Elevating Excellence in HR+, HER2- EBC and MBC Care: Success Strategies for Community Oncology Practice

Chair and Presenter Sara M. Tolaney, MD, MPH, and Gregory A. Vidal, MD, PhD, discuss breast cancer in this CME/MOC/NCPD/CPE/AAPA/IPCE activity titled “Elevating Excellence in HR+, HER2- EBC and MBC Care: Success Strategies for Community Oncology Practice.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3zyjh6r. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until March 18, 2026.

1. Elevating Excellence in

HR+, HER2- EBC and MBC Care
Success Strategies for Community
Oncology Practice

Sara M. Tolaney, MD, MPH Gregory A. Vidal, MD, PhD
Chief, Division of Breast Oncology Director of Clinical Research
Dana-Farber Cancer Institute Lee S. Schwartzberg Research Center
Associate Professor of Medicine Chair, Breast Oncology Program
Harvard Medical School A West Cancer Center
Boston, Massachusetts a: and Research Institute
Associate Professor
University of Tennessee Health
Sciences Center
Memphis, Tennessee

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

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2. Our Goals for Today

Equip you with knowledge about the efficacy, safety, and evolving clinical roles
of the latest treatment options for patients with HR+, HER2- breast cancer

Enhance your skills in formulating individualized treatment plans for patients
with HR+, HER2- EBC and MBC

Improve your ability to implement team-based strategies to anticipate, detect,
and manage treatment-related AEs in patients with HR+, HER2- breast cancer
receiving systemic therapies, and maximize adherence and persistence

Copyright © 2000-2025, PeerView

3. + Breastcancer.org is our patient advocacy partner in this activity

+ Their mission is to help people make sense of the complex medical and personal
information about breast health and breast cancer, so they can make the best
decisions for their lives

+ To help the global community of patients and care partners, Breastcancer.org offers
trusted educational content, community conversations, and other resources

+ Please access and use the supplemental downloadable resources made available
as part of this activity

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4. Module 1

Keeping Recurrence at Bay
Risk Assessment and Treatment

of High-Risk HR+, HER2- EBC

5. Conducting Risk Assessment to Identify
Patients With High-Risk HR+, HER2- EBC

6. Clinical Outcomes Among Patients

With a Recurrence Score of 11 to 25!

IDFS Freedom From Recurrence at a Distant Site
10 Chemoendocrine therapy Eg 10 Chemoendocrine therapy
5 E “2 oe Endocrine therapy
2 ;
5 Endocrine therapy $805
3 06 88 06
Bos i Sos
2 04 5504
3
8 92] HR for IDR, second primary cancer, z $02] HR for recurrence at a distant site = 1.10
& 02] or death = 1.08 (95% Cl, 0.94-1.24) $501] (05% Cl, 085-141)
‘| P= 26 83°) | P=48
O 12 24 36 48 60 72 84 96 108 © Oo 12 24 36 48 60 72 84 96 108
Time, mo Time, mo
No at Risk No, at isk
CET gt 9204 3104 2000 2049 2045 2998 1701 1.130 523 CET IBZ IIS 9442 2089 2905 279% 2492 1.006 1.97 as
Er" 3306 329 Stas dont 2069 2741 2401 1860 Kier 507 ET 368 0018 3200 J tar 3000 2000 2697 190? 1207. ati

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1. Sparano JA ell. N Engl Med. 2018:379:111-121.

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7. RxPONDER: IDFS Stratified by Number of Nodes

and Menopausal Status!
Postmenopausal

Premenopausal

10 ET 5-y IDFS 92.3% 10 CET 5-y IDFS 94.4%
os os
ios) CET (n= 1,090; 84 events) CET 5-y IDFS 92.7% woe] CET (n=536; 29 events) ET 5-y IDFS 89.2%
1 Node 5 ET( ‚099; 97 events) 1 Node u ET (n= 548; 61 events)
041 Adjusted HR = 0.90, (95% Cl, 0.67-1.21); 2047 Adjusted HR = 0.50, (95% Cl, 0.32-0.77);
P= 49 P= 002
02] No Statistically Significant IDFS Difference 22] 5.year IDFS Absolute Difference: 5.2%
o
7 o 41 2 3 4 5 6 7 8 9 o 1 2 3 4 5 6 7 8 9
No.atRisk Time Since Randomization, y No. at Risk Time Since Randomization, y
CET 1000 995 6 ası 753 644 406 195 60 2 2
ET 1099 1028 962 O61 705 668 428 213 MB Ee ee Vs à 0 0
m ET 5-year IDFS 91.2% 1 CET 5-y IDFS 93.8%
os os
23 poo} CET(n=585;63 events) CETS-YIDFSEOI% 23 ggg | CETM=20822evens) ET SY IDFS 88.7%
2°) ET (n=576; 61 events) ET (n= 283; 30 events)
Nodes Qo4j Adjusted HR = 1.09, (95% Cl, 0.77-1.55); Nodes G04] Adjusted HR = 0.58, (95% Cl, 0.34-1.02);
P= 63 P= 057
°21 No Statistically Significant IDFS Difference 92] 5.year IDFS Absolute Difference: 5.1%
Vo TT 3 ae 5 7 5 à Vo TT FT 3 € FT 8 à
oat ik Time Since Randomization, y oso Time Since Randomization, y
as AO ae ame oe m na me
& se Se 0 EEE 5 2 Ze) ET 2 me mo tt ie EIA 2
1. olnay lal SABCS 2020, Asta 08301 PeerView

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8. Phase 3 OFSET: Adjuvant Trial Evaluating the Addition

of Chemotherapy to Ovarian Function Suppression + ET
NRG Breast Trial BR009 AKA “OFSET”

» Premenopausal patients with pN0/1, ER+, HER2- breast cancer and selected Oncotype scores

Arm 1: Ovarian
suppression +
+ Premenopausal aromatase inhibitor
+ ER+, HER2- Stratification
+ One of three subgroups + Eligibility subgroup
a) pNO with Oncotype (a, b, c)

RS 21-25 + Intent to receive
b) pNO with RS 16-20 CDK4/6i (yes vs no)
and risk factors + Age (18-39 vs 40+) Arm 2: Ovarian
c) pN1 with RS 0-25 suppression +
N = 3,960 aromatase inhibitor +
adjuvant
chemotherapy

1 hips Tenia gowstudyINCTOS879028. PeerView

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9. Which HR+, HER2- EBC Patients Benefit
From Chemotherapy?!

N

24LN sone

signature

N + 1-3LN

Clinical high risk +
genomic low risk
0-3+ nodes

Premenopausal

Postmenopausal ET
Premenopausal CET
QA AA

<20% of premen HR+
patients TAILORx,
RxPonder,
and MINDACT had
LHRH agonist

Postmenopausal

NCCN— T1aN0: ER+ and HER2:: ET only and ER-, HER2+, and TN no chemoRx
T1bNO: consider chemoRx (+ trastuzumab and ET as appropriate)

1. Proded courtesy of Prol Peter Sn, FRCP, MD, PhD! PeerView

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10. Evidence on Adjuvant CDK4/6 Inhibition
to Reduce the Risk of Recurrence
in High-Risk HR+, HER2- EBC

Copyright © 2000-20;

11. Study Desi

Cohort 1 (91%)
High risk based on

clinical pathological On-Study
features Treatment Period
+24 ALN or 1-3 ALN and 2 years

at least 1 of the following
- Grade 3 disease

N 150 mg twice d
- Tumor size 25 cm
HR+, HER2-, + ET (SOC) Followup
node+, Stratified for prior chemo, 1 ET38 years
high-risk menopausal status, and region aay
as clinically

EEC indicated

Cohort 2 (9%)

bah ete 3 High risk based on Ki-67
+ 1-3 ALN and Ki-67 220% | . Primary objective: IDFS
cohort 2
and grade <3 and tumor ra in high Ki-67 lati
en + Secondary objectives: IDFS in high Ki-67 populations,
DRFS, OS, safety, PK, and PROs
* Recruitment from July 2017 to August 2019. * ET of physician's choice (eg. Al, tamoxifen. LHRH agonist). Pe e rvi ew

1.Harbeck N. ESMO 2023. Abstract LBAT7. 2. Rastogi P etal. J Chin Onco 2024:42:387.66,

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12. monarchE 5-Year Update: Sustained IDFS Benefit in ITT!

927
= 89.2
100 (a = 28) (4248) a

A = 6.0) €

ET

où ET
o
$ IDFS events, n 407 585
~ HR = 0.680 (95% Cl, 0.599-0.772); nominal P < .001
2-y abemaciclib = =
treatment + 32% reduction in the risk of an
period i IDFS event
6 12 18 24 30 36 42 48 54 60 66 72 | + KM curves continue to separate;
No. at Risk Time, mo absolute difference in the IDFS rates
Atomaciib + ET 2808 2621 2549 2479 2408 2347 2264 2220 2095 1.175 490 74 0 between arms was 7.6% at 5 years

ET 2820 2653 2573 2474 2374 2281 2,105 2,125 1974 1,124 473 67 0

Roa Pet J Gh Oncol 20244290726 PeerView

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13. nefit in IT

Abemaciclib + ET
ET
Abemaciclib + ET ET
345) (n = 501)
.675 (95% Cl, 0.588-0.774)
Nominal P < .001

2-y abemaciclib
treatment
period

+ 32.5% reduction in the risk
of a DRFS event

+ KM curves continue to separate and
absolute difference in DRFS rates

Abomaciclb + ET 2008 2630 2567 2,500 2494 2375 2313 2258 2,141 1,202 500 75 0 between arms was 6.7% at 5 years
ET 2829 2660 2500 2499 2410 2327 2243 2178 2092 1,181 488 72 0

& 72
No. at Risk

1. Rastogi Petal J Ch Oncol, 202442997.00. PeerView

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14. ET

80 Abemaciclib + ET

70
x © Abemaciclib +
w 50
© 40

2y

En
(n= 234)

307 sbemaciclib HR = 0.903 (95% Cl, 0.749-1.088)
204 “treatment Nominal P < .284
10 period | H
o r r + r r r + +
0 6 12 18 24 30 36 42 48 54 60 66 72
No. at Risk Time, mo
Ibomacicid + ET 2808 2666 2614 2606 2518 2455 2407 2373 2200 1271 52% 80 0
Étaome 2829 2705 2604 2000 2,545 2498 2440 2082 2249 1279 588 77 0
1. Raslog Petal. Gin Orca 20244298799. PeerView

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15. Fewer Patients With Metastatic Disease in t

Additional
Follow-Up 1 (ITT) OS IA2 (ITT) OS 1A3 (ITT)
Data cutoff: April 1, 2021 Data cutoff: July 1, 2022 Data cutoff: July 3, 2023
so Survival Status
400 u Alive with
€ metastatic
g disease
5 m Deaths due
y 20 toBC
a
66 = Deaths not
related to BC
0 a r r
Abemaciclib+ET E Abemaciclib+ET ET Abemaciclib+ET ET
Imbalance of incurable metastatic recurrence continues to be substantial at OS IA3
1. HarbeckN.ESMO 2023. Abstract LEA 17 PeerView

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16. monarchE: Toxicity!

Abemaciclib + ET Er
n, % = 2,791 n, % = 2,800
220% in either arm mG3+m=G2 Gi G1 =62 mG3+
Diarhea 34 QU lo Median duration of abemaciclib: 23.7 mo
Fatigue «a e
Arthralgia 2 MW of interest, “he 791) % (n=2,800), %
Neutropenia co 6 Any Grade
Leukopenia se m |: us = rn
Abdominal pain 36 [U Lo 7 a
ILD 32 13
Nausea x M lo
Hot flush 15 D ES
Anemia 2s || +
100 80 60 40 20 20 40 60 80 100
Patients, %
1. etnston SRD et el. Lancet Oncol 20282470 PeerView

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17. monarchE: Dose Modi

and Occurred Early

+ 42.5% required dose reduction, most frequently in the first few months

+ 30% discontinued abemaciclib early; 18.5% due to AEs, most within the first 6 months of treatment; over
half did not have a prior dose reduction

Dose Modifications Due to AE, n(%) _Abemaciclib + ET (N = 2,791)

Patients with dose reductions due to AE 1,187 (42.5)
2” M Grade 23 dose reduction pecas = en
5 u i jose reduction 4
das = ae re aptos AE leading to dose reductions 1,187 (42.5)
H >
g IB Grade 1/2 dose hod Diarrhea 474 (17)
oO panes 2.0088: Neutropenia 217 (7.8)
Be Fatigue 124 (4.4)
A Leukopenia 97 (3.5)
Sis Patients with dose holds due to AE 1,661 (59.5)
3 AE leading to dose holds 1,661 (59.5)
En Diarrhea 530 (19)
3 Neutropenia 427 (15.3)
= Leukopenia 193 (6.9)
gs Fatigue 135 (4.8)
2
a

0 1 2 3 4 5 6 7 8 9 10 14 12 13 14 15 16 17 18 19 20 21 22 23 24
Time, mo .
1. Rugo HS. SGBCC 202.2. Rug HS ea. Am Once 202238616827 PeerView

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18. chE: Abemaciclib Benefit Is Maintained

IDFS According to RDI in Patients Treated . , : .
With Abemaciclib (All Ages Included) nee ne
impact of dose adjustments on

100}
— 0% to 66% abemaciclib efficacy:
9
” 295% _ patients treated with abemaciclib

E] 6% 10 93% were classified into three equal-sized
x nee en ‘subgroups by RDI
E men cu 87.1 — IDFS rates were estimated within
ô GT 92.9) (84.0-89.7) each subgroup

25 89.5 864
2] "PRES eN Sen 3) een

4-y IDFS rates were generally consistent
(87.1% vs 86.4% vs 83.7% from the

6 aoe ENE 24.209 607883 lowest RDI group to the highest)
D, E 4 7 rima, a der u 108} — Similar findings were observed in
MA mo ee ee 0 patients treated with abemaciclib
Su te 60 me mm Tm mo a we M 0 in cohort 1
“Rol en nava ay dna aora eine ov met Gon ee te A oe (150 m) Beeivien

1. Hamiton EP et al, ASCO 2023. Abstract 501.

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19. TRADE: Phase 2 Dose-Escalation Trial
of Adjuvant Abemaciclib and ET

Adjuvant ET
Abema: Abemaciclib MT ETES
50 mg BI 100 mg BID Qe =)
AA AAA AAA

Days 1-14 Days 15-28 >28 days
Intrapatient dos lation

HR+, HER2- EBC
Adjuvant
abemaciclib is

indicated based
on patient
risk/stage

Screening

Up to 2 years of
abemaciclib

+ Primary endpoint: composite AE rate (discontinuation of adjuvant abemaciclib for any reason and/or
need to dose reduce by 12 weeks of therapy)

+ Secondary endpoints: TRAEs, discontinuation/hold rates, incidence of grade 22 diarrhea, adherence to
therapy, dose intensity, QOL/PROs

+. tps nice govstudyNCTO6001762. PeerView

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20. Community Connections
Implications, Challenges, and Solutions

Gro

21. NATALEE: Study Design!

+ Inthe ITT population, 78% of patients completed 3 years of ribociclib treatment or discontinued early;
21% were still on treatment at the time of this analysis (data cutoff: July 21, 2023; median follow-up: 33 mo)

+ Patients with HR+, HER2- EBC
+ Prior ET allowed up to 12 months
+ Anatomic

— {NO with grade 2 and evidence of
(Ki-67 220%, Oncotype DX breast
recurrence score 226, or high risk via

Patients with
stage IANO :
(T2NO) disease +
required
additional
specified high-
risk features

+ All patients with
stage IIB NO

(T3NO) and 1118

NO (TANO)

Randomization stratification

‘Anatomic stage: II vs Ill
Menopausal status: men and premenopausal
women vs postmenopausal women

Prior (neo)adjuvant chemo: yes vs no
Geographic location: North America/Western

Europe/Oceania vs rest of world
1. Yardley D ot a. ASCO 2024. Art S12

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+ Primary endpoint:
IDFS (STEEP
criteria)

+ Key secondary
le or anastrozole endpoints:
5 years + goserelin MMS
in men and PROS, safety and
premenopausal ue tolerability, PK
+ Exploratory
endpoints:
locoregional RFS,
gene expression
and alterations in
tumor CIDNA/CIRNA
samples

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22. + AtESMO 2024, results from a 4-year landmark analysis of NATALEE were reported, with an additional
10.9 mo of follow-up since the final IDFS analysis, assessing efficacy and safety beyond the planned 3-year
treatment duration with all patients off ribociclib

„88.5 Ribociclib + NSAI

i
186 NSAI alone

i
& 60 1 1449
al ı 1
4 40 , h
al ib+NSAI NSAI Alone
Events/n (%) 263/2,549 (10.3) 340/2,552 (13.3)
20 0.715 ;09-0.840)
El <,0001
0 +
o 6 12 18 24 30 36 42 48 54 60 66
No. at Risk Time, mo
Ribocicib + NSAI 2549 2351 2275 2207 2133 2078 1843 1480 914 155 8 0
NSAI alone 2,552 2,240 2,168 2,082 2,006 1,935 1,687 1,366 848 150 6 0
1. Fasching PA tol ESMO 2024, Abstract LEA. PeerView

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23. Stage Il Stage Ill

1 ı
14.41 1
100 554, 193.9
NSAI al
5 9271 one Ribociclib +
217! 189.6 Ribociclb + A NSAI
NSAI \ .
& 60 4 1143 51 NSAI alone
2 Median follow-up | ! td Median follow-up! 459
S 404 forIDFS:47.4mo ! ! S 40] foriDFS: 38.7 mo 1
Ribociclib + NSAI NSAI Alone 20 Ribociclib + NSAI NSAI Alone
20) “Eventsin (%) 62/1,012(6.1) 96/1,034 (9.3) Events/n (%) 200/1,627 (13.1) 244/1,512 (16.1)
HR (95% Cl 0.644 (0.468-0.887 HR (95% Cl 0.737 (0.611-0.888
o 0 + y
0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66
Time, mo Time, mo
(Wo, at Riek No. at Risk
Reel joe 00 904 aus 802 040 825 700 so os 7 0 MO tam 1410 1382 4310 1262 1209 1000 676 0 60 1 0
NSAIaone 1034 948 924 804 Bra ME B12 772 40 85 5 0 SAINTS 1.208 1.240 1104 1.128 1.000 871 580 982 05 1 0
1. Fasching PA etl ESMO 2026, Abstract LBA. PeerView

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24. LEE: IDFS by Nodal Stat

92.1
NSAI alone

87 | Ribociclib

a 2. + NSAI

2 Median follow-up as
2497 for IDFS: 49.1 mo |
Ribociclib + NSAI NSAI Alone
20] Eventsn(%) 23/285(8.1) 38/328 (11.6)
HR (95% Cl) 0.666 (0.397-1.118)
ol
0 6 12 18 24 30 36 42 48 54 60 66
Time, mo
No, at Risk
Roce ze 262 258 250 244 AO 200 21 18 37 2 0

1. Fasching PA eta ESMO 2024. Abstract LBATS.

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N1-3
100) i. Ribociclib

488 + NSAI

87.
183 NSAI
42. alone

AS

Median follow-up

for IDFS: 44.2 mo
Ribociclib +NSAI NSAI Alone

Events/n (%) 240/2,261 (10.6) 301/2,219 (13.6)
HR (95% Cl) 0,731 (0.617-0.866)

6

o
o

12 18 24 30 36 42 48 54 60 66

Time, mo
No. at Risk

cc 2201 2000 2014 1958 1390 1895 1012 1200 758 118
RSA one 2219 1997 1812 1793 1727 1068 1485 110 680 117

6
4

o
o

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25. NATALEE: Key Secondary Endpoints!

DDFS os

Ribociclib + NSAI 100 Ribociclib + NSAI

NSAI alone

NSAI alone

Soo Median follow-up se 60 Median follow-up
@ for DDFS: 44.2 mo a for OS: 44.3 mo
Q 40 Tr Ó 40
a Ribociclib + NSAI_NSAI Alone
Eventsin (%) 240/2,549 (9.4) 311/2,552 (12.2) Events/n(%) 105/2,549 (4.1) 121/2,552 (4.7)
20 HR (95% Cl) 0.715 (0.604-0.847) 20 HR (95% Cl) 0.827 (0.636-1.074)
Nominal P_ <.0001 Nominal P_ 0766
o o
0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 68
Time, mo Time, mo
No. t Rsk No. t Rsk
PROC. 254923502282 2218 2.146 2000 1854 1,07 où 485 & 0 PROD 2349 2404 2206 2300 2,200 2217 2000 1648 4002 105 41 0
AGA alone 2462 2264 2171 2080 2021 1040 1.701 1378 966 152 6 0 NSMlalo 2.552 2002 2296 220 2164 2117 1046 4571 991 20m 19 0
Fasching PA etal ESNO 2026, Abstract LEA. PeerView

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26. Ribociclib 400-mg Dose Was Safe and Well Tolerated!

RIB + NSAI

Liver-related AEs? z 83
QT interval prolongation® 10

ECG QT prolonged 4.2 02
TLD pneumonitis? 15 0

Other clinically relevant AEs,%

Arthralgia 36.5 10
Nausea 23.0 02
Headache 22.0 0.4
Fatigue 21.9 0.7
Diarrhea 142 06
VIE 14 08

10.6
12
0.7
0.8

425
7.5
16.5
127
54
06

NSAI Alone
(n=2

01

13
0.04
0.2
0.2
0.1
0.2

+ The most frequent all-grade AEs
(RIB + NSAI vs NSAI alone) leading
to discontinuation were:

- Liver-related AEs: 8.9% vs 0.1%
— Arthralgia: 1.3% vs 1.9%

+ Most of the AE discontinuations of

RIB occurred early in treatment
— Median time of discontinuation,
4 months

Lower rates of neutropenia and
QTc prolongation than 600 mg

dose, but no difference in grade 3
LFT abnormalities

* This 6. groupes term that combines neutropenia and neutrophä count decreased. » This isa grouped term that includes al preferred terms denied by standarsized
|MedDRA queries fr drug-related hepatic iscrders. This 's a grouped term. * This is a grouped term that includes al preferred terms denied by standardized MecORA

queries for intrsital ng sense.
1. Slamon DJ el al ASCO 2023, Abstract LBASOO,

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27. NATALEE: Ribociclib Dose Reduction Due to AEs

Did Not Affect Ef

acy!

IDFS by Dose Reduction
at 25th Percentile (1.87 mo)*

IDFS by Dose Reduction
at 50th Percentile (3.17 mo)*

IDFS by Dose Reduction
at 75th Percentile (7.28 mo)*

With dose 5
00 Without dose x reduction id Without dose
reduction reduction
80 e Without dose 80 With dose
With dose reduction reduction
eo reduction Leo 8
y 5 G
Lao En Lo
e Without Dose With Dose =] Without Dose With Dose RE] Without Dose With Dose
5 Reduction Reduction AAN Reduction Reduction AN Reduction Reduction
Eventsin 208/2,315 13/123 Eventsn 193/2117 19/276 Eventsin 15811,933 35/406
o o o
O 6 12 1824 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 O 6 12 18 24 30 36 42 48 54
Time, mo Time, mo Time, mo
wos LI 10100 O MOM a m 6 9 MD va tome va ir ote ame te 6

+ Of dose reduction tim, calculated from randomization
4. Banos G ot al. 2024 ESMO Breast. Abstract 113MO.

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28. Community Connections
Implications, Challenges, and Solutions

Gro

29. PeerView

Case 1: Assessing Risk of Recuri
n HR+, HER2- EBC

ce and Selecting Therapy

Patient History and Presentation

A 62-year-old postmenopausal woman

Underwent a routine mammogram screening and was
found to have a mass in the left breast
Mammogram/ultrasound showed a 3.5-cm mass +
enlarged, suspicious axillary lymph nodes

Core biopsy: grade 3 IDC, ER+, PR+, HER2-

Lymph node biopsy: cells consistent with breast cancer
Staging scans: no distant disease

Germline testing: negative

Left mastectomy and axillary lymph node dissection
was performed: 3-cm tumor, grade 3 IDC, 1/3 lymph
nodes positive

Oncotype Recurrence Score: 21

com/HBX827

Context and
Current Clinical Setting

Y Followed-up with breast surgeon
2 weeks after surgery

Y” Met with you, her medical
oncologist, after initial diagnosis
and before surgery > now
coming in to discuss results, risk
of recurrence, and next steps

Let’s discuss the considerations
and recommendations

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30. Module 2

Customizing Care
Multifactorial Decision-Making in 1L CDK4/6i Treatment
Selection in HR+, HER2- MBC

10-2025, PeerView

31. Phase 3 Trials of CDK4/6 Inhibitors Show
Consistent PFS Benefit in the First-Line Setting!

PALOMA-2

Phase 3
AL

Letrozole

Palbociclib

666

MONALEESA-2

Phase 3
«fe

Letrozole

Ribociclib

668

MONARCH 3

Phase 3
1c;

Letrozole or
anastrozole

Abemaciclib

493

MONALEESA.

Phase 3
AL and 2L

Fulvestrant

Ribociclib

367

PO OOO OOOO

PALOMA-
t Phase 2
Design AL
Endocrine
partner Letrozole
CDK4/6 Seti
inhibitor Palbociclib
Patients on
study, n 165
IHR 0.49
L
PFS, mo 20.2 vs 10.2

0.58

24.8 vs 14.5

0.56

25.3 vs 16

0.54

28.18 vs 14.76

1. Finn RS et al Lancot Oncol 2015:16:25-35.2. Finn RS ot al. N Eng! J Mod. 2016,375:1925-1996. 3. ortobagyi GN et al. Ann Oncol 2018:28:1581-1547.
4 Johnston Se al. NP Breast Concor. 2019.55. 5. Slamon DU ot al. N Engl J Mod 2020:382:5 14-524.

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054!

33.6 vs 19.2

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32. Median OS, mo (95% Cl)
Ribociclib (n = 334): 63.9

Placebo (n = 331): 51.4 al
HR = 0.76 (95% Cl, 0.63-0.93) ie
P=.008

4 8 12 16 20 24 2 32 36 40 da 48 52 56 60 4 $8 7 76 80 84 88

Time, mo

Ribociclib + letrozole showed a significant OS benefit, with a 1-year improvement over placebo
in HR+, HER2- advanced breast cancer

1.Horebagyi GN et .N Eng Me. 2022398942950. PeerView

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33. PALOMA-2: OS Not Statistically Significantly Improved Wi

First-Line Letrozole + Palbociclib'?

os: TT Post-Hoc Sensitivity Analysis: Excluding
Median parara] Patients With Survival Data Not Available
Follow-Up, 90 mo (n=444) _(n= 222) PAL + LET PBO + LET
si MedianOS,mo 539 2 (n= 385) (n= 175)
(95% Cl) (28608) (437-589) MedianOS,mo 516 446
Lo Stratified HR 0.956 e (95% CI) (46.9-57.1) (37.0-52.3)
= (85% Cl (0.777-41.177) a Unstratiied HR 0.869
E 2
3 3
3
E ELE 3 H PAL + LET
a a 4
8 Q it
° PBO + LET ó pl PBO + LET
2 à & We 4 % & © À à %
mae Time, mo Denn Time, mo
mm m 0 mn ne wm mm wk
+ Median follow-up: 7.5 years
+ Missing survival data: 13% palbociclib + letrozole and 21% control
+ More crossover to CDK4/6i in the control arm: 27% vs 12%
+ _At7.5-year follow-up, 10% of patients continued on palbociclib and letrozole
Fon RS ta Jn Oncol 202240! I}LBAICODLBATONE.2 Sun DJJ Cr Oca 24425041000 PeerView

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34. MONARCH-3: Abemaciclib + NSAI Resulted in a Numerically

er OS vs NSAI Alone, but Statistical Significance Not Met‘?

100 Placebo +
© NSAI
pe Median OS, mo 66.8 537
m Abemaciclib + NSAI HR (95%) 0.804 (0.637-1.015)
20 66.8mo — 2sidedP. 0664"
O Ba le nn an )
Ss Preplanned OS analysis
5 Data cut: Sept 29, 2023
»

Abemacic + NSAI 198 (60%)

Placabo + NSAI 185 118(70%)

0 5 RDM Dee m MM E

No at Risk Time, mo
PH 528 JM I Me A7 Ze Zi tm tere Me BE Ze ee wg
Sa ee Mas uo toe 17 Né 14 © 7 EME © % %

Long S with abemaciclib + NSAI was clinically significant
but not statistically significant; the observed improvement in median OS was 1:

+ Da mo reach tvesnot (0094) fr stas sglcarco a ta fal ana i
Vote era, SABES 2028 Annan 6801 12.2 Coote MP era Am Oncol 2028°26:718-727. PeerView

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35. MONARCH-3: Abemaciclib + NSAI Resulted in a Numerically Longer OS vs NSAI Alone

in the Subgroup With Visceral Disease, but Statistical Significance Not Met?

Abemaciclib + NSAI Placebo + NSAI

9 Median OS, mo 63.7 48.8
a HR (95%) 0.758 (0.558-1.030)
1 2-sided P O757
DJ 2 63.7 mo (A = 14.9)
8 « 48.8 mo
= Patients,n Events, n (X) Abemaciclib + NSAI
297 Avemacicid +NSAL 173 119.65) Placebo + NSAI

Placebo + NSAI 90 6572)

E DE DEE EU DE DEE DE E DE PE
so art Time, mo

Abomaciclb + NSAI 173 161 147 138 126 118 107 100 95 86 78 72 63 53 46 45 27 3
Placebo+NSAI m 83 80 74 64 56 49 44 40 34 29 24 22 19 17 16 9 0

2 D ot each vegas (008) ar tal since a i na anar. x
Vota Mé an SABES 2028 Annan 6801 12.2 Goou MP etal Am Oncol. 2024 257 18-727. PeerView

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36. Comparing MONARCH-3 and MONALEES, OS Analyses!

Median follow-up, y
Randomization
Variable

Patients, n

Deaths, n (%)
Post-study CDK4/6i, %
Median OS, mo

HR for death
1. Tolaney 8. SABCS 2029. Presentation.

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MONARC | MONALEESA:
8 (96 mo, final OS) 5.8 (70 mo, lA20S) 6.6 (80 mo)
2:1 24 11
Abema+Al PBO+Al Abema+Al PBO+AI RIB+Al PBO +Al
328 165 328 165 334 334
198/328 (60) 116/165 (70) 158/328 (48) 97/165 (59) 181/334 (54) 219/334 (66)
12 32 - - 22 34
67 54 67 54 64 (52-71) 51 (47-60)
0.804 (0.637-1.015); 0.754 (0.58-0.974); 0.76 (0.63-0.93);
P= 0664 P= 0301 2-sided P = .008
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37. K4/6 Inhibito

Fulvesti and Everolimus Efficacy Afte

PFS and OS in patients treated with everolimus and fulvestrant in the whole population
and according to previous palbociclib treatment duration

10 Median PFS: 6.8 mo 10 Median OS: 38.2 mo

>modian a 810 8 2 0 median 27 23 20 6

1. Vasseur A etl, Oncogene 2024:43.1214-1222 PeerView

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38. PeerView.com/HBX827

K4/6i After Progressi 1L CDK4/6i?

MAINTAIN PACE PALMIRA
Patients, n 120 166 198
First-line CDK4/6i Palbociclib (84%) Palbociclib (90%) Palbociclib (100%)
First-line CDK4/6i >12 mo, % 67 75 86
Fulvestrant (83%) or Fulvestrant (90%) or

Endocrine therapy Fulvestrant (100%)

exemestane letrozole

“Continuation” CDK4/6i Ribociclib Palbociclib

PFS ET only, mo

PFS fulvestrant + CDK4/6i, mo

+ Dieron tutes, dasons, ty popular, and subgroup efron. Vi
Kama Ket a Cm Goo! 202544004 0132 Mayer Exot a SABCS 2022. Abstact 653.06, 3 LlobartCussac Aetal. ASCO 2023. Abstract 101. PeerView

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39. Placebo +

od Fulvestrant Fulvestrant
90 (n = 182)
80 Events, n 17
7 Median, mo (95%
gl en ae 6.0(56-86) 5387-56)
6 © 50% HR (85% CI) 0.73 (0.57-0.95)
2 Ñ Log-rank P 2
a 40 i
30 Abemaciclib + fulvestrant
20
10 | “ Placebo + fulvestrant
cl |
NovatRisk 0 3 $ 3 y 5 18 21
Abemacc + Time, mo
Be m à 2
Placebo +
ET ET ee a ” 7 3 o

Abemaciclib led to 27% reduction in the risk of a PFS event

1. Kalinshy ot al. ASCO 2024. Abstract LBA1001

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40. EMBER-3: Imlunestrant Showed Reduced Risk of Progression o
Death Compared With SOC ET i

Imlunestrant 5 mo

eee soc 3.8 mo
; HR: P 0.62; <.001

Imlunestrant

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

No. at Risk Time, mo
Imlunestrant 138 95 74 56 45 35 22 18 15 8 4 4 3 2 0 0
SOC 118 74 51 33 19 7 5 3 2 1 0 0 0000

Imlunestrant led to a 38% reduction
in the risk of progression or death in patients with ESR1m

The mean flou vas 187 arth in o miunestant am nd 138 more ne SOC ET am.

+ Due to dene o nor proononal hazards a sentry anal of PFS using RST was conduced. Estinaled RMST at 194 mons was 7:9 months (95% CL 6.81) e

imlunesran arms 54 mana (8% Cl 46:62) nthe SO ET arm (üfrenee 26 monte (12.95) i
‘haves Kat at SABCS 202, Provantaton 6810 PeerView

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41. Imlunestrant SOC ET
(n= 331) (n=330)

78 Events, n 237 253
x Median, mo (95% Cl) 5.6 (5.3-7.3) 5.5 (4.6-5.6)
gs HR (95% Cl) 0.87 (0.72-1.04)
a

25 Imlunestrant iP 12

x i socet | Prespecified critical HR <0.84> |

2 14 16 18 20 22 24 26 28 30
RE Time, mo

imlunastant 391 225 173 135 118 89 62 47 43 30 20 19 13 10 0 0
SOCET 330 221 165 122 89 63 51 41 38 23 17 14 10 2 0 0

The majority subgroup of patients without ESR1m showed no difference in PFS.
HR = 1.00 (95% Cl, 0.79-1.27)

2 The median fav 16.6 montan e mutant arm and 16 months in the SOC ET am. * Atal abba .
4. shaver Ket al SABCS 2024, Presanlaton 681.01 PeerView

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42. Primary Endpoint: Investigator-Assessed PFS
With Imlunestrant + Abemaciclib vs Imlunestrant Alone in All Patients
Imlunestrant

66 + Abema
75 i 213)
e i 42 Events, n 114
= i f Median, mo (95% CI) 9.4(7.5-11.9) 5.5 (3.8-5.6)
£ 0 ! i mune HR (95% Cl) 0.57 (0.44-0.73)
T i abonado <.001
25 | +
| | Imlunestrant
N |
0 2 4 6 8 10 42 14 16 18 20 22 24 26 28 90
a Time, mo
MA zu 165 141 122 06 72 48 29 25 19 6 5 3 0 0 0
asta 219 HO 108 77 87 4 2% 2 18 0 9 2 0 0 0 0
Imlunestrant + abemaciclib led to a 43% reduction
in the risk of progression or death over imlunestrant alone in all patients

Efficacy analyses confine tothe imiunesrant population concurrently randomized io Imlunestrant + abemacici treatment am. The median follow-up was
13. months n Ihe munestrant + sbemaccio arm and 13.7 month inthe mlunestant arm

1 have Wel al SABOS 2024. Presenaton 051.01 PeerView

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43. Community Connections
Implications, Challenges, and Solutions

Gro

44. Patient History and Presentation
A 61-year-old postmenopausal woman with a history
of IDC of the breast, pT2N1, grade 3, ER+, PgR-, HER2-
+ Mammogram/US showed a 2.7-cm mass + enlarged,
suspicious axillary LN
= Underwent lumpectomy > adjuvant chemotherapy (TC) >
breast RT > adjuvant Al
— Has long-standing history of depression, takes an SSRI
2 years after Al initiation, develops right hip pain > bone scan
reveals lytic bone lesions
CT C/AP also showed numerous liver and bone metastases
involving spine, hip, and ribs
Liver biopsy showed ER+, PgR-, HER2- carcinoma c/w breast
Liver function studies were normal
BRCA1/2-
Baseline EKG: QTc 585 ms

Case 2: 1L Therapy for a Patient With HR+, HER2- MBC

Let’s discuss the considerations
and recommendations

What treatment would be the best option
for this patient, and which factors should
you consider in determining the best 1L
therapy for her?
Comorbidities (depres:
Liver disease/function
Tumor biology: endocrine resistance,
timing, PR- status
Drug dosing (continuous vs intermittent)
Drug-drug interactions (medications,
supplements)
Patient needs and preferences
What if ... the patient had bone-only
disease, or CNS metastases?

, cardiac health)

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45. Module 3
Maximizing the Potential of CDK4/6i
Therapy in HR+, HER2- EBC and MBC

AE Management and Improvement of
Adherence/Persistence

46. DK4/6 Inh
in EBC and MBC

itors: Safety Profiles and Dosing Schedules

Palbociclib Ribociclib Abemaciclib

+ Neutropenia (81%)
+ Diarrhea (25%)

+ Increased ALT (8%)
+ Increased AST (9%)

Schedule: 3 wk on/1 wk off

Dose: 125 mg/day

1st dose reduction: 100 mg/day
2nd dose reduction: 75 mg/day

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+ Neutropenia (69%-78%)
Diarrhea (29%-35%)
Increased ALT (15%-46%)
Increased AST (13%-44%)
QTc prolongation (6%)

Schedule: 3 wk on/1 wk off

EBC: 400 mg/day
MBC: 600 mg/day

1st dose reduction: EBC, 200
mg/day; MBC, 400 mg/day

2nd dose reduction:
MBC, 200 mg/day

+ Neutropenia (41%-46%)

+ Diarrhea (81%-86%)

+ Increased ALT (13%-16%)

+ Increased AST (12%-15%)

+ Thromboembolic events (5%)

Schedule: Continuous daily dosing

150 mg BID EBC and MBC.

1st dose reduction: 100 mg BID
2nd dose reduction: 50 mg BID

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47. Main Toxicities With CDK4/6 Inhibitors‘

Patients With Patients With bg
mul Cardiovascular Hepatic anes
Disease Impairment

Neutropenia,

m Diarrhea Y
x Thromboembolic Y Y Y
g events
=
5 30 Reversible
3 transaminitis # # #
= QTe prolongation Y Y
20
10
0
Neutropenia Thrombocytopenia Diarrhea Fatigue Nausea
M Palbocicib I Abemacicib M Ribocilb
Mr À Cuno ©, NFU Brest Cancer, 20192927. PeerView

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48. Factors Influen

for Improvement!+

g Adherence/Persistence and Interventions

Adherence is a multidimensional phenomenon
and is influenced by various factors
Patient Related Healthcare System Related
+ Perception of necessity, + Shorter duration of
benefit, QOL follow-up visits
+ Forgetting and self-efficacy: + Prescribing errors
+ Preference for alternative Different physicians

+ Routinization responsible for follow-up
+ Depression or anxiet + Relationship with HCPs

i + Lack of patient involvement
Tracer male in decision-making

+ Modifications and complexity
of regimen

+ Duration and variations

of therapy

Social & Economic Related

+ Younger or older age

+ Higher out-of-pocket cost

+ Lower income and
education level

+ Unmarried

isease Relates
+ Comorbidities
+ Unknown tumor size

+ Node-positive disease

T hips emo nt 2 Verbruggne Metal Cancor Treat Rov, 2013 JO GIO SY à Parampe Reta. roa Gancor ROS Treat TOTO 170207-308.

4 Spoolsra SL, Ratenberg CN. Gin J Oncol Nas. 2016:18:47-52.

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There are a variety of measures
to improve adherence

Therapy-Related Interventions
+ Simplification of regimens
+ Education on the use of medications
+ Clear instructions
+ Patient-tailored prescriptions
+ Continuous monitoring and reassessment of treatment
+ Assessment and management of AES

Patient-Related Interventions

+ Interventions to redress treatment misconceptions
and encourage patient-oncologist dialogue

+ Assessment of psychological needs

+ Use of conventional (brochures) and digital
(web-based) tools to educate on the use of medications

+ Remote monitoring tools for AEs and adherence

+ Behavioral motivational intervention

+ Good patient-provider relationship

+ Self-management of disease, treatment, and AES

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49. Workshop Summary
and Key Takeaways

1000-2025, PeerView