HER2-Targeting Therapy in HER2+ MBC With and Without CNS Metastases: Selection and Sequencing

Chair and Presenters Sara A. Hurvitz, MD, FACP, Carey K. Anders, MD, FASCO, and Vyshak Venur, MD, discuss metastatic HER2-positive breast cancer in this CME/NCPD/CPE/AAPA/IPCE activity titled “Fine-Tuning the Selection and Sequencing of HER2-Targeting Therapies in HER2-Positive MBC With and Without CNS Metastases: Expert Guidance on How to Individualize Therapy Based on Latest Evidence, Disease Features, Treatment Characteristics, and Patient Needs and Preferences.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4f8sUs7. CME/NCPD/CPE/AAPA/IPCE credit will be available until March 2, 2026.

1. Fine-Tuning the Selection and Sequencing of
HER2-Targeting Therapies in HER2-Positive MBC
With and Without CNS Metastases

Expert Guidance on How to Individualize Therapy Based on Latest
Evidence, Disease Features, Treatment Characteristics, and Patient
Needs and Preferences

In Women’s Health Division Chief of Medical Clinical Research Director

Sara A. Hurvitz, MD, FACP Carey K. Anders, MD, FASCO Vyshak Venur, MD

Professor of Medicine Professor of Medicine, Division Associate Medical

Smith Family Endowed Chair PR ofmecical Oncology M Director—Inpatient Oncology
‘=

Head, Division of Hematology Oncology, Interim Medical for Neuro-oncology

‘and Oncology Director of the Duke Center for Assistant Professor

Senior Vis Present, Ciné Jal ANN Brin and Sune Meios Clinical Research Division
Research Division Translating Duke Health Scholar Fred Hutchinson Cancer Center
Department of Medicine Duke Cancer Institute Department of Medicine
University of Washington Medicine Duke University Health System University of Washington.

Fred Hutchinson Cancer Center Durham, North Carolina Seattle, Washington

Seattle, Washington

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

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2. Our Goals for Today

Equip you with knowledge about the latest evidence and
recommendations to guide the selection and sequencing of
HER2-targeting therapies in MBC, including as systemic approaches for
brain metastases

Enhance your skills in integrating current therapies into individualized
treatment plans for patients with HER2-positive MBC, with and without
brain metastases

Copyright © 2000-2025, Peerview

3. Laying the Foundation for Resilient
Care in HER2-Positive MBC

Modern Goals Guiding Sequential Treatment &

Real-World Insights

1000-2025, PeerView

4. Gaps Persist Despite the Expanding Arsenal of Therapies

for HER2+ MBC"

HER2-targeting therapies have revolutionized treatment, disease trajectory, and outcomes for patients with HER2+ metastatic
breast cancer (MBC), now including those with active and stable brain metastases (BM)

+ With a multitude of treatment options

available and emerging, it can be menager
challenging to navigate the selection,

sequencing, and use of different treatment | ==="
‘options for patients with HER2+ MBC i.

+ Treatment of patients with HER2+ MBC ty u
with BM poses additional challenges, but ES

new data and options are challenging the [=
long-standing role of local treatment as 7 = ae
default clinical pathway for BM and carry (es TE, ES
significant implications for sequential = so
decision-making SS 7 e Le

+ Patients with HER2+ MBC with BM lack ES =e
resources and information about diagnosis, | "99 — Ei

treatment, and survivorship

+. Mee Bernstam Fe al. Cin Cancer Res 201825:2033-2041. PeerView

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5. ain Metastases in HER2+ Breast Cancer!

+ Breast cancer is one of the most common causes of BM and LMC

+ The incidence of BM in HER2+ tumors is 20% to 30% and is associated with a better prognosis than in
other subtypes of breast cancer

+» There are different options to treat BM depending on several factors

100

11.9% 6.9% a 14% 8.5% 1.3%

® EN 62% | A 6%
peor e 9.8% 7.8 11.2% 29%

3

Seo 16.4%

©

8

A 14.6%

5%

3

El

= Lung = Breast
Melanoma = Colorectal
5 Renal CUP o
Others 1986-1999 2000-2009 2010-2020

1. Kuksis Metal Neuro Oncol 2021;23:894-904. 2. Romakcishna N et el. / Cin Oncol, 2018:36:2804.200. Year of BM Diagnosis
3. Hurviz SA el al. Cin Cancer Res. 2019252433241, 4. SleindlA el al. Eur J Concer. 2022:162 170-181,

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6. Incidence of BM in HER2+ MBC:

RWD From the US Flatiron Database’

HR+, HER2-
[HR+,

Line
of Therapy
Prevalence of BM, n (%)

134 (2.5) 109 (10.3)
[199 (2.8)] [88 (12.1)]
150(4.4) 97(17.6)
149012) | 275 (587 ua
3 1232 281 25015 102069 | 2794) 160 Goal
104(7.2) 38 (24.7)
199.281 STH | 1189 (9:41 136 (27.0)

120265) 20069) | eos, 8057)

193 (6.3) 101 (11.2)

2 1936 478 341 (17.6)

+ Data from 18,075 patients with MBC in the Flatiron database who had initiated a 1L of therapy up to
March 1, 2021, to allow a follow-up of at least 2 years

+ By3Lof therapy, 21.5% of HR+, HER2+ and 36.3% of HER-, HER2+ patients have developed brain metastases
+ Older data from the HERA trial? where HER2+ patients were followed until death reported that 47% of
trastuzumab-treated patients eventually developed brain metastases

4. Sammons SL etal, SABCS 2023. Abstract POS-20-02, 2 PestloziBC et al Lancet Oncol 2019,14:9264-248, PeerView

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7. After BM Diagnosis, Survival is Most Favorable in HER2+ MBC"

No. at Risk
GPA3.5-4.0
GPA2.5-3.0
GPA1.52.0
GPA0.0-1.0

1. Sperduto PW et:

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Breast Cancer

o 12 24 36

Time Since Initial BM Treatment, mo

173141 88 60
654 449 262 148
769 369 162 69
376 86 32 13

J Cin Oncol. 2020 38:37733784.

Prognostic
Factor Patient
by Cancer Score
Type
Breastcaner = — — — - =

KPS <60 70-80 90-100 NA NA =

CPASSAD Aga 260 <60 NA NA NA =
GPA25-3.0

GPA1520 BMn 22 1 NA NA NA =
GPA 0.0-1.0

48 60 ECM Present Absent NA NA NA -

HER2
Luminal or

à Subtype — Basal A NA pias =

2 >

38 Sum = MS (mo) by GPA: 0-1 = 6; 1.5-2.0= 13;

3 25-3.0= 24; 35-40=36

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8. Discussion llenges and Opp nities for Improvement in

HER2+ MBC With/Without BM

+ Goals of care and sequential treatment principles for HER2-positive MBC,
centered on the earlier use of more effective HER2-targeting regimens to prolong
survival while maintaining quality of life

» Profile and responsibilities of the care team for the safe, effective, and
patient-centered management of HER2-positive MBC, including the integral role
of neuro-oncologists for BM management

+ Unique patient needs in HER2+ MBC, including in those with BM
+ Other considerations and multidisciplinary perspectives

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9. Module 1
The Sequence is Key
in HER2-Positive MBC

Evidence, Guidelines, and Clinical Factors
to Optimize Treatment Selection and Patient Outcomes

Copyright © 2000.

10. CLEOPATRA: Study Design’

Pertuzumab + trastuzumab
Patients with HER2+ octal + Primary endpoint:
MBC centrally (n= 406) PFS (BICR)
confirmed .

+ Secondary endpoints:

Patients with known BM ; OS, investigator-

See) Placebo + trastuzumab assessed PFS, DOR,
(N = 808) + docetaxel and safety

+ Randomization was stratified by geographic region and prior treatment status
(neoadjuvant chemotherapy received or not)
+ Study dosing Q3W (26 cycles recommended) until disease progression
—Pertuzumab: 840 mg loading dose, 420 mg maintenance
—Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
—Docetaxel: 75 mg/m?, escalating to 100mg/m? if tolerated
—<6 cycles allowed for unacceptable toxicity or disease progression; >6 cycles
allowed at investigator discretion

+. Bailout © et al. Br J Cancer 2021:124:142155, 2. Swain SM tal. Ann Oncol 201425:1116-121. PeerView

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11. CLEOPATRA End-of-Study Results:

Adding Pertuzumab to Taxane + Trastuzumab Improves PFS and OS!

® Median PFS: 18.7 mo 201
ez Pertuzumab + trastuzumab
ge + docetaxel Landmark PFS at 8 years:
eS 16%, 304 events (76%)
| iestuzmab doco Landmark PFS at 8 years:
°° 2 D » © a Rn 0 © we wo im 10%, 329 events (81%)
wea Time, mo
Rice” mo zum mas go mm a mer e am ve zum ten dan
un (Bas 30 10 20 SE 20 30 20 10 00
so Median OS: 57.1 mo P< .0001
o Pertuzumab + trastuzumab +
La docetaxel Landmark OS at 8 years:
ge 37%, 235 events (58%)
7 —_— rn Landmark OS at 8 years:
» 23%, 280 events (69%)
at 1e, mo
Stem" so anno mes amen ax

on 1069 100 moco Tıma 20047 one
a 1068 TE TE TER ET TE alo FUN VUE
1. Swain Set al. Lancet Oncol. 2020,21:519-530.

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12. PATINA Trial!

PATINA Trial: CDK4/6i Maintenance

Induction
treatment

HR+, HER2+ MBC

+ No prior treatment in the
advanced setting beyond
induction treatment

+ Noevidence of disease
progression after induction
treatment

(N = 496)

Palbociclib + anti-HER2
therapy + ET

Anti-HEI ET

22 therapy +

+ ArmA: Palbociclib at a dose of 125 mg orally once daily, day 1 to day 21, followed by 7 days
off treatment in a 28-day cycle, in addition to standard anti-HER2 therapy and standard ET

+ ArmB: standard anti-HER2 therapy and ET

+ ET: Al of choice or fulvestrant. Premenopausal female patients must receive ovarian
‘suppression with a LHRH agonist if the patients have not documented ovarian ablation or
bilateral oophorectomy before randomization or during the conduct of the study

1. Mts clncalras govstucyNOTO4398797.

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13. PATINA

Results!

Lu Palbocicli Anti-HER2
E) + Anti-HER2 + ET +ET
2 Events, n/N 126/261 136/257
5 (8 Median PFS, mo (95% CI) 44.3 (32.4-60.9) 29.1 (23.3-38.6)
CES HR (95% CI) 0.74 (0.58-0.94)
* NominaltsidedP________ 0074
B 60
Bs Palbociolib
6 + anti-HER2 + ET
3 40 Median follow-up on
a patients who are alive
Ésa Anti HER2 + ET and kee
E X
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 24
pashan Time, mo
abocklib +
E ger 261 231 208 103 146 128 119 94 78 55 33 14 4 1 0
AnWHERZandeT 287 198 158 137 116 102 87 68 51 29 14 6 1 0

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1. Metzger O et al. SABCS 2024. Abstract GS2-12.

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14. T-DXd in the First-Line Setting: What's Next?13

DESTINY-Breast09: T-DXd Until PD DEMETHER: T-DXd Induction

Induction Maintenance Post-treatment
„therapy therapy, follow-up ,

(“ Advanced and/or metastatic
breast cancer

+ HER2+ (IHC 3+ or ISH+)
by central confirmation

+ No previous chemotherapy or
HER2-targeted therapy for advanced
or metastatic breast cancer

+ Patients will be stratified by prior
treatment status (de novo vs

recurrent) HR status (positive vs

negative), and PIK3CA mutation

status (detected vs not detected)

N= 1,134

+ HER2+

aBC
“AL

setting
we UE 3 [eos

BL C2D1 C1D1 C2D1 y

Primary endpoints: 1-year PFS; 3-year OS

HER2CLIMB-05: Tucatinib Maintenance

Tucatinib + HP
ra Primary endpoint: PFS

(4-8 cycles)

1. dinicarilgovstucy/NCTO4784715. 2 ira. govstudy/NCTO6172127. 3. inicalas govshudyiNCTOS 132582. PeerView

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15. DESTINY-Breast03

y Design!

Randomized, Open-Label, Multicenter Study (NCT03529110)

T-DXd
5.4 mgkg Q3W

Unresectable or metastatic HER2+* Stratification
breast cancer

| y + HRstatus 261)
+ Previously treated with trastuzumab + Prior treatment
and taxane in advanced/metastatic with pertuzumab
setting or (neo)adjuvant setting with + History of visceral
recurrence within 6 mo of therapy? disease

+ 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.

+ MER INC 3 or INC 20s based on centalconfrmaton*Progessn dung or tin montas completing aden Paray vohngtasureb and a ane
“tok pra Rd res Se mien E ne Flle andy nad ito spor Te Pra u mete tse ne
actual OS events at the data | ri
{ors tal ESM 201 Abad BAL. PeerView

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16. DESTINY-Breast03: PFS and OS!

Xd T-DM1
00 Median, mo (95% Cl) 28.8 (224-37.9) 6.8 (56-82)
“o HR (95% Cl) 0.33 (0.26-0.43)
So B <.0001
G
Lo T-DXd (n = 261)
ae T-DM1 (n = 263)
a 12345678 9 1011121314 151617 18 192021 222324 252627 28293031 3233 34 3536 37 38 39404142434445
Time, mo
100
so
Lo T-DXd (n = 261)
a T-DM1 (n = 263)
© | Median, mo (95% Cl) NR (40.5-NE) NR (34.0-NE)
ap | HR (95% Cl) 0.64 (0.47-0.87)
729.567 5 ETIENNE SEE EPP IESO SIRO TE
1.Hundz SA et. Lancet, 2023:401:105:117, Time, mo PeerView

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17. DESTINY-Breast03: Updated Results’

cORR PFS
DMA

100
cORR=78.9% mPR a CR 63)
80 100 Median, mo 72
(95% ci) (237400) (6833)
60 CORR = 35.9% HR (95% Cl) 0.30 (0.240,38)
* 42 ee 129 449.4) 197049)
2 T-DXd: 45.7% (95% Cl, 38.9-52 2)
N 2" T-DM1: 12.4% (95% CI, 8.1-17.7)
OM El i
T-DM1 ds
) 263) a T-Oxd3 4 moka
‘CORR, n (%) 206 (789) 97 (362) a
(95% che (735837) (510430) 5
OR, n (0%) 33 (12.6) 1142) 7
PR. n C4) 1366) 86(327) VE ed
SD,n (4) 48 (18.4) 119452) an
PD, n (4) 208) 34 (129) o
HA) eich aie 0.2 3 8 8 101214 6102020047070505054 3690404244640 032313838
Time, mo

DOR® median (95% Cl, mo 30.5 (23.0-NE) 17 (141-237) ve sian
DOR rate at 36 mo (85% — ¿y ad zo zante

(413-561) 28.7 (189-392) Fou Ammann

Based on Copper Pearson melva for single proportion and forthe dienende of 2 propotons wih continuity coecton. © Median som Kaplan Meier anal. Cor median was.
‘computed using the Brookmeyer-Crowley methods PeerView
Hamon Ee a. ASCO 2024, Abstract 1025.

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18. DESTINY-Breast03: Updated OS Results!

Median, mo (95% CI) 526 (4B.7-NE) 42.7 (35.4-NE)
HR (95% Cl) 0.73 (0.56-0.94)
Patients with events, n (%) 110 (42.1 126 (479)

x T-OXd: 62.5% (05% C 962.683)
E T-DM1: 50.1% (95% Cl, 43.6-56 2)
Soo
3
3 T-DXd: 87.6% (95% Cl, 61.3-73.0)4 T-DM1 36 mgkg
A 21

Em TOM 65.7% (85% Cl, 492-81.7)! T.0Xa54 maña
7
o

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60
Time, mo
Mo. at Rsk

250 244 239 236 291 219 212 202 198 188 182 178 173 169 183 162 156 151 143 115 91 60 40 32 15 6 4 1
TOM 263.253 244 238 233 225 213 201 183 185 175 170 167 187 151 146 140 134 130 128 121 100 85 63 45 39 21 10 5 2 1

ing T-DM1
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(d compared with thos

nts receiving

by 27% for pi

1. Hamiton Ee a. ASCO 2024, Abstract 1025.

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19. DESTINY-Breast03:
Most Common TEAEs in 220% of Patients’?

Blood and lymphatic system disorc
RE
Platelet count decreased 114 (437) 52 (199)
White blood cell count decreased 16 (6.1) 2 (0.8)
Fee
er A rite
ee z 2 A pri
Constipation 96 (37.4) 0 51 (19.5) 0
Diarrhea 83 (323) 3(12) 21(8) 2(0.8)
see
Fatigue 79 (30.7) 15 (5.8) 53 (20.3) 2(0.8)
Headache 61 (23.7) 1(0.4) 40 (15.3) 0
Se en AUGE a '
Aspartate aminotransferase increased 72 (28) 2(0.8) 108 (41.4) 14 (5.4)
Alanine aminotransferase increased 59 (23) 4 (1.6) £ 2 6
een
Decreased appetite 46 (17.6) 1(04)
Wooht deveared (sm san] en 2103)
En

aa EE 7

+ Es ere managed cer othe prosa! © Cases of alepec repoted cin the stuty wer graded based one cicaluégment o he vesbgator. ne case of abpeci was
(legerzed as grade 3 bythe mvestgardespte grade 3 alopecia nc berg recopier Nl Common Terminology cea, The ever odeame was pated

‘5 recovered by the investiga. PeerView
‘Phas Seta SABCS 2022 Abstract 652.02

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20. DESTINY-Breast03:
Adjudicated Treatment-Related ILD/Pneumonitis!

Grade 1 Grade2 Grade3 Grade4 Grades AnyGrade
Toma (n= 257), as) 280101) 2108) o o 2
n (%)
TOM (n= 261), 4 4.5) 3 (1.1) 1 (0.4) o o 8 (3.1)

n (%)

+ Adjudicated treatment-related ILD/pneumonitis rates were similar to other MBC trials with T-DXd22

+ 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 four additional grade 1, eight 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 treatment-related grade 4 or 5 events

1. Huriz Set al. SABCS 2022. Abstract 682.02. 2. Modi eta N Eng! J Med. 2020.382:610:621. 3. Powell CA et al. ESMO Open, 2022:7 100864. PeerView
4. Cortés Jet al. N Engl. Med, 2022.388.1143-1154,

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21. DESTINY-Breast02 (Randomized, Phase 3, Open-Label,

Multicenter Study): Study Design and Efficacy’

+ Centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+) + Primary endpoint: PFS (BICR)

unresectable or MBC. nn ines + Key secondary endpoint: OS
. DRE Ent progression after most = ose + Secondary endpoints: ORR

= (BICR), DOR (BICR), PFS
+ Previously treated with T-DM1 Teo cart (investigator), safety
‘Stratification factors di
trastuzumab/capecitabine + Exploratory endpoints: CBR

° MENT daa (BICR), PFS2 (investigator)

+ Prior treatment with pertuzumab lapatinib/capecitabine Median follow-up ~20 mo
+ History of visceral disease =

i int: ox tec Key Secondary Endpoint: OS Wedan. m2 25
Primary Endpoint: PFS by BICR = Yt —E ONG: an BEN Ga) (RCD) (ZZNE) (21.0NE)
(85% Ci) (143208) (558.4) TPC: 74.7% (99% CI, 67.4804) O Le
T.DXd: 62.9% (25% CL 57.067.1) HR(SSMCH 0.3589 (0284004535) fe pints
PC 272% (95% Cl. 201348) p 2000001 = T-DXA: 65.9% (85% CL, 607-707)

TPC: 54.3% (95% C1, 483516)
TOXG 42.2% (5% CL 365-478) Re
TP 139% (95% CL 78216) e DK n= 406)

Toxa(n=405) O a]

“Inthe TPC arm
“Tenens states sente sos. + 69.3% (1401202) of patients received a new systemic anticancer treatment Doe View
1 Keepy tal SABCS 222.Abstact S201. 25.72% (52/202) of patients received T-DXd in the post-trial setting

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22. HER(/EGFR HER2 HER3 HER4

Tyrosine
kinase al
domain

Tucatinib has high specificity to
Tucatinib (HER2) HER2 receptors compared with
Lapatinib (HER1, HER2) lapatinib and neratinib, which

also bind to other HER receptors
Neratinib (HER1, HER2, HER4)

Dent et Cur Oncol Rep 202428128. 2. Muthy RK el Lancet Oncol 201919990580. PeerView

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

HER2+ metastatic breast cancer Tucatinib +
Prior treatment with trastuzumab, trastuzumab
pertuzumab, and T-DM1 + capecitabine

ECOG 0-1 (21-d cycle)
Follow-up

(survival)

Brain MRI at baseline

- No evidence of brain metastases, or
- Untreated, previously treated stable,
or previously treated progressing

brain metastases not needing
immediate local therapy (21-d cycle)

Placebo +
trastuzumab
+ capecitabine

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),

+ Region of the world (United States, Canada, PFS among patients with brain metastases, ORR

or rest of world)

Notable baseline characteristic: 48% of patients had CNS metastases
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1. Murthy RX et al N Engl J Med. 2020;282:597-609.

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24. HER2CLIMB: PFS and OS!

PFS
Events/otal, HR Median PF
(95% Cl) mo (95% CI) Eventatotel ess cr)
Tucatini z y 5
combination 319410 057 49991 (62983) combination O 0.73 cog (16289)
Placebo (0.47-0.70) “ 49 Placebo serrzo2 59000) * 192

combination 163/202 4.1-5.6) _ combination (16.4-21.4

6mo 1y 19

Sa ge
$ =
Qos Sos
2. Eau Placebo
Pl Model 5 ‚combination
ucatinil
a” combination So
i Tucatinib combination
ea 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 4 81 0 3 6 9 12 18 18 21 24 27 90 33 M6 39 42 45 48 51
min Time, mo mas Time, mo
amas 20 à 0 8 € à E rs ss

+. Gurñglano Get al. Am Onc 2022.53 321-320, PeerView

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25. 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 T-DM1
HER2-positive breast cancer with : 3.6 mg/kg Q21D
progression after trastuzumab and taxane

+ Patients with or without BM

Placebo
N = 460 BID

T-DM1

g Q21D

+ Primary endpoint: PFS by investigator assessment per RECIST v1.1
* Key secondary endpoints: OS, ORR by investigator assessment per RECIST v1.1

1.Hundz SA ell, SABOS 2023 Abstract 0801-10 PeerView

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26. HER2CLIMB-02: PF

TDM+ T-DM1+
Tucatinib Placebo
(n=228) — (n=235)

09 Events, n 151 182
03 Median PFS (95% Cl), mo 9.5(7.4-10.9) 7.4(5.6-8.1)
3 be T-DM1 + HR (95% Cl) 0.76 (0.61-0.95)
8 os tucatinib P 0163
2 04
© 03
Q 02
01
o
0 3 6 El 12 15 18 21 24 a 30 33 36 39
Time From Randomization, mo
No. at Risk
A 9 62 47 40 OZ HW #0 5 4 1 o
TOM placebo 235 177 120 81 5 48 40 Z% 1 10 8 5 3 O0
1 Muniz SA ll SABCS 2023 Ain 6601-10 PeerView

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27. HER2CLIMB-02: OS!

T-DM1 + tucatinib

T-DM + placebo

Median OS
(959% Cl), mo NR(NR-NR) 38 (31.5-NR)

HR (95% Cl) 123

OS, Probability

0 3 6 9 2 15 18 21 22% 27 3 33 36 39 42

Time From Randomization, mo

No. at Risk
T-DMi+tueainb 228225 27 20 202 189 m 132 89 55 30 16 7 3

T-DMi +placebo 235 227 22% 212 201 19 180 1% 9 58 32 16 10 4

Median foll ip 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< .0041

2 Te proportional hazard asunpton was nat manned post 18 months, wth extensive censorng on both ams. n
‘Muniz SA ela. SABOS 202 Aba 801.10. “ PeerView

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28. + RWE database data on tucatinib in routine use (950+ patients)

+ Flatiron, Komodo, and MarketScan

— Previous therapy situation (median two previous therapies each); high proportion of
brain metastases (70%-76%)

— Unicancer: later therapy situation (median of four previous therapies); lower proportion
of brain metastases (39%)

— With prior therapy, the efficacy parameters of the Unicancer cohort are numerically
slightly lower than H2C; Flatiron, Komodo, and MarketScan are comparable
to HER2CLIMB in a similar pretreatment situation

— The results underscore long-term efficacy of tucatinib in HER2+ MBC

— With tucatinib-based therapy, relevant efficacy was observed in all four studies after
T-DXd (4L to 5L)—33% response rate; MOS up to 13.4 mo

1. Kaufmann PA eta. Front Oncol 2023:13:1264861.2, Anders Cet al. ASCO 2023, Abstract 1051 and Poster. 3. Anders Ct al. AMCP 2023. PeerView
Abstract C9 and Poster. 4. Frenel JS ell JAMA Netw Open. 2024.7:e244435.

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29. NALA (Phase 3 Study):

Neratinib + Capecitabine vs Lapatinib + Capecitabine!

Centrally Confirmed PFS os

= 8.8 mo vs 6.6 mo os 24 mo vs 22.2 mo
=" A2.2mo os 41.8 mo
gu P= 0003 EN P=NS
nu jan Sos
Bos Restriction: Y Restriction:
Ea 24 mo É 48 mo
> 04 Neratinib + cape
fe Neratinib + cape Sos

aa 02 Lapatinib + cape

ox os

o o
STR AAA IA SIT ss

es Time, mo man Time, mo

na 2 2? am amm
+ 4-year 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 neratinib + cape vs lapatinib + cape (22.8% vs 29.2

= 043)
PeerView

1. Saura C et a J Cin Oncol. 2020,38 3138-3149.

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30. rrent Standard of Care for HER2+ MBC

Trastuzumab + pertuzumab Trastuzumab deruxtecan Tucatinib + trastuzumab

+ taxane

or

+ Continue HP after induction

+ HR+: Consider addition of
palbociclib and endocrine
therapy to HP

Tier teen Trastuzumab deruxtecan

or

Trastuzumab emtansine
M1
A

AILIA
+ Activity post T-DXd?
PeerView

Factors include extracranial
disease burden, intracranial
disease burden, comorbidities,
patient preference

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31. ns for HER2+ MBC: “Dealer’s Choice”

ate Line Op:

Fourth Line + Many possible agents,
including
Trast b emtansi + Vinorelbine
fastzuman emlansiie Trastuzumab + chemo + Eribulin
+ Gemcitabine

Doxil
Margetuximab + chemo

Trastuzumab + lapatinib

EGF104900

Carboplatin
SOPHIA

Special consideration
in HR+/HER2+:
fulvestrant/abemaciclib/

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

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32. Case Discussion

+ Awoman aged 71 years presents to clinic for newly diagnosed metastatic breast cancer
Presentation

+ Originally diagnosed with 1.3-cm node-negative + Went to ER, where imaging revealed an
invasive breast cancer, ER+, PgR+, HER2+ 18-cm liver with multiple solid metastases
4 years ago Liver enzymes elevated (3X ULN),

+ Underwent breast-conserving surgery and then but function is normal
lost to follow-up; did not receive radiation or
systemic therapy

+ Developed abdominal fullness, RUQ pain, and
significant fatigue

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

PeerView.com/ZPG827 Copyrigh

33. Case Discussion Continues

+ She initiates therapy with THP

+ After two cycles, she is symptomatically much + She is developing moderate neuropathy as

improved well as edema related to the taxane; drops
+ After four cycles she has 70% reduction in tumor the taxane but continues HP

burden, and after 6 cycles, she has a CR + She initiates an aromatase inhibitor

in the liver concurrently with the HP

20 Months Later

+ She has progression in the liver, with a new 1-cm metastasis, as well as new lung metastases

PeerView

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34. Factors Gu

ies in HER2+ MBC

+ Which treatment option(s) would you recommend for the second-line treatment
of this patient?

+ What if the patient received treatment with T-DXd in second-line setting, but
developed further treatment?

+ What is the influence of prior treatment and resistance on sequencing HER2-
targeting therapies?

+ What are strategies to prepare for AE management with T-DXd and
tucatinib-containing regimens, and ensuring adherence and persistence with oral
therapies such as tucatinib?

+ Other treatment, patient-, and disease-related factors, such as patients’
performance status, disease burden, needs, and preferences

PeerView

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35. Module 2

Meeting the Challenges of Brain Metastases
With HER2-Targeting Therapies

Guidance on Modern Sequencing and Multidisciplinary
Care to Reinforce Therapeutic Resilience

Copyright © 2000

36. Discussion: Should We Screen Asymptomatic Patients W

HER2+ MBC for BMs?

“There are insufficient data to recommend for or

° against performing routine magnetic resonance
imaging to screen for brain metastases; clinicians
should have a low threshold for MRI of the brain

AMERICAN SOCIETY OF CLINICAL ONCOLOGY | because of the high incidence of brain metastases

among patients with HER2+ advanced breast cancer.”

GOOD SCIENCE “Screening at diagnosis is potentially justified in
BETTER MEDICINE HER2+ and TN MBC (EANO: IV, n/a; ESMO IV, B).
BEST PRACTICE This approach will result in a higher rate of detection

of asymptomatic BM.”

PeerView

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37. cussion: Identifying and Class

g BMs

+ Best practices on screening for and identifying neurologic symptoms of possible
BM (eg, excessive fatigue, seizure, edema)

+ Symptoms that can inform the differentiation between active and
inactive metastases

+ Insights and expert recommendations on surveillance and imaging

PeerView

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38. Local Therapies’?

+ Surgery in the case of a 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. Baier € et Br J Concer. 2021;124:142-155 2. Mahajan Ae Lancet Oncol. 2017:18: 1040-1048, PeerView

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39. Systemic Therapies"

New era of treatment of HER2+ tumors

+ TKIs (tucatinib, and others under
development...)

+ ADCs (trastuzumab deruxtecan)

y

Is systemic treatment the best option

for patients with BM and HER2+
breast cancer??

A cme AF nstmone LO] Magie {G) Sromalcllmetaasis

Limit nduson of patents van EM cia ts =
Val etat BV Cancer 2021 124.42 IS, PeerView

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40. NCCN Guidelines for BMs: Expanding Arsenal of Recommended

ystemic Therapy ions for Patients With HER2+ MBC and BM!

HER2+ Breast Cancer

+ Preferred regimens

—Tucatinib + trastuzumab + capecitabine
(category 1) [if previously treated with 1 or more
anti-HER2-based regimens]

+ Other recommended regimens
—Fam-trastuzumab deruxtecan-nxki
—Ado-trastuzumab emtansine (T-DM1)
—Capecitabine + lapatinib
—Capecitabine + neratinib
—Pertuzumab and high-dose trastuzumab
—Paclitaxel + neratinib (category 2B)

1. NON Cinca Proc Guidelines in Orly Central Nereus Systm Cones. Version 4 204. nos ww nen rrotessontican_cspaens par Peer View

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41. HER2CLIMB: Study Design and Efficacy’

+ Benefit of tucatinib in ITT population and in patients with BM

Tucatinib 300 mg PO BID
+ trastuzumab 6 mg/kg Q3W, loading dose

Key Eligibility Criteria al . none Ph Soe
o E Im?
HER2+ MBC Stratification capecitabine mg Im‘
+ Prior treatment “pi f b for days 1-14
with trastuzumab, CECI 21-day cycle
en metastases (yes/no) 2
Pe! 0 + ECOG status (0 or 1) a di
T-DM1 y à
+ ECOG performance + Region (US, Canada,
rest of world) |
status 0 or 1 |
+ Brain MRI at baseline n=202 |
|

Patients with or without brain metastases
+ PFS HR = 0.54; medians 5.6 vs 7.8 mo; P< .001 Patients with brain metastases
+ OS HR = 0.66; medians 17.4 vs 21.9 mo; P= .005 + PFS HR = 0.48; medians 5.4 vs 7.6 mo; P< .001

1. Murty RK eta. Engl Med 2020:382.507-609 PeerView

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42. HER2CLIMB: OS Benefit in Patients

With BM, Including Active BM!

All Patients With BM

Tucatnib + trastuzumab
+ capecitabine

OS Probability

i H a

All Patients With Active BM

CE

oia

Tucatinib +
trastuzumab +
capecitabine

ol
0 3 6 9 1215 18 21 24 27 30 33 36 39 42 45 48 61 o

ime, mo estan

iH tm 1m 07 0 54 6 7 1 0 6 6 2

4
9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time, mo

Ae

Fontaine
EA ee
Lee Es

Median OS = 12.5 mo—21.6 mo

HR = 0.6 (0.44-0.81); P< .001

1. Lin et al JAMA Oncol. 2023.9:197-205.

PeerView.com/ZPG827

Median OS = 11.8 mo—21.4 mo

HR = 0.5 (0.36-0.77); P <.001
PeerView

Copyright © 2000-2025, PeerView

43. HER2CLIMB: Durable | ses in Patients Wi

Active, Measurable BM!

Confirmed CNS ORR Tucatinib Placebo

(RECIST 1.1) + Trastuzumab + Trastuzumab
+ Capecitabine + Capecitabine

P= 03%

80
47 Best overall intracranial

= go | (637612)

: Complete response (CR) 36.5) 1 (5.0)

5

4 Partial response (PR) 23 (41.8) 3 (15)

= Stable disease (SD) 24 (43.6) 16 (80)

ra

a Progressive disease (PD) 2 (3.6) 0
Not available® 365) o

Tucatinib + Placebo +
trastuzumab + trastuzumab + Subjects with objective response

26 4

re on of confirmed CR or PR, n

{AVE los rear are noi and ware cine om ested Ip. Conrad Ds crepe assess pa REGIS 1

TURN ta v cin en 200030261626, PeerView

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44. HER2CLIMB

: Prolongation of CNS PFS With Tucatinib*

Events/ Median PFS, mo
Tot (95% ci)
10 Tucabnib + trastuzumab +
2 Tae A ug REM
508 Placebo + trastuzumab + (0.266-0.559) ~~
3 Fab ts 4993 423657)
© os ee
à
@ 04 a Tucatnib +
e Placebo > trastuzumab +
@ 024 trastuzumab + capecitabine
2 capecitabine
© 00 +
0 3 6 9 12 Bm 2 2% 27 30 33 3% %
Naar Time, mo
Tics a aa
Pace vom A
Subgroup Treatment Events HR (95% CI) P |Median CNS PFS)imo
Patients with Tucatinib + trastuzumab + capecitabine 69/118 0.339 un
<.
‚active BM Placebo + trastuzumab + capecitabine 35/56 (0-215-0.536)
Patients with Tucatinib + trastuzumab + capecitabine 25/80 0.406
treated stable BM_ Placebo + trastuzumab + capecitabine 13/37 (0.194-0.850) * 56 (3.0-NE)
1. Un Neal ANA On 20239 197.205, PeerView

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45. TUXEDO-1 Trial DEBBRAH Trial ROSET-BM

Intracranial Tumor
Activity by RANO-BM

I Cohort 1
Wi Cohort 3

Maximum Change in Tumor Size
Change From Baseline, %

ORR-IC = 73% ORR-IC = 44% =
in patients with active BM in patients with active BM BEVOR BETH
1. Bartsch Reta Nat Me, 202228 1840-1847. 2 Pérez Garda JMet al. Neu Oncol 202325.157-168.3.Nikura N ll NPL reas! Cancer: 0230.82 PeerView

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46. DESTINY-Breast01, 02, and 03: Pooled Analysis

of T-DXd in HER2+ MBC With Brain Metastases’?

DESTINY-Breast0t (N= 253)
hase 2 study
Patents previously rated wth TOM

‘Patients wäh asymplomatc and previous locally
‘vealed BM elle

+ Prior EM therapy wihin 60 days prohibited

DESTINY -Broast02(N = 6082

+ Phase3 study

+ Patients previously treated with TOM

+ Patients wäh asymptomatic and previously
‘wealeduntested BM elgble

+ Prior BM therapy wihin 14 days of randomization
prohibited

DESTINY-Breast03 (N= 524p*

+ Phase 3 study

+ Patients prevousy treated vith trastuzumab anda y
taxane in metastatic or (neo)aduvant setting wih
recurence within 6 months of therapy

+ Patients wäh asymptomatic and previously
resteduntested EM etgiie

+ Prior BM therapy within 14 days of randomization
Prohibited

Endpoints

+ ICORR (CR +PR
in bran) per BICR
per RECIST vi

+ ICDOR perBICR

= GNS PFS per BICR

+ Safety and
telerabiry

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 in the 5.4mg/g T-OXG ams were pooled from the D8-01, DB-02, and 02-03 tras. Comparator data were posted fromthe DE-02

1008 tls. Altvee studies were

‘conducted in unresecable/NBC, HERZ status was confrmed central, and a documented radiographic progression after most recent treatment was required.» The presence of BMs was not

‘a Sretfiatn factor. «Data cof March 25, 2021. Data cult: June 30, 2022. Deta cutof! May 21, 2021. 5 4mgikg Q3W. 36 mghkg QW.
1. Hurvtz Se al. ESMO 2023. Abstract 3770.

PeerView.com/ZPG827

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Copyright © 2000-2025, PeerView

47. Pooled Analysis of DESTINY-Breast01, 02, and 03:

Exploratory Best IC Response, ORR, and DOR per BICR*

Intracranial ORR”
‘Comparator BM Pool

T-DXd BM Pool

m Complete response
1 Partial response

Intracranial ORR, %

Untreated/Acti
(n= 25)

Best overall IC response, n (%)
Stable disease 48 (462) 15 (34.4) 28 (48.3) 15 (60)
Progressive disease 3(29) 123) 7021) 5 (20)
Not evaluable/missing 6(58) 8(182) 7421) 28)
IC-DOR, median, mo (95% Cl) 12394 17503. 1115.6-16) Nine

+ T-DXd consistently demonstrated superior rates of IC responses over comparator in patients with
treated/stable and untreated/active BMs

+ A trend in prolonged median IC-DOR was most pronounced in the untreated/active BMs subgroup

Te table considers both target and nontarget lesions at baseline. Lesions in previous} inadated areas were no considerecmeasurabl target lesions unless there was demonstrated
‘progression in the lesion.» IC-ORR was assessed per RECIST v1.1. DIC-DoR NA due to small number of responders (a <10). PeerView
1. Hurvaz Seta. ESMO 2023. Abstract 3770.

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48. Pooled Analysis of DESTINY-Breast01, 02, and 0

Exploratory CNS PFS per BICR!

Treated/Stable BMs Untreated/Active BMs

Median, mo 123 87 Median, mo 18.5 40
(95% Cl) (111-138) (6.3-11.8) (95% CI) (136-233) (2.7-5.7)
HR (95% CI) _0.5905 (0.3921-0.8895) HR (95% CI)__ 0.199 (0.1060-0.3473)

8

PFS, %
0858388833883

T-DXd treated (n = 104) T-DXd treated (n = 44)
‘Comparator

treated (n = 58)

PFS, %
888333388

03

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 24 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 24
Time, mo

Time, mo

1. Hurvte ol ESMO 2023. Abstnel 3770. PeerView

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49. DESTINY-Breast12: Study Design’

+ Phase 3b/4, multicenter, single-arm, two-cohort, open-label study of T-DXd in previously treated HER2+
MBC with and without BMs; the largest prospective study of T-DXd in patients with stable or active BMs

Patient Population Baseline BMs Primary endpoint
+ Aged 218 years (n = 263} + PFS
+ Pathologically documented + Stable BM (previously treated) Additional endpoints
HER2+ advanced or metastatic + Active BM (untreated + CNS PFS
breast cancer with or without or previously treated/progressing + OS
baseline BMs [not requiring immediate + ORR
+ Received <2 prior lines of therapy local therapy]) + CNS ORR
in the metastatic setting + Safety and tolerability
(tucatinib naive)
+ Disease progression on prior Ñ a
HER2-directed regimens Primary endpoint
À en sai ted No baseline BMs Additional endpoints
Foi (n=241) +08

leptomeningeal metastases

+ Safety and tolerability

* Data reported forte full analysis sa (al patients eroled in the study who received at east one treatment dose) and say analysis sat (dentcalt full analysis set No hypothesis testing
où companson of cohorts. Response and progression assessed by ICR per RECIST 1.1 both cohats. Patents were enoles rom Austra, Canada, Europe, Japan, and Unted States,
* Concomitant use of 3 mg of dexamethasone daiy or equivalent allowed for symplom control of BMs baseline BMS cohort only)“ Unt RECIST 1.1-defned disease

TERN era ESMO 200, Abr LATE PeerView

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50. DESTINY-Breast12 Baseline BMs: PFS (Primary Endpoint)"

Overall Population (KM Analysis)
N= 263 Data maturity = 42.2%
Median PFS (post hoc analysis): 17.3 mo
(95% Cl, 13.7-22.1)

12-mo PFS: 61.6% |
(95% Cl, 54.9-67.6)

>
2
3
El
2
E
o
e
o

No at Risk

ot 2s 8 6 6 7 8 8 SE 2 19 4 15 16 17 18 19 20 2 2% 2 da 2 26 27

Time, mo
283 257 248 202 225 208 193 185 177 159 190 114 105 100 78 70 SO 46 MoM D HB 2 2 0

| Active BM Subgroups
il _ Previously
Population | "(n= 157) | (n= 106) Untreated (n = 38) | Treated/Progressing (n = 67)

(N = 263) Post Hoc Analysis
Post Hoc Analysis

Overall events, n 20 27
12-mo PFS, % 47 667

DXd showed consistent 12-mo PFS in patients with stable and active BMS

AN a ED EE A ATs PeerView

Overall | Stable BMs | Active BMs

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51. DESTINY-Breast12 Baseline BMs: CNS PFS"

Overall Population (KM Analysis)
N = 263 Data maturity = 38.4%

se
ER
8 06
Qos
pes 12-mo CNS PFS: 58.9%
Do (95% CI, 51.9-65.3)
Bor
600
0123486709 0 ie 1 17 de 19 20 21 22 23 24 20 28 27
Time, mo
Note 263.258 242 229 224 208 182 170 168 192 107 95 85 78 80 52 33 30 M Bw 5 4 2 2 0
Overall Population Stable BMs Active BMs
(N = 263) (n= 157) (n= 106)
Overall events, n 101 61 40
12-mo CNS PFS, % 58.9 57.8 60.1
(95% CI (51.9-65 (48.2-66.1 (49.2-69.4)

-DXd showed consistent 12-mo CNS PFS in patient stable and

"= Patients who had systemic progression but no CNS progression were censored atthe lime ofthe progression assessment: the analysis dd not account for

systeme progression asa competing event CNS PFS assessed by ICR per RECIST 1.1 .
ANN etal ESUO 202 AG LEA IE PeerView

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52. reast12 Baseline BMs: CNS ORR":

Patients With Measurable CNS Disease at Baseline

© go 10 (Post Hoc Analysis)
HE
Pos
8.53%
FE
asien
Bag eo
=
moo 400

Active BM Subgroups

Measurable CNS Disease All Patients StableBMs Active ms Untreated RAR
(n=23) Treated/Progressing

at Baseline (M=138) — (n=77) | (n=61 Mie me
Analysis Post Hoc Analysis

Confirmed CNS ORR, %

* Dashed ne cotes a 30% decease in target tumor ize (PR) Impules values: a value of +20% vos imputed i es percentage change could tbe calculated
because of mssig data a patent had anew lesion or progression of nontarel esos r large! elos, orhad haran because of PD and had no evaluate ape
View

lesion dota before o at PO.
1 Un etal ESMO 2024, Abstract LEA.

Copyright © 2000-2025, PeerView

53. HERCLIMB-02: Does Tucatinib Add to T-DM1?'

(© HER2+ LAMBC T-DM1 3.6 mg/kg ass
with progression + tucatinib pray

= 2: , :
ane | |: Unsctisamentérmonaae nantes
ECOG PS <1 EUG) 11 Key secondary (hierarchical)
Prevauy teat ste, |" Hotmene reepkr sats es

progressing, or untreated + PFS in patients with brain

brain metastases not Presence onhilsiory of brain metastases

metastases (yes vs no)
requiring immediate + CORR per RECIST V1.1
local therapy Ecos Fs (Os 1) T-DM1 + OS in patients with brain

N=460 + placebo metastases

The primary analysis for PFS was planned after =331 PFS events to provide 90% power for HR of 0.7
at two-sided alpha level of 0.05. The first of two interim analyses for OS was planned
at the time of the primary PFS analysis, if the PFS result was significantly positive.

T-DM1+Tucatinib T-DM1 + Placebo
(n= 228) 35)

Presence or history of brain metastases, n (%)

Yes 99 (43.4) 105 (44.7)
50 (21.9) 57 (24.3)
49 (21.5) 48 (20.4)

No 129 (56.6) 130 (55.3) Ji
1. Huw SA tal SABCS 2023 Abstnet 6801-10 PeerView

Active

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54. HERCLIMB-02: Tucatinib Prolongs PFS When Added to T-DM1"

PFS: ITT Population PFS: BM Subset
TOMi+ T.DMI+ TOM+ TOMI+
Tucatinib Placebo Tucatinib Placebo
10 (n= 228) (n= 235) (n=99) _(n= 105)
09 Events, n 161 182 Events, n 70 s
pos Median PFS, Median PFS,
E mom 25074108) 7.4(56-8.1) mo (0% cy) 78 (67-100) 5:7 (4.67.5)
gos HR (95% CI) 0.76 (0.61-0.95) HR (95% CIP 0.64(0.46:0.99
Bos pP 0163
E 04
Pos T-DM1 + tucatinib 2 03 T-DM1 + tucatinib
a 02 oz

T-DM1 + placebo

= “a T-DM1 + placebo
09 oo
0 3 6 9 12 15 18 21 24 27 30 33 36 39 5 3 6 8 2 15 de 21 24 27 0 33 % %
Most Time From Randomization, mo oathtiok Time From Randomization, mo

mom m1 8 4 0 2% 0 Er Oo mm # » w 2 © 6 3 2 1 0 0

Overall ORR = 36.1% vs 42% favoring the combination
CNS ORR not reported

OS, no difference at median follow-up 24.4 mo; await more mature data

{Miva oe tal CASOS 2025 Absit 6601.10 PeerView

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55. Other Drugs and Combos in BM

Study Type Active BM IC-ORR

Ten v2 en Phase 2 Yes 8%

Neral + capecitabine Phase 2 Yes 39% (lapatin treated)
3

Rests + capecitabine FRE po ee

a Phase 3B No 21%

ee u Fee Ves A

Sven Phase 3 No T-DM1 20.5%

CES Phase 2 Yes 47%

Tucatinib + trastuzumab + capecitabine

1. Freedman RA, et al J Cin Oncol, 2016:34:945-652. 2. Freedman RA et al J Ci Oncol, 2018;37:1081-1089. 3. Saura Cet al JCIn Oncol. 2020;38:3138-3149,
wro Feta. Ann Oncol 2020.31.1350-1358. 5. Freedman RA et al, SABCS 2022, Abstract PO7-03, 6, Hutz SA e al ESMO Open, 2024 9.102524 PeerView

4 Monte
7.Un NU etal, ASCO 2020. Abstract 1005

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56. Ongoing MBC Studies With BM Outcomes of Interest?

HER2CLIMB-05
Phase 3, randomized, double-blinded trial

incorporating tucatinib/placebo with the CLEOPATRA

regimen in 1L advanced HER2+ breast cancer

Patient

Population
AL HER2+ MBC.
Completed
induction
therapy:
trastuzumab +
pertuzumab +
taxane

+ 4-8 cycles

Tucatinib +
trastuzumab +
pertuzumab

Primary
endpoint

secondary
endpoint
+ os

Placebo +
trastuzumab +
pertuzumab

1. dlnicails govstudy/NCTOS132582. 2 dricalsials gowstudy/NCTO47E4715,

PeerView.com/ZPG827

DESTINY-Breast 09
Phase 3 study of trastuzumab deruxtecan (T-DXd) with
or without pertuzumab vs taxane, trastuzumab, and
pertuzumab for patients with HER2+ MBC.

Study Design T-DXd +
+ HER2+, 1LMBC tuzumab-matching
placebo

+ No prior
chemotherapy
or HER2-targeted
therapy for
advanced or
metastatic breast
cancer

(N= 1,134)

1,134

trastuzumab

Primary endpoint: PFS by BICR
Secondary endpoints: PFS by investigator assessment, OS,
ORR by BICR and investigator assessment, DOR by BICR and
investigator assessment, time to second progression or death
(PFS2) by investigator assessment, HRQOL, PK,
immunogenicity, safety and tolerability of trastuzumab deruxtecan
(alone or with pertuzumab) PeerView

Copyright © 2000-2025, PeerView

57. The Role of the Multidisciplinary Tumor Board and Deciding

B en Local or Systemic Therapy for Patients With BMs

In Favor of Local Strategies
Controlled extracranial disease
Neurological symptoms
<10 lesions (maybe radiation
oncologists will say more!) >
SRS or surgery

In Favor of Systemic Therapies

Medical oncologists HER2+ subtype
Radiation oncologists Asymptomatic disease
Neurosurgeons Progressive extracranial
Neuroradiologists disease

Pathologists High BM velocity
Good agents (with evidence of
CNS activity) available
Previous radiation

Big lesions

“Bad” localization
(cerebellar lesions)

Low BM velocity

Edema

Need for tissue

Disease amenable to SRS

Concern for RT toxicity

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58. Meeting Unmet Needs of Patients and Their Care Partners
Educational and Support Resources

There has been a lack of patient- and care partner-directed resources and information about
diagnosis, treatment, and survivorship of CNS metastases, but advocacy organizations can help!

MBCBrainMets

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 a medical advisory board

LEARN ENGAGE EXPLORE TRIALS

We have also partnered with GRASP as part of this activity

+ Please visit graspcancer.org to lear more about this organization

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

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59. Case Discussion

+ A woman aged 71 years presents to clinic for newly diagnosed metastatic breast cancer
Presentation

+ Originally diagnosed with 1.3-cm node-negative + Went to ER, where imaging revealed an 18-cm

invasive breast cancer, ER+, PgR+, HER2+ 4 y ago liver with multiple solid metastases

Underwent breast-conserving surgery and then lost + Liver enzymes elevated (3X ULN),
to follow-up; did not receive radiation or but function is normal

systemic therapy Biopsy demonstrates metastatic breast cancer,

Developed abdominal fullness, RUQ pain, and ER+, PgR+, HER2+, high grade
significant fatigue

Brain imaging shows a single 2-cm BM
What treatment would you recommend, and why—what factors would you consider?
What if the patient had no baseline BM but developed them upon progression?

How would you counsel, educate, and prepare the patient?

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