20.5%

À Montana etal Ann Onc! 2020311980 1088 à Freedman RA tal SABCS 2022 Asset POI 09.6 Hurts SA ela ESUO Open Zones Peer View.com

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40. Multidisciplinary Tumor Board

In Favor of Local Strategies

Neurological symptoms

<10 lesions (maybe
radiation oncologists will say
more!) > SRS or surgery

Big lesions

“Bad” localization
(cerebellar lesions)

Edema
Need for tissue

PeerView.com/SBE827

In Favor of Systemic Therapies

Medical oncologists HER2+ subtype

Radiation oncologists
Neurosurgeons

Asymptomatic disease

Neuroradiologists Good drugs (with evidence

of CNS activity) available

Pathologists

Previous radiation

PeerView.com

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41. Meeting an Unmet Need for Patients

Breast cancer patients lack resources and information about diagnosis,
treatment, management, and survivorship of CNS metastasis

MBCBrainMetsos

A one-stop resource hub for breast cancer patients with brain
metastasis, connecting them to cutting-edge information,

community, and support tailored to their needs—curated by
patients, for patients, and vetted by Medical Advisory Board

LEARN ENGAGE EXPLORE TRIALS

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42. Returning to Our Case—Panel Discussion

jear-old woman with HER2+ MBC

History and Presentation

+ Diagnosed with 2.2-cm breast tumor and two clinically positive
lymph nodes
Biopsy confirms ER+, PgR+, HER2+ breast cancer
Staging workup reveals 18-cm liver, multiple solid metastases
Liver enzymes mildly elevated (3X ULN), but function is normal
Biopsy demonstrates metastatic breast cancer, ER+, PgR+,
HER2+, high grade
No baseline brain metastases
Initiates firstline therapy with THP > symptoms improve after 2
cycles > 70% reduction in tumor burden after 4 cycles > CR in
liver after 6 cycles
Develops moderate neuropathy and edema related to the taxane;
drops the taxane but continues HP > initiates Al concurrently
with HP
20 months later: progression in liver with new 1.5-cm
metastasis and new lung metastases

PeerView.com/SBE827

What treatment would you recommend for
this patient?

Do you use brain imaging to help select the
next line of therapy?

What if a single 2-cm brain metastasis is
detected?

How often are you scanning for ILD?

How do you manage common toxicities such
as T-DXd-related nausea?

Is cold capping for alopecia effective?

What is the preferred treatment after
progression on T-DXd? What factors help with
that decision, or any data?

Copyright © 2000-2024, PeerView

43. + A 62-year-old woman was diagnosed with stage | breast cancer 6 years ago; HR+,
HER2 IHC 0 > now presents with metastatic disease

History and Presentation

+ She was prescribed 5 years of adjuvant letrozole

+ CT showed a solitary lesion on the right lower lobe of the lung

+ She has received two lines of endocrine therapy (including CDK4/6i) and one line of
chemotherapy (capecitabine)
CT scan shows enlargement of the pre-existing lung lesion and additional lesions in the
lung
ctDNA testing is negative for ESR1 and PIK3CA mutations
HERZ re-testing reveals IHC 1+

PeerView.com/SBE827 2024, PeerView

44. Perspectives and Practicalities
on Testing and Treatment of
HER2-Low Breast Cancer

Prof. Giuseppe Curigliano, MD, PhD

Full Professor of Medical Oncology

Department of Oncology and Hemato-Oncology

University of Milano

Director

Division of Early Drug Development for Innovative Therapies
European Institute of Oncology, IRCCS

Milano, Italy

Copyright © 2000-2024, PeerView

45. HER2-Targeting ADCs

46. The “Traditional” HER2 Pie Chart!

+ Tumors lacking ERBB2
amplification are collectively
defined as HER2 negative

HER2 Negative

1. Mo À eta. J Cin Oncol 2018:36:2105-2122. PeerView.com

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47. HER2 Negative’

Could they
benefit from
HER2 blockade?
HER2
SCORE 0 SCORE 2+/ ISH-
1. Marehi C et al, Semin Cancer Biol 2021:72:122-135. PeerView.com

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48. The New Pie Chart of HER2 Targetability!

HER2 testing by validated IHC assay

y y +
Weak-to-moderate complete Incomplete membrane staining NO EC nu

membrane stanngin>10%0t | |matistanUbarey perceptble and eee eee
Cade) A Sariy cote fainvbarely perceptible and in <10% of tumor cells
THe 2+ neh role

£

Circumferential membrane
staining that is complete, intense,
and in >10% of tumor cells
IHC 3+

Reflex ISH
test negative

HER2+ BC 15%

HR+
HER2 Low

(~60% of HR+ tumors)
HER2-low BC 45%-55%

TNBC
HER2-0 BC 30%-40% HER2 Low

(~40% of TNBCs)

1. Adapted trom Tarantino Peta. J Clin Oncol. 2020;38 1951-1962. PeerView.com

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49. NSABP B-471

A phase 3 trial was conducted to understand if adjuvant trastuzumab was beneficial for HER2-low patients

Docetaxel/cyclophosphamide

+ Node-positive or high-risk node-negative
breast cancer
+ IHC 1+, 2+ and FISH negative

e 60 HR = 098 (95% Cl, 076-125); P=.85 HR = 1.33 (95% CI, 0.90-1.95), P= 15
¢
6 40
Treatment No. Events
20 chemotherapy 1008 48
— Chemotherapy + trastuzumab 1602 Bi
o
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Time, mo Time, mo
No, at Risk No. at Risk
Chemotherapy 1602 1558 1423 1003 595 140 Chemotherapy 1603 1576 1508 1008 703 169
Chemotherapy + 1598 1828 1404 1010 502 118 Chemotherapy + 1602 1883 1407 HAS 683 140
trastuzamad trastuzumab

1. Fehrenbacher Let al. J Cin Oncol. 2020:38:444-453, PeerView.com

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50. Pertuzumab for HER2-Low MBC"

+ Similar results were observed in the metastatic setting

+ Ina population of largely (90%) HER2-low MBC patients,
treatment with pertuzumab led to an ORR of 2.5% and
a median time to progression of 1.5 months

18 439 14 378
2 49 2 54
21 512 2 505
o - 1 27
Clinical benefit (CR + PR + SD 224 uk) 4 98 2 54
Duration of cnical bent, uk.

us 6
21749 310363

No clinical benefit with blockade

of the HER2 pathway in HER2-low breast cancer ee

“0
Range, 20370 27303

Probability of Time
to Progression

Timo, d
4. Gianni Leta. Gin Oncol 2010:28:1131-1137, PeerView.com

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51. T-DM1 for HER2-Low BC!

+ — Retrospective evaluation of T-DM1
in 21 cases of HER2-nonamplified
MBC.

+ Only 1 response (ORR 4.8%)

Median PFS
NE (95% Cl, 4.6-NE)
+ HER2+<median(n=25) 4.2 (95% CI, 27-68)
= HER2 normal (n = 21) 2.6 (95% Cl, 14-39)

and mPFS 2.6 months 5 08
E
806
Little activity of T-DM1 En
in HER2-negative MBC. ao.
E o A E A PS
0
0 2 4 6 8 10 12 14
Time, mo

1.Buris HA tal. Gin Oncol 2011:20:398-408 PeerView.com

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52. T-DXd MOA: Bystander Effect and Rationale
for Targeting HER2-Low MBC13

| Neighboring
Tumor Cell
TDX binds \
to HER2

Tumor Cell

em
> \

ir
‘Topoisomerase | Nr

inhibitor enters
nucleus 3

Toxd
internalized |)

releasing
topolsomerase //
Inhibitor

1. ModiS et al J Gin Oncol 2020.38:1887-1898, 2. Nakada Tet a. Chem Pharm Bul (Tokyo). 2019,7:173-185. e
3. Opitan etal. Cin Cancer Res. 201622 5097-5108. PeerView.com

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53. DESTINY-Breast04: First Randomized Phase 3 Study of T-DXd
vs Treatment of Physicians Choice for HER2-Low MBC12

An open-label, multicenter study (NCT03734029)

T-DXd

+ HERZdow (IHC 1+ vs IHC Stratification 5.4 mg/kg Q3W

24/ISH-), unresectable, and/or i

MBC treated with 1-2 prior lines of est

chemotherapy in the metastatic + 1vs2 prior lines of pets doo

setting chemotherapy HR-= 60

+ HR+ (with vs without prior

+ HR+ disease considered treatment with CDK4/6 inhibitor) ’

endocrine refractorya vs HR- apecitabine

abine, paclitaxel, nab:
Primary endpoint Key secondary endpoints
+ PFS by BICR (HR+) + PFS by BICR (all patients)
OS (HR+ and all patients)

Theray HR+ All patients

T-DXd TPC T-DXd

(n=331) (n= 163) (n=373)
Prior CDKA/6 inhibitor, n (%) 233 (70) 115 (71) 239 (64) 119 (65)
Median lines of chemo, n (range) 103) 102) 103) 102)

‘i patients had HR+ MBC, prior endocrine therapy was required. * Performed on adequate archived or recent tumor Biopsy per ASCOICAP guidelines using the VENTANA HER2neu (485)
investigational use only (UO) Assay system. <TPC was administered accoringl tothe label. ¢ Other secondary endponts included ORR (BICR and nvestgator), DOR (BICR), PFS (nvestgator)
and sat, efcacy in the HR cohort was an exploratory endpoint u

Modi Set al. ASCO 2022. Abarat LAS. 2 Modi Set al. N Engl Med. 2022:387:020 PeerView.com

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54. DESTINY-Breast04: PFS by Investigator
in HR+ and All Patients!

HR+ Cohort

Tamm 10m Pom HR
© E CES mein osc
© Par 8 ET

La anaes (4100 (449) (030047)
= Ud 26 a
da wom ao aka oma
3%

Po

&

gor 24-mo landmark (95% Cl).
En T-OX 15.4% (113-200)

Time, mo

-OXd (n = 33)

All Patients

3

adn TONO Om MR
BOSCH (nes) mein 05% en
7 ry
ods) (3004

42 os
6049 (020045)

24:mo landmark (85% Ci)
T.OXE: 14.5% (108187)

0X0 (9 = 373)

PFS Probability, %

Bessa ses

Time, mo

+ Median PFS was consistent with results from the primary analysis, showing a reduction in risk of disease
progression or death of 63% and 64% in the HR+ cohort and all patients, respectively, for the T-DXd arm

compared with the TPC arm

1. Modi Set al, ESMO 2023. Abstract 3760.

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55. DESTINY-Breast04: OS in HR+ and All Patients’

HR+ Cohort
EE
100 Toxd(n=331) BR wen win) ORC
= ee
Pied EZ pin mile alle
En ES Ske celda. a

0 74 6 8 1012141618202224202830323436304042444048
Time, mo

All Patients
Team ue Mn m
100 ES
E rom ee om
Lo Son moan use puce
Bro ao mins 35009
Beo Er]
Fausses
3% ES

TE
T-0Xd (a= 273)
TPC (n= 184)

0748 B 10121410182022242028208224 263404244404
Time, mo

+ In the HR+ cohort and all patients, median OS was consistent with results from the primary analysis, showing a
31% reduction in risk of death for patients receiving T-DXd compared with those receiving TPC

1. Modi et al, ESMO 2023. Abstract 3760.

PeerView.com/SBE827

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56. DESTINY-Breast04: PFS and OS
in HR- Patients (Exploratory Endpoints)!

HR-Negative
os PFS by Investigator
Tessa TINEO TPE mo MR pa Toxine Tem AR
on ne) mem sen 0 tone wei wem orten
Pay 102 F5 ow ge Pinay mann 65 7 048
ee Wenn zo Creer asin aks) eo
re . a 20 vpn 63 29 0
Sons E 7 Gegen 4285) (uam 038057,
A
24 mo ona (5% Cd 2»
un Ee ames,
TO
& 20
2 ox (n= 40)
5 Ten ga
OF 4 6 8 10121416 ezo zzz 292930323030 39404248 OT 254507 8 B sostsasover6101710102001220000052027
Time, mo Time, mo

+ There was a 42% reduction in risk of death and 71% reduction in risk of disease progression or death for
HR- patients receiving T-DXd compared with TPC

* PFS by investigate was no analyzed for e HR-Goho a he me tv primary an =
Mae et at ESMO 2023 Ana 3760, meer PeerView.com

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57. DESTINY-Breast04: Drug-Related TEAEs

in 220% of Patients (Safety Analysis Set)!
Nausea Be
Fatigue? CI °° ee
» ú TPC, grade 23
Transaminases increased” CN + ee z
Alopecia Ss
Neutropenia® sc i >
Anemiat « Ma =
Vomiting se be
Decreased appetite O er
Thrombocytopenia® s Ee
Leukopenia' = o :
Diarrhea CI
Constipation EA
Patients Experiencing Drug-Related TEAE, %
E AAN A AM TR add
pp epi cp olaa pe oo dean eine ac
PS ger ts Du laa tare eran vn ran apa en PO ds a se, ceased ers
‘orn erin wet andara Pale en Tu Eg ees panes maana oo co apar

4. Modi et al ESMO 2023. Abstract 3760. PeerView.com

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58. DESTINY-Breast04: Efficacy of T-DXd in Patients
With Brain Metastases at Baseline’

Intracranial Response CNS-PFS of Patients With Asymptomatic BM
Den mon aora u ano ann)
„rc B en
cer LA sl ¿3
DR 2 E
la ÉS roxein=26
0 20 40 60 80 E
Intracranial Response, % 4

al Response. ‘No, at Risk ris
TOE amnwwwwwentor76645335522200

e Ei] > OS of Patients With Asymptomatic BM
La zen 9) m0. Median, mo (95% C1)
so 1260) 7638) Pe Bea is (67288)
PO o 101 En
ve 142 o 35
Missing” 5208) 30273) re
+ Median CNS-PFS by BICR forthe patients randomly assigned to the T-0xd. 8 it
arm was 9.7 months (95% Cl, 4.4- 15.1 months) ors CHRD ODM eR
+ Median OS for the patients randomly assigned to the T-DXd arm was 16.7 Time, mo
months (95% Cl, 6.7-24.5 months) u
1 mme us nr 643 111 0
Gonfemation was required for CR and PR. Data were not avaiable or analysis

1. Teurutan Jet a, ESMO 2023, Abstract 38. PeerView.com

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59. DEBBRAH: CNS Activity of T-DXd in HER2-Low
Breast Cancer With Brain Metastases’

Eligible Patients
Cohort 1
HERZ+ BC with nonprogressing BM
{after WERT + SRS + surgen)
Cohort 2
HER2+ or HER2-ow BC
with asymptomatic untreated EM
Cohort 3
HER2+ BO with progressing BMs (ENS ORR
aftr local treatment
Cohort 4

HER24ow BC with progressing BM
after cal treatment

= (A
Hana an Bo Le

1. Vaz Batista et al, SABCS 2021. Abstract PD4-0.

Primary Endpoints

==>)

PeerView.com/SBE827

Tumor Respon

CBR, n (%)
DOR, median (min-max) 4.5(35-71) 58(5561) 55 (35-71)
PFS, mo (95% Cl)

Intracranial Tumor Activity by RANO-BM

a Cohon2
cohort
Patients
Overall Response in HER2-Low Patients
Cohort2 Cohort4 Over
(n=6) (n=6) [X
ORR, n (%) 360.0) 2(833) 5417)
3(60.0) 3(50.0) 6(50.0)

5.67 (4.7-NA); events: 9/12
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60. Timeline of Approval of T-DXd for HER2-Low MBC

August 5, 2022 January 26, 2023

... for patients with HER2-low (IHC 1+ or IHC 2+/ISH-) MBC who have received
a prior chemotherapy in the metastatic setting or developed disease recurrence during
or within six months of completing adjuvant chemotherapy

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61. The New Pie Chart of HER2 Targetability!

HER2 testing by validated IHC assay

Ez y

Weak-to-moderate complete Incomplete membrane staining
membrane staining in >10% of

+
No staining observed: HER2 null

or

Membrane staining thats incomplete and is

fainvbarely perceptible and in <10% of tumor cells
THC O+

HC 2+

HER2+ BC 15%

T-DXd not

But what if T-DXd approved
also worked in HER2-0 BC 30%-40%
HER2-0?
1. Adapted rom Taran Peal ln nce 2020381051102 PeerVie

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62. A Hint From the DAISY Phase 2 Trial!

T-DXd for HER2-0 MBC
BOR = 30% (11/37; 95% Cl, 15.9-47.0)

100

Change From Baseline, %

1, Dieras V et al. SABCS 2021. Abstract POS-02 PeerView.com

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63. DESTINY-Breast06: Expanding the Benefit of T-DXd!

+ DESTINY-Breast06 phase 3 includes HER2 “ultralow” (IHC >0 <1+) expression and
may expand the population of patients deriving benefit from T-DXd

Archived sample Trastrunal,
HER2 low (IHC 1+ 2+) deruxtecan (T-DXd)

or
HER2 ultralow (IHC >0 <1+) Primary endpoint: PFS
HR+ Physician's choice

22 lines ET or POD on ‘st line of single-agent* |
CDK4/6 inhibitor capecitabine, paclitaxe

+ Key differences with DESTINY-Breast04: includes IHC 0+ (“ultralow’), larger (N = 850), restricted to HR+
disease, and includes chemo-naive patients

Options ine el nab-pacitaxel. Treatment continues unt PD or toieiy. HERZ IHC 0+ defined by any IMC staining up o 10% of tumor cet,

capecitabine, pacita
FU ana HERE IN Oc coor wl be conducted e
1. ps cinicatials govit2/howMNCTO4404425. PeerView.com

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64. DESTINY-Breast06: T-DXd vs TPC in HR+, HER2-Low,
or HER2-Ultralow MBC With Prior ET!

+ T-DXd demonstrated a statistically significant and clinically PFS in HER2-low
meaningful PFS benefit vs TPC (chemotherapy) in
HR+, HER2-low mBC in an earlier line of treatment than

DESTINY-Breast04

+ Results in HER2-ultralow were consistent with HER2-low

+ Confirmed ORR was 57.3% (T-DXd) vs 31.2% (TPC) in ITT

+ No new safety signals were identified; interstitial lung
disease remains an important safety risk of T-DXd

DESTINY-Breast06 establishes T-DXd as an
effective new treatment option for patients with
HR+, HER2-low and HER2-ultralow mBC following
21 endocrine-based therapy

1. Gurigiano Geta ASCO 2024, Abstract LBA 1000 PeerView.com

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65. The Past, Present, and Future of HER2 Low!

==

Continuous spectrum
of HER2-ow expression
1. Tarantino P etal. Cancer Discov. 2022:0F1-0FS.

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DESTINY-Breast06

y

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66. TROP2-Targeting ADCs

67. ADCs Targeting TROP2'

Regulatory approval and Biologics license application

indications of SG in éd eo a (BLA) accepted in the US
metastatic TNBC and HR+, for patients with previously
HER2- advanced/metastatic | treated metastatic HR+,

aa HER2- breast cancer
u | —
= ss
NZ NG
SN38 payload nes
mn
/ ges \

Humanized
ant -TROP2 1961 mAb

1. Pais et al. Cancor Troa Rev. 2023:118:102572 PeerView.com

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68. ASCENT: SG in TNBC'

PFS os
10 Pants PRE PFs,
a3 (events) HE) 10 nen
22 7 09 es
se wo Fe 08 me est
z Sactuzumab so2r eo por Sacituzumab 297 na
Bos gontecan con 649 À 6 gontecan 201) (105-138)
3 os ed Taste
dl PE 05 Suites 9 C= 0514 422062)
pare & oa
g ais dos
aa ‘govitecan 02
0 01
o
o
zZ u 2 2 u E 0 3 6 9 12 15 18 21 24 27 30
Time; mo Time, mo
No. at Rak
No. at
WO oe a dE Æ 0 € > à mme 2 we me a nme 7 3 0
Sent er % 2 M 3 0 Scheme 7 m2 200 (0 6 9 6 42 2% 2
1. Bardia À et al. J Cin Oncol. 2024:42:1738-1744 PeerView.com

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69. ASCENT: SG Efficacy by HER2 IHC Status’

HERZ NCO HER2-Low (MC, IHC2+18h-

PFS and OS in the HER-evaluable
population were comparable with
those in the ITT population

SG improved PFS and OS for both
HER2 expression subgroups

HERZ Low (HC+, IHC2+18H-
Ps

oT etna a NT DD re eee)
Time, mo

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70. ASCENT: PFS by TROP2 Expression’

PFS, Probability

PFS, Probability

1. Bardia A et al J Ci Oncol. 2024:42:1738-1744,

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PFS
x (score: 0.13)
e ae

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71. ASCENT: OS by TROP2 Expression’

at (H-Score: 0.130)

Time, mo Time, mo

1. Bardia A et al J Ci Oncol. 2024:42:1738-1744,

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72. TROPiCS-02: SG in HR+, HER2- MBC1

+ 1L CDK4/ inhibition was given to 31% patients in the SG group and 37% patients in the control group, and 67% in the SG
group and 62% in the control group in the 2L or later-line setting
+ Patients had received a median of three previous lines of chemotherapy

A E
Er =
a À © ‘Shute obs 60
cama | à tna Em een
mungen | à 3 N
Genre men | E EEES
paró opus | E
die e popa | 5 à
‘at each landmerk Eso Zen.
Tmemo
en FLE pre
‘SGeoinediodenonvete | E & PTE ETES
imprormentinos Teo | 70 e 2000)
aingenowe sts racin (3 2 E EE
ee |B 2
proponen pias enanos |E ©
rr | & ©
8 Te
KG Ha TT
Pant ann)
1.Tolaney S et al. ASCO 2023, Abstract 1003. 2. Rugo HS et al. Lancet, 2023; 402 (10811): 1423-1433, PeerView.com

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73. 100 sc Trc
=” BICRAnaiysis na ga Ga)
# © MedanPFSmo 58 42
En (5% cH) ares (2845)
q. HR (95% C1) 0.60 (0440.82)
3 so
lo
ra
= 2
10 Sacituzumab govitecan
o
0 3 6 9 1215 1 A à 2 0 5 %
Time, mo
Son!
EW wo e240 296520. ens se zen 207 zn 10m ou
Me ID 1708 sum 209 109) tm 909 Dim Bam am OU BU

TROPICS-02: SG Efficacy in HR+, HER2- MBC
by HER2 IHC Status!

HER2-Low (IHC1+, IHC2+/ISH-)*

HER2 IHCO*

100 “

e EEC men)
Le Medan PFS: mos 35
En (95% cl 6972 (1842)
a8 HR (95% C1) 070051098)

so
8%
2»
& 20

10

os 69 2 1

18 21
Time, mo

27 30 33 38

OO ar 615059 Ten sm 316) 269 Lam ou Den OW oem
MENOS Um) 20 208) 109 109 100 110) 009 00%

+ SG consistently improved PFS vs TPC in the HER2 low (IHC1+, IHC2+/SH-) and the HER2 IHCO groups with

longer follow-up

*MERZ IHC was determined by local assessment on lst available pathology sample. 57% of patients were HER2-ow (IMC, IHC20/SH-) and 43% were HER2 IHCO.

PFS probabilty was estimated using an unstrafied Cox model using treatment (SG vs TPC) as the only presto.

1.Tolaney S et al ASCO 2023, Abstract 1003,

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74. TROPICS-02: SG Efficacy in HR+, HER2- MBC
by TROP2 Expression!

H-Score <100* H-Score 2100*
bt we oca Sin
ea #3 oa eo
io En En _ eeimusm
3 0 3 ©
PFS HE i :
ia ia
Tape EEE RENE
a NS
H-Score <100° H-Score 2100°
5 = as e de
> a8 ze aie ats
os i: ie :
8: 8%

Time, mo

242% had H-score <100 and 58% had Hore = a
1. Tolaney Set al ASCO 2023, Abstract 1003, PeerView.com

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75. TROPION-Breast01: Dato-DXd vs Chemotherapy in Pre-Treated
Inoperable or Metastatic HR+, HER2- Breast Cancer!

TROPION-Breast01: randomized, open-label phase 3 trial evaluating Dato-DXd vs investigator's choice of single-agent
chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine) in patients with inoperable or metastatic HR+, HER2-low, or -
negative (IHC O, IHC 1+ or IHC 2+/ISH-) breast cancer who have previously progressed on or are not suitable for endocrine
therapy and have received at least one systemic therapy

Key Inclusion Criteria
+ HR#/HER2- inoperable or metastatic breast cancer with
disease progression following 1 or 2 lines of
chemotherapy (and progressed on and not suitable for Dato-DXd
endocrine therapy) 6 mg/kg IV Q2W
+ Targeted agents (ie, inhibitors of mTOR, PD-1/PD-L1,
CDK4/6, PARP) and endocrine therapies on their own
do not count as prior lines of chemotherapy
21 measurable lesion
FFPE tumor sample
Adequate organ function
Randomization stratified by Investigator's choice of chemo (ICC)
+ Lines of chemo in the inoperable/metastatic setting late, vinorelbin
(1 vs 2) itabine, or gemcil
+ Geographic location (United States/Canada/Europe vs
RoW)
+ Previous CDK4/6 inhibitor use

Dual primary endpoints:

PFS by BICR per RECIST
vi.1 and OS

Chemotherapy wil be administered at the folowing doses: en mesyae: 14 mpim2 on days 1 and 8 f a 21-day cycle vi IV infusion: vnorebin: 25 mofm2 on day 1 and 8 of a 21-day eye
va IV infusion: capectatine: 1000 or 1250 mgim2 po BID on days 1 o 14 of a 21-day cycle; gemctatine: 1000 mp2 on days 1 and 8 of a 21-day cycle. ars
Y Bardia At al. Future Oncol, 202420423-438 PeerView.com

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76. Primary Results From TROPION-Breast01:
PFS by BICR (Primary Endpoint)!

10 Dato-DXd icc
3
5 os Median PFS, mo (95% Cl) 6.9 (5.7-7.4) 4.9 (4.2-5.5)
E os 533% HR = 0.63 (95% CI, 0.52-0.75; P < .0001)
2 os
cs
TS
>
a ze
a
No. at Risk Time From Randomization, mo
as se ‘a a à y
a = = = a :

PFS by investigator assessment: median 6.9 vs 4.5 months; HR

1. Bardia A et al. ESMO 2023, Abstract LEAN PeerView.com

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77. Primary Results From TROPION-Breast01:
Response Rate and Interim OS

Response Rate
=P. = Complete response
x aaa NEN OS: Dual Primary Endpoint
a CR:0.5
$ = OS data were not mature: median follow-up
g © 9.7 mo
3 25 ORR: 22.9
x u Atrend favoring Dato-DXd was observed:
E HR = 0.84 (95% Cl, 0.62-1.14)
15
E do The study is continuing to the next planned
2 F analysis for OS
Es
o + 50% greater response rate with Dato-DXd
Dato-DXd (n = 365) ICC (n = 367) vs ICC

50% greater response rate with Dato-DXd vs ICC

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1. Bardia A et al, ESMO 2029. Abstract ALBA.

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78. Primary Results From TROPION-Breast01:
TRAEs in 215% of Patients!

System Org

Preferred Term, n (%)

Blood and lymphatic system disorders

‘Anemia 40(11) 4(1) 6920) 7(2) + Most TRAES were grade 1-2 and manageable
Neutropenia Bm) 4 (1) 10 108(31)
Eye disorders + AESIs
Dry eye 78(22) 20) 276) 0 — Oral mucositis/stomatitis: led to treatment
discontinuation in one patient in the Dato-DXd
Gastrointestinal disorders group
Nausea 1845) 50) 83024) 21 - E
asi MOD Ge uate 30 ed events: most were dry eye; one patient
Vomiting TC) 40) 28 2m iscontinued treatment in the Dato-DXd group
Constipation 65(18) 0 32(9) 0 - Adjudicated drug-related ILD: rate was low;
mainly grade 1/2
General disorders
Fatigue 85(24) 62) MU 7)
‘Skin and subcutaneous disorders
‘Alopecia 13136) 0 7221) 0
Adjudicated drug-related ILD 2@ 2 0 0
1. Bardia A et al. ESMO 2023, Abstract LEAN PeerView.com

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79. Additional Safety Analysis From TROPION-Breast01: AESIs!

Treatment-related Dato-DXd ff treatment-related Dato-Dxd | Adjudicated drug-related Dato-DXd
oral mucositis/stoma (n= 360) ff ocular surface events“, n (%) (n= 360) FB ILD*,n(%) (n= 360)
Al grades? 200(556) Ai grades? 444 (40.0) Allgrades 1283)
Grade 1 NH Gage 1 moro) det 514)
Grade 2 84 (23.3) Grade 2 an
Grade 2 26(72)
Grade 3 25 (69) Grade 23° 3(08)
Grade 3 308)
Leading to dose reduction 48 (133) Leading to dose reduction 103
Leading to dose reduction andlor 12183)
Leading to dose interruption 5(1.4) interruption Leading to dose interruption 3008)
Leading to dose discontinuation 1(03) Leading to dose discontinuation 1(03) Leading to dose discontinuation 5(14)
+ Median time to onset: 22 days + Median time to onset: 65 days + Median time to onset: 84.5 days
+ Median time to resolution: 36.5 days + Median time to resolution: 67 days + Median time to resolution: 28 days

‘Comprising te prefered terms of apthous cer dysphagia, losis, mouth uleraton, od mophagia, oral mucosal Biserng, ral pain ropharyngeal pain, pharynge a inflammation,
and stomatts. No grade 4/5 events. © Comprising the preferred terms of: blepharts, conjuncivits, comeal disorder, comea rosion, comeal lesion, dry eye foreign body sensation in
eyes, keraii, keralopaty,lacrimaton increased, Imbal stem cel deficiency, meiboman gland dysfunction, ocular only, photophobia, punctate Krai, superior Imbie

Keratocojuncivits, erative Keats, vision bed, visual imparment and rerophtaimia. “Comprising te prefered terms of nterstial lung disease and preumontis.* Grade 3
(08%) grade 5:n= 1 (0.3%) u
‘shaver Komal et al. ESMO Breast Cancer 2024. Abstract LBAZ. PeerView.com

-2

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80. Returning to Our Case—Panel Discussion

+ 62-year-old woman diagnosed with stage | breast cancer
6 years ago; HR+, HER2 IHC 0 > now presents with
metastatic disease

History and Presentation

Was prescribed 5 years of adjuvant letrozole
CT showed a solitary lesion on the right lower lobe of the
lung

She has received two lines of endocrine therapy
(including CDK4/6i) and one line of chemotherapy
(capecitabine)

CT scan shows enlargement of the pre-existing lung
lesion and additional lesions in the lung

ctDNA testing is negative for ESR1 and PIK3CA
mutations

HER2 re-testing reveals IHC 1

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What treatment would you recommend for this
patient?

What if the HER2 IHC had been 0 at the time of
retesting?

How do you select and sequence the different
ADCs in HER2-Iow breast cancer?

How should we identify patients with HER2
expression in the lower ranges of expression? Is
testing necessary?

How will you decide between SG and Dato-DXd
‘once the latter is approved for HER2 IHC 0? Does
lack of OS data yet from TROPION-Breast01
impact that decision?

For HR- HER2-low, how do you sequence ADC?
What if HR- HER2-low patients also present with
brain metastases—does that impact your decision?

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81. Emerging Options and Future
Directions in HER2+ and HER2-Low

Breast Cancer

Javier Cortes, MD, PhD

Head

International Breast Cancer Center (IBCC)
Barcelona, Spain

(.
as

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82. Ongoing Research to Expand the
Therapeutic Options for HER2+ and

HER2-Low Breast Cancer

83. Current Standard of Care for HER2+ MBC

Trastuzumab + pertuzumab Trastuzumab deruxtecan Tucatinib + trastuzumab
+ taxane (T-DXd) + itabine
L DB! IME
or or
Tucatinib + trastuzumab +

DB03

Factors: extracranial disease or
burden, intracranial disease a
preference, etc. EMILE Tear =

+ Activity post T-DXd?
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84. Late Line Options for HER2+ MBC: “Dealer’s Choice”

Fourth Line + Many possible agents,
including

+ Vinorelbine
a . + Gemcitabine
TH: A + Doxil
+ Carboplatin

Margetuximab + chemo Trastuzumab + lapatinib

Special consideration
in HR+/HER2+:
fulvestrant/abema/trastuzumab

Neratinib + capecitabine

Or tucatinib/capecitabine/trastuzumab, or T-DXd if not already received PeerView.com

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85. DESTINY-Breast07: Dose-Expansion Interim Analysis of T-DXd Monotherapy
and T-DXd + Pertuzumab in Previously Untreated HER2+ MBC*

+ This is the first dataset of T-DXd monotherapy and T-DXd + pertuzumab as first-line treatment
for HER2+ mBC

+ T-DXd monotherapy (n=75) and T-DXd + pertuzumab (n=50) showed robust efficacy:
- Confirmed ORR was 76.0% and 84.0% for T-DXd monotherapy and T-DXd + pertuzumab, respectively

- Median DOR was not reached for T-DXd monotherapy or T-DXd + pertuzumab

= PFS rate at 12 months was 80.8% and 89.4% for T-DXd monotherapy and T-DXd + pertuzumab, respectively;
the number of PFS events was small and most patients were censored

‘There are 62.7% and 56.0% of patients receiving ongoing study treatment, with a median duration
of follow up of 23.9 months and 25.3 months, in the T-DXd monotherapy and T-DXd + pertuzumab
modules, respectively

Encouraging clinical activity was observed with T-DXd monotherapy and T-DXd + pertuzumab in firstine

HER2+ mBC, irrespective of disease status and HR status

+ The safety profiles of T-DXd and pertuzumab were consistent with their individual known profiles

~The incidence of ILD/pneumonitis events was 9.3% and 14.0% in the T-DXd monotherapy and
T-DXd + pertuzumab modules, respectively; there were no ILD/pneumonitis-related deaths in
either module

+ T-DXd monotherapy and T-DXd + pertuzumab are being evaluated versus THP, in patients
with HER2+ mBC in the first-ine setting, in the Phase 3 DESTINY-Breast09 clinical trial

1. Andee F et a. ASCO 2024, Abstract 1008, PeerView.com

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86. DESTINY-Breast09 (1L Trial in HER2+ MBC): Study Design’

1L Standard May Soon Change
(n = 378)

Untreated metastatic breast cancer T-DXd + Be
(n= 378)

But how will QoL compare after taxane is dropped in the THP arm?

+ Primary endpoint: PFS

1. Mtps flats govistudy/NCTOAT84715. PeerView.com

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87. DEMETHER: Maintenance of Trastuzumab and Pertuzumab
Following T-DXd as Induction Treatment for HER2+ Breast Cancer!

DEMETHER (NCT06172127): A phase 2 trial aims to optimize the first-line
treatment in patients with HER2 overexpressing breast cancer

Induction therap Maintenance therapy

Post-treatment follow-up

Physician’
choices

O

Baseline C2D1

"Defined as he date of disease progression, death, discontinuation fromthe study treatment for anyother reason,
1. ps classic cnicavils goviet2/show NCTOB172127.

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88. DESTINY-Breast12: Pre-Treated Patients
With or Without Brain Metastases’

A Phase 3b/4, Open-Label Trial

HER2+ advanced or
metastatic breast cancer

+ Absence or presence of BM
at baseline

$2 prior lines of therapy in
the metastatic setting

Secondary endpoint

Cohort 4 (n
BM at ba

T-DXd 5.4 mg/kg q3w +

250)

Primary endpoint
ORR in Cohort 4
+ PFS in Cohort 2

+ OS, DOR, time to progression, DOT on subsequent lines of therapy, and PFS2 in both cohorts
+ Incidence of new symptomatic CNS metastasis during treatment in cohort 1

+ ORR, CNS PFS, time to new CNS lesions, CNS ORR, and CNS DOR in cohort 2

+ Change in symptoms, functioning, and HRQOL

+ Safety and tolerability

1. ts www ciicaitials gov'studyNCTO$730761,

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89. Exploring Other Targets in HER2+ Breast Cancer

CEACAM CD166 cD71

HER3 Nectin4 FRa MESOTHELIN MUC1

Trop2

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90. Patritumab Deruxtecan (U3-1402, HER3-DXd):
HER3-Targeting ADCs’

HER3 is expressed in >95% of breast cancers,
with half showing strong overexpression
~

Bl ps

Patritumab deruxtecan (U3-1402) is a novel ADC
coupling an anti-HER3 mAb to DXd with a high DAR (8:1)

1.Lultla Set al. BMC Cancer. 2018;18:1045. PeerView.com

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91. HER3-DXd Efficacy’

A phase 1/2 study (NCT02980341) of patritumab deruxtecan in patients with HER3-expressing MBC

HR+/HER2-
(n= 113)
HERS High HERS High
30.1 226 429
(21.8-39.4) (123362) ar)

Outcomes (BICR per RECIST 1.1)

Confirmed ORR, % (95% Cl)

Best overall response, %
PR 30.1 226 429
sp 50.4 56.6 50.0
PD 115 17.0 71
NE 80 38 o

DOR, median (95% Cl), mo 72 59 83

(63-NE) (6.034) (28-264)
74 5.5 11.0

fe nee (47.34) 89:58) (4.4-16.4)
53.5 38.2 51.6

Esc ltd (43.4-62.6) (24.2-52.0) (22.1-74.8)

146 146 195
Ce emedian 5 CI Mo 413-195 112-172 12.2:NE

HER3-DXd demonstrated durable antitumor activity across BC subtypes
‘Confirmed ORR forall patients (N = 182), 28.6% (95% Cl, 22.1%-35.7%); median DOR, 7.0 mo (95% Cl, §.5-8.5 months)

1. Kop Let al ASCO 2022. Abstract 1002. PeerView.com

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92. ICARUS-BREAST01: HER3-DXd in HR+, HER2- Advanced
Breast Cancer!

Key Eligibility Criteria®

Unresectable locally
Primary endpoint

advanced/metastatic BC + Investigator-assessed ORR

HR+/HER2-negative/HER2-low

Progression on CDK4/6i + ET Secondary endpoints

Progression on one prior + DOR, PFS, CBR, OS

‘chemotherapy for ABC + Safety and tolerability

Prior PISK/AKT/mTORI allowed
No prior T-DXd

Tumor response by 3 eros) TEAES 2 25% of

months from treatment a all patient
initiation, n (%) ce
2 All grades Grade 23
Partial response 16 (28.6) Fatigue 50 (89.3) 8 (14.3)
Stable disease 30 (53.6) Nausea 420750) 266)
Progressive disease 10 (17.8) Diarrhea 26 (46.4) 26.6)
Alopecia 25 (44.6) NA
Constipation 15 (26.8) 3(53)
2 HERIerpression prescree membrane post at 10) was removed by amendment on Apr =
{pith bret ESMO Brest 2003 Adna 1600 ió Sn ni EE PeerView.com

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93. HER3-DXd: Other Ongoing Trials

VALENTINE Trial (NCT05569811)'

+ Phase 2 neoadjuvant three-arm study in patients with HR+/HER2- BC with high risk
(Ki67 220% and/or high genomic risk)

+ Evaluating HER3-DXd with or without letrozole as neoadjuvant therapy vs standard of
care neoadjuvant chemotherapy

TUXEDO-3 Trial (NCT05865990)?
+ Phase 2 single-arm study of HER3-DXd in patients with active brain metastases from
BC and NSCLC.

HER3-DXd in patients with MBC (NCT04699630)?

+ Phase 2 three-part study evaluating HER3-DXd in patients with MBC
* HR+/HER2- or TNBC post other ADCs.

1. htps:esnieatialsgowstudyINCTOSSE0811. 2. hps:/enicatials govstudy/NCTOSSE5900 3, tips einiatrias gowstudy/NCTO4690630. PeerView.com

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94. TROP2 ADCs in HER2+ Breast Cancer!
SATEEN: A single-arm phase 2 trial of SAcituzumab govitecan and Trastuzumab after progrEssion on ENhertu

Currently open for enrollment
so+T 86 sort so soerso sorTS0 soerse se»rso

‘Metastatic or unresectable locally
advanced breast cancer
HER2+ (any HR status)

Prior progression on taxanes,
trastuzumab, pertuzumab, PD
osa Week 1 M | Week15
¡No limit of prior lines =
Has not previously received a a a
anti-TROP2 ADCs > »
N=40 Phase 1b dose de-escalation cohort
+ First 6 pts treated will comprise a
dose de-escalation cohort (starting at
full/standard dose of both drugs) with

+ Primary endpoint (phase 1b dose de-escalation cohort): RP2D

associated DLT monitoring and

+ Primary endpoint (phase 2): ORR prespecified rules to dose reduce if
needed; declare RP2D

1. tps ease lnicatias gov/e®showNCTO6100874 PeerView.com

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95. Trispecific Antibodies‘

Atrispecific antibody targeting HER2 and T cells (CD3 x CD28) stimulates regression of HER2+
and HER2-low breast cancers in a humanized mouse model through a CD4-dependent mechanism

HER2+ Model

— Vehicle
777 50 ug ko"
—— 10pgkg*

Ant-HER2

Tumor Volume After
Implantation of HCC1954, mm?
ë

‘Time Post Implantation, d

1. Seung E et al. Nature, 2022:503:328-394.

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HER2-Low Model
. Vehicle

— 10g kg"
2 | — 0x0
É 10 ug kg"

Ee | — vaio"

LE

is

35

i

20

4

‘Time Post Implantation, d

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96. Selected Investigational Strategies
for HER2-Low Breast Cancer

Trial Treatment ent Population Study Endpoints
DESTINY-Breast08
(NCT04556773) T-DXd combinations HER2-Low Safety, ORR, PFS, DOR, OS, and pharmacokinetics.
DESTINY-Breastt5
(NCTOS950945) T-DXd HER2-Low or HER2 IHC 0 TTNT, real-world PFS, TTD, ORR, and safety
BEGONIA TNBC
(NCTO3742102, arm 6) T-DXd + durvalumab (including HERZ-Low) Safety, laboratory findings, ORR, PFS, DOR, and OS
NCTO5633979 T-Dxd + valemetostat HER2-Lowlulra-iowinull Safety, MTD, and ORR
TROPION-Breast02 TNBC
(NCTOS374512) papa (including HER2-Low) PFS, OS, ORR, DOR, and safety

HR+, HER2-
ASCENT-07 Sacituzumab govitecan (including HER2-Low) PFS, OS, ORR, DOR, and safety
NCTO2277717 trastuzumab duocarmazine HER2+ and HERZLow Safety and ORR
NCTO4400695 disitamab vedotin HER2-ow ORR, PFS, DOR, DCR, and OS
NCTO4742153 MRG002 HER2-Low ORR, PFS, and safety
DYNASTY-Breast02 BNT323/DB-1303 HER2-Low PFS, OS, ORR, DOR, and safety

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97. New Strategies for Better Outcomes

in HER2+ and HER2-Low Breast Cancer

98. The Evolving Pie Chart of HER2'

negative

y
From selecting

responders to
excluding few

nonresponders
through novel

HER? assays ca ms

of HER2-4ow expression DESTINY-Breastos
1. Tarantino P et al. Cancer Discov, 2022:0F1-0FS.

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99. Can We Cure Stage | HER2+ Tumors
With Fewer Side Effects?1?

ADEPT: 6 Cycles of Adjuvant T-DM1 — T

ATEMPT 2.0: 6 Cycles of Adjuvant T-DM1 — T

+ Stage | HERZ* breast cancer

Patient QOL
and symptom

(baseine, 6,
12,18 mo)

+ Agurant XRT at eating tans cretion na
ielnicalials gov/study/NGTO4803108. 2. hips swww cancer goireseareh/paricpatelcinicakals-searchV?i6=NC12020-1397 18721. PeerView.com
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100. PHERGain-2: Chemotherapy-Free pCR-Guided Strategy With
SC Trastuzumab-Pertuzumab and T-DM1 in HER2+ EBC"

PHERGain-2 (NCT04733118)
A phase ll study to assess the efficacy of a chemotherapy-free pathological complete response
(pCR)-guided strategy with trastuzumab and pertuzumab (given as a subcutaneous fixed-dose
combination) and T-DM1, for patients with previously untreated HER2+ early breast cancer

Patients 218 years
Histologically
confirmed invasive
carcinoma of the
breast

HER2 IHC 3+ tumors
Node-negative status
Tumor size >5 mm
0 30 mm (MRI)
ECOG 0/1

ypTtmi2 and/or. E
YPNO(+), ypNO ee) { cos |
(mol), ypNtmi au

i
3

No prior treatment
LVEF >55%

Follow-up (5 years) )

* Physician's choice chemotherapy is alowed before adjuvant TOM 3
1. tips wn ciicatials govstudyNCTOA733118 PeerView.com

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101. PHERGain: Primary Endpoint!

3-year iDFS rate in group B (ITT populations)

LS RS
E '
Eos 3-year iDFS rate: 95.4% i
3 (95% Cl: 92.8-98.0%) |
5 wr Events: 12/267 1
1
¿ 1
ä = Second primary endpoint was met 1
2 _ with < 15 patients with ¡DFS events (p < !
5 0.001) 1
é 1
m |
SIT 8 & 7 EA à à
Time since surgery (months)
Number at risk
CSSS NS NS US NUS NE
4. Contes Jet al. ASCO 2023, Abstract LBAS06. PeerView.com

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102. Can We Cure More Patients
by Escalating Treatment? (Early)'2

DESTINY-Breast05: Substituting Post-Neoadjuvant CompassHER2-RD: Adding Tucatinib
T-DM1 with T-DXd mi to Post-Neoadjuvant T-DM1
tvoctment

u"
ht.

LEE
> E Pen

1. tips encata gowstudyNCTO4622319. 2. ps einialrals govstudyNCTO44S7506 PeerView.com

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103. Can We Cure Stage II-III HER2+ Tumors
With Fewer Side Effects?!

CompassHER2 pCR: Neoadjuvant THP > pCR — HP

Preoperative
Phase: All Patients
THP x 4 Cycles EA1181
Paclitaxel QW x 12 pCR CompassHER2-pCR
= ypTorTis ypNo)

Stage Il or IIIA HER2+ docetaxel Q: 40%

BC (T2-3, NO-2) wi

+ eNO eligible if22 cm trastuzumab (H)

+ CN1-2 eligible 21.5 cm. and pertuzumab (P)

+ ER+ and ER- eligible Wx4

Arm A: pCR (no invasive disease)

(nab-paclitaxel “Group 1: preop THP — AC, CHP x4
allo (Group 2: preop TCHP, AC-THP + no further chemo

+ HER2+ RD
+ ER-and ER+

(ER+ must be N+)
(~30% of A011901
‘expected fo come from
EA1181)

1. htpsiicnicatils govistudyNCTO4286249. PeerView.com

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104. Can We Cure More Patients
by Escalating Treatment? (Metastatic)!

SAPPHO: intensifying First-Line Treatment for Patients With De Novo HER2+ MBC.

Stage IV HER2+ BC,
no prior systemic
anti-BC therapy

ll

Trastuzumab
deruxtecan
(12 weeks)

T-DM1/tucatinib
(12 weeks)

HP/tucatinib Disease
(1 year) follow-up/survivale

Mandatory breast biopsy «ed | (MRD testing
(if available) ping |. Baseline
Metastatic baseline biopsy + C2D1 all therapies

(if accessible) + Pretreatment switch

+ Every 6 months
Tissue testing

ER + BC continues on HR tx + Optional progression biopsy
4. Parsons H et al. Transaiante Exchange in Oncology.

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105. Final Panel Ha
Discussion + O

Audience Q8A

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