Safeguarding Patients With HR+, HER2-, High-Risk, Early Breast Cancer: A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting

Chair and Presenters Professor Stephen Johnston, MA, PhD, Patrick Neven, MD, PhD, and Joyce O’Shaughnessy, MD, discuss breast cancer in this CME/MOC/CPD/NCPD/CPE/AAPA activity titled “Safeguarding Patients With HR+, HER2-, High-Risk, Early Breast Cancer: A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CPD/NCPD/CPE/AAPA information, and to apply for credit, please visit us at https://bit.ly/49HZ5fH. CME/MOC/CPD/NCPD/CPE/AAPA credit will be available until June 21, 2025.

1. Safeguarding Patients With HR+,
HER2-, High-Risk, Early Breast Cancer

A Practical Roadmap for CDK4/6 Inhibition
in the Adjuvant Setting a

Professor of Breast Cancer Medicine 8 Head of Medical Oncology

Consultant Medical Oncologist & Head of The Breast Unit

The Royal Marsden NHS Foundation Trust & The Institute of Cancer Research
Chelsea, London, United Kingdom,

7 Joyce O'Shaughnessy, MD
Etico han ptas Celebrating Women Chair in Breast Cancer Research &
Fee co ET Baylor University Medical Center
da Director, Breast Cancer Research Program
lultidisciplinary Breast Centre Texas Oncology

University Hospitals a ee
Leuven, Belgium J Dalles, Texas

y Le

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

Copyright © 2000-2024, PeerView

2. PeerView.com/WUM827

Our Goals for Today

Enhance your ability to identify patients with HR+, HER2- EBC who are at high risk
of recurrence and may benefit from adjuvant CDK4/6 inhibitor therapy

Augment your skills for formulating individualized treatment plans for patients with

high-risk, HR+, HER2- EBC based on latest evidence and key factors

Expand your repertoire of strategies for improving adverse event management and
adherence/persistence among patients undergoing adjuvant CDK4/6 inhibitor therapy

3. Let’s Start With a Case

Tina, a 57-year-old postmenopausal woman, who is a real estate agent and travels
frequently for work, presents to your clinic with symptomatic mass in the right breast;
further assessment is undertaken followed by surgery, with the following results:

Mammogram/US showed a 3-cm mass + enlarged, suspicious axillary LN
Core biopsy: grade 3 ILC, ER 90%, PgR 25%, HER2 nonamplified by FISH
LN biopsy + carcinoma

PET CT staging and germline testing negative

Right mastectomy and axillary LN dissection performed: 2.3 cm, grade 3 ILC, 1/3 LN+

PeerView.com/WUM827 c

4. ADJUVANT COKA/61 in HR+, HER2-, HIGH-RISKEBC | OUTLINE

Safeguarding Patients With HR+,
HER2-, High-Risk, Early Breast Cancer

A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting

d 2 3

Conducting risk Integrating the latest Mitigating AEs, improving

assessment in HR+, evidence to support adherence/persistence,

HER2- EBC to identify multifactorial clinical and maximizing treatment

patients at high risk of decisions about adjuvant benefits from CDK4/6

recurrence CDK4/6 inhibition inhibitors in high-risk HR+,
HER2- EBC

PeerView.com/WUM827 Copyright © 200

5. ADJUVANT COKA/6I in HR+, HERZ-, HIGH-RISKEBC | OUTLINE

Safeguarding Patients With HR+,
HER2-, High-Risk, Early Breast Cancer

A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting

1 2 3

Conducting risk Integrating the latest Mitigating AEs, improving

assessment in HR+ evidence to support adherence/persistence,

HER2- EBC to identify multifactorial clinical and maximizing treatment

patients at high risk of decisions about adjuvant benefits from CDK4/6

recurrence CDK4/6 inhibition inhibitors in high-risk HR+
HER2- EBC

PeerView.com/WUM827

6. Conducting Risk Assessment
in HR+, HER2- EBC to Identify =~
Patients at High Risk of Recurrence

Joyce O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research
Baylor University Medical Center

Texas Oncology

Sarah Cannon Research Institute

Dallas, Texas

PeerView.com/WUM827

7. Risk of Recurrence With Early Breast Cancer:

IBCSG Trials I to V12

Annual Hazard of BC Recurrence for ER+ BC
os

— 24 positive nodes
04 —— 1-3 positive nodes
—— 0 positive nodes

Recurrence Hazard Rate (95% Cl)

0 2 4 6 8 10 12 16 16 16 20 22 24

ER Time, y
Opal Go 4 4 6 2 tw vu
a GS D tw “
pr 67 2 10 7 © a Py

4. Collon Metal. J Cin Oncol 2016;34:927-835, 2. O'Shaughnessy et al. SABCS 2022. Oral presentation.

PeerView.com/WUM827

Invasive Disease-Free Survival of Stage WII
Breast Cancer Patients: RWE US Database 1995-2021

IDFS in Patients With Stage Il and Stage Ill Disease

IDFS, Proportion

Stage Il

0 5 0 75 Im 1m Im ım 20 25 20 25

No. at Risk Mo, Censored) Tie, o
DREIER us 1000 m AO
Sen (9) a) 99 1.70 03) (480 (1382) (1869 (1.707) (172 (23)
Ses Sean “ian! Cae” 6 (2 pie
Son © 60 (en (M am dm En am m cs) Ge cs)
PeerView.com

Copyright © 2000-2024, PeerView

8. Prognostic Factors for Premenopausal ER+

y

Patients: SOFT/T EXT Trials!

%

Patients Free From DR,

0123456789
Time, y

By TA, T2/T3

Patients Free From DR, %

Om eis a's, 072038)
Time, y

4, Pagani O etal. J Gin Oncol 2020;38:1289-1903

PeerView.com/WUM827

By NO, M, N2

ot #28 8

Patients Free From DR, %.

0123456789
Time, y

By ER expression

3

Patients Free From DR, %
o 3888

ES euro
Time, y

PeerView.com

Copyright © 2000-2024, PeerView

9. Prognostic Factors for Premenopausal ER+
Patients: SOFT/TEXT Trials!

By PgR Expression Level

%

Patients Free From DR,

Patients Free From DR, %
e 3888

x Pitan OR Ba 060

sos crea

1. Pagani O etal. J Gin Oncol 2020;38:1280-1903

PeerView.com/WUM827

Time, y

By Tumor Grade

Patients Free From DR, %
o3328

EZEITIEIE
y

PeerView.com

Copyright © 2000-2024, PeerView

10. ET Resistance Increases Risk of Recurrence
in NSABP B-14 Adjuvant Tamoxifen Trial

Proliferation Module vs RS*
Spearman's p= 0.36 |

ER+ Node-Negative EBC: 10-Year Distant
Recurrence Rate by RS Group?

6.8%
$
© 0 14.3%
É intermedateri 143%
3 - 30.5%
9 a yf © © 60] NSABP B-14: tamoxifen x 5 y LU
Estrogen Module vs RS! 5
ä
A 40 E
E Multivariate Cox Model
É RS prognostic independent of age and tumor size
E 204 — Low risk (RS <18) 338 patients (51%)
5 — Intermediate risk (RS 18-30) — 149 patients (22%)
E — High risk (RS >30) 181 patients (27%)
Zo HA
0 2 4 6 8 10 12 14 16
Time, y
5 8 0 ©
1. Buus Ret al. Cin Oncol. 2021;38:126-135. 2. Pak Set al. N Engl J Med. 2004;351:2817-2826. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

11. Which HR+, HER2- EBC Patients Benefit

From Chemotherapy?!

Premenopausal

NCCN —

4. Provided courtesy of Prof. Peter Schmid FRCP, MD, PhD.

PeerView.com/WUM827

70-gene
signature

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

Postmenopausal ET
Premenopausal CET

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

T1aN0: ER+ and HER2+: endocrine therapy only and ER- HER2+ and TN no chemoRx
TINO: consider chemoRx (+ trastuzumab and ET as appropriate)

PeerView.com

Copyright © 2000-2024, PeerView

12. Patients With Persistent High Ki-67 With
Neoadjuvant ET Alone Had Significantly
Higher Risk of Recurrence’

RFS by Risk Group in P024 RFS by Risk Group in IMPACT
10 10 Group 1
gos at Los Group
& Group 2 2
06 ° 06 Group 3
2 2 =
gu Group qa
Eo Ê 02
o o
RA OR Hw IRA
Time, mo Time, mo
No. at Risk No. at Risk
Gow iat 41 99 97 M 27 1 Gopi st 7 217 9 6 4 1
Group2 65 65 58 46 42 97 4 Gow2 97 W 71 59 À 16 9 3
Group3 52 49 42 26 21 18 0 Group3 76 63 55 35 16 10 2
Group 1 (Green): PEPI score 0 (pT1-T2, pNO, Ki-67 <2.7%)
Group 2 (Red): PEPI score 1-3
1. Ells MJ et al. J Natl Cancer Inst. 2008:100:1380-1388. Group 3 (Purple): PEPI score >4 PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

13. ADAPT Trial: ER+, HER2-
Pre- and Postmenopausal EBC

Presentation Surgery

nz
je ns
A RS>25

3 weeks

Chemotherapy
trial

RS 12-25, Ki-67 >10%

RS 12-25, Ki-67 510% |" = 1422
Experimental arm
treatment

Endocrine
treatment

Biopsy or

Biopsy excision biopsy

PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

14. Prognostic Effect of ET Response (4-wk Lead-In)
on IDFS in ADAPT1 (Median Follow-Up: 60 mo)

K67 510%
100 ——
075] au patients Ki67 10%

2

Unadjusted: HR 0.59 (0.47-0.75); P < 001
Adjusted: HR 0.73 (0.56-0.94); P=.017

2
oat Risk iene
Neo 1% 1m ss or 5
Norme 299 A 63
100 1067 <10%
SE an)
teks CCE
2
oso
41-50 y (premenopausal)
025 7 Unadjusted: HR 0.51 (0.31-0.84); P = .009

Adjusted: HR 0.63 (0.

à 3
o 12 2 36 4 E

Time, mo
Kormos se 4 ss a ase wo

F2
1. z UA et a. J Cin Oncol 2022:40:2567-2567. 2. Ghz O et al. ESMO 2022. Abstract LBA14,

PeerView.com/WUM827

16-67 510%
(CT 15.8%)

K67 >10%
(crx 905%)
<40 y (premenopausal)
Unadjusted: HR 0.59 (0.27-1.30); P= .191
Adjusted: HR 0.63 (0.24-1.65); P= 346

2
Time, mo
17

Pra

A
(1X 13.9%)

1:67 >10%
2 075 cr)
Sos
>50 y (postmenopausal)
025 | Unadjusted: HR 0.63 (0.46-0.87); P=.005

Adjusted: HR 0.78 (0.54-1.12)

o
o 12 2 36 8 $0
Time, mo
No. at Riek
KA BA 0 air

PeerView.com

Copyright © 2000-2024, Peerview

15. HR+, HER2-, High-Risk EBC: Summary =

Endocrine therapy resistance is a key feature of HR+, HER2-, high-risk EBC
that recurs within 5 years of diagnosis

Tumor size, nodal status, and grade impact recurrence risk and improve
prognostic accuracy of gene expression signatures

Higher proliferation and lower ER levels increase risk of recurrence
Luminal B, HER2 enriched, and basal like are HR+, HER2-, high-risk EBCs

Failure of preoperative ET to suppress Ki-67 predicts poor outcome
with adjuvant ET

PeerView.com/WUM827

16. Returning to Our Case

Tina, a 57-year-old postmenopausal woman, who is a
real estate agent and travels frequently for work, presents
to your clinic with symptomatic mass in the right breast;
further assessment is undertaken followed by surgery, with
the following results:
Mammogram/US showed a 3-cm mass + enlarged,
suspicious axillary LN Considerations for lobular vs ductal?
Core biopsy: grade 3 ILC, ER 90%, PgR 25%, HER2
nonamplified by FISH How would you categorize her risk of
LN biopsy + carcinoma recurrence based on available info?

Let's discuss

Y Do we have enough information to
assess this patient's risk of
recurrence?

PET CT staging and germline testing negative Wel iraddicnal esting reveaie
Right mastectomy and axillary LN dissection performed Oncotype DX RS 21, Ki-67 15%?
2.3 cm, grade 3 ILC, 1/3 LN+

PeerView.com/WUM827 Copyright

17. ADJUVANT COKAI6I in HR, HER2-, HIGH-RISK EBC | OUTLINE

Safeguarding Patients With HR+,
HER2-, High-Risk, Early Breast Cancer

A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting

1 2 3

Conducting risk Integrating the latest Mitigating AEs, improving

assessment in HR+, evidence to support adherence/persistence,

HER2- EBC to identify multifactorial clinical and maximizing treatment

patients at high risk of decisions about adjuvant benefits from CDK4/6

recurrence CDK4/6 inhibition inhibitors in high-risk HR+,
HER2- EBC

PeerView.com/WUM827

18. Integrating the Latest Evidence
to Support Multifactorial Clinic
Decisions About Adjuvant
CDK4/6 Inhibition

Professor Stephen Johnston, MA, PhD & x.
Professor of Breast Cancer Medicine & Head of Medical Oncor
Consultant Medical Oncologist & Head of The Breast Unit ==
The Royal Marsden NHS Foundation Trust & The Institute

of Cancer Research

Chelsea, London, United Kingdom

PeerView.com/WUM827

19. monarchE Study Design‘?

HR#HER2.,
node-positive,
high-risk EBC

ITT includes both
‘cohort 1 and cohort 2

* Recruitment rom July 2017 to August 2019. Endocrine therapy of physician's choice (eg, aromatase inhibitors, tamenifen, LHRH agonist)
41, Harbeck N. ESMO 2023. Abstract LBA17. 2. Rastog P et al J Cn Oncol 2024,00:17.

PeerView.com/WUM827

Cohort 4 (91%)
High risk based on
clinical pathological features

+24 ALN or 1-3 ALN and at least
1 of the following
- Grade 3 disease
- Tumor size 25 cm

‘Stratified fr prior chemo,
‘menopausal status, and region

Cohort 2 (9%)
High risk based on Ki-67

+ 1-3 ALN and Ki-67 220%
‘and grade <3 and tumor size
<Scm

On-study treatment period

+ endocrine therapy

Endocrine therapy

+ Primary objective: IDFS

+ Secondary objectives: IDFS in high Ki-67 populations, DRFS, OS,
safety, PK, and PROs

Follow-up period
Endocrine therapy.
3-8 years as
clinically indicated

PeerView.com

Copyright © 2000-2024, PeerView

20. 5-Year Efficacy Results From a Prescribed
monarchE Analysis‘?

On-study treatment period
2 years

Abemaciclib + endocrine therapy
Endocrine therapy

_-_E_>——_—_ _————J————————————————————

Follow-up Year 1
time
+ Extent of follow-up at OS 1A3 allows for robust estimation of IDFS and DRFS at the clinical 5-year landmark
+ Median follow-up time is 4.5 years (54 months)

+ All patients are off abemaciclib
— More than 80% of patients have been followed for at least 2 years since completing abemaciclib

Data auf: July 3, 2023. a
41, Harbeck N. ESMO 2023. Abstract LBA17. 2. Rastogi P et al. J Cin Oncol 2024:00:1-7. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

21. monarchE 5-Year Update:
Sustained IDFS Benefit in ITT‘

92.7 (2.8)

E) 83.6 (427.6)
Abemaciclib + ET

ET alone
Abemaciclib+ET ET Alone
IDFS events, n 407 585

HR = 0.680 (95% Cl, 0.599-0.772); nominal P < .001

IDFS, %
388588388

+ 32% reduction in the risk of developing
an IDFS event

Ô 6 nn om D % 2 à E: TE

a + KM curves continue to separate; absolute
No at Risk ane difference in the IDFS rates between arms
ds ai ea on SOS ic UE SE à was 7.6% at 5 years

Data cutoff: July 3, 2023. =
1. Rastogi P et al. J Clin Oncol, 2024:00:17. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

22. monarchE 5-Year Update:
Consistent IDFS Benefit Observed in Subgroups’

41, Rastogi P et al. J Clin Oncol 2024:00:17. PeerView.com

PeerView.com/WUM827

Copyright © 2000-2024, PeerView

23. monarchE 5-Year Update:
Sustained DRFS Benefit in ITT’

100: A a
N nó en

one
807 Abemaciclib + ET
oo
792, ET alone

Abemaciclib + ET ET Alone
(n= 345) (n= 501)

HR = 0.675 (95% Cl, 0.588-0.774)
‘Nominal P < 001

y
2
[7
6

* 32.5% reduction in the risk
of developing a DRFS event

+ KM curves continue to separate and

2 8 à 0 & À

EE %

Time, mo absolute difference in DRFS rates

No, at Risk between arms was 6.7% at 5 years
Abemoci + ET 2808 2630 2567 2500 2434 2375 2313 2258 2,161 1202 500 75 0
no

ET alone 2829 2660 2500 2499 2410 2327 2243 2176 2032 1,161 488
1. Rastogi P et al. J Clin Oncol 2024.0:1-7. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

24. monarchE 5-Year Update: OS in ITT!

Abemaciclib + ET
ET alone

Abemaciclib + ET ET Alone
50 (n= 208) (n= 234)

‘903 (95% Cl, 0.749-1.088)
Nominal P < .284

0 6 12 18 24 30 36 42 48 54 60 66 72

Time, mo

No. at Risk
Avemacio HET 2908 2666 2614 2568 2518 2055 2407 2373 2260 1211 5%
ET alone 2829 2705 2664 2500 2545 2406 2440 2082 2263 179 508

38

1. Rastogi P et al. J Clin Oncol 2024.00:17. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

25. Fewer Patients With Metastatic Disease
in the Abemaciclib Arm!

Additional Follow-Up 1 (ITT) OS 1A2 (ITT) OS 1A3 (ITT)

Data cif Apel Y, 2027

Patients, n

Abemaciclib + ET

Abemaciclib + ET ET Abemaciclib + ET ET

Imbalance of incurable metastatic recurrence continues to be substantial at OS 1A3

PeerView.com

1. Harbeck N. ESMO 2023. Abstract LBA17.

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

26. monarchE: Inferred 21-Gene
Oncotype Risk Scores!

21-Gene Oncotype Expression Signature

——
Abema + ET. ET alone

Avena + ET ET none
Score Inferred From RNAseq
EEE

enter 1800523) 77A(At0S) 182885(31) 698(66.1737) 0.70(056088) — e

tre

per MOD POZO) MES RATIO GO

ce

ret

Sean RE TOM HEN ME OMS e
ET Alone Abema + ET ‘score >25

00 05 10 15

Interaction P (inferred oncotype scores high and low) = .532

2 à + The selected biomarker subset is enriched for IDFS events using case-cohort design

(Observed high percentage of tumors with RS >25
risk score, reflective of high-risk patient population

4, Tuer Net al, SABCS 2025. Abstract GS 03.06,

PeerView.com/WUM827

+ IDFS rates are presented as indicative of relative prognosis across subtypes but do not
inform the actual risk of recurrence within each subtype because of IDFS enrichment

PeerView.com

Copyright © 2000-2024, Peerview

27. monarchE: Adjuvant ET + Abemaciclib
and ctDNA Dynamics!

ctDNA Positivity at 24 mo Following ET + Abemaciclib

ff,
seh ‘ors Tne me
os

1. Graf S el al SABCS 2023, Abstract PS06-01

PeerView.com/WUM827

‘rom ON», me

oe

PH

DNA
at0mo

DNA
at 24mo

M Poste
o, opa
X Recurrence
Recurrence
YON
aa
63 | 105
von
2] 0
28 | 108

PPV=70%
NPV=63%

PPV = 100%
NPV = 79%

Summary of Cohort ctDNA Positivity

ON at

1066) 10(100) 70) (70)
Remained
brs TE) 7100) 7100) 7(00)
Geared
an sun 30000) 00) 0m
Became CIONA+
Pere 35(197) 00) 3S(100) 35100)
Persistenty =

00 00) 26411)

ON.
{@t0 and 24 mo) 047
PeerView.com

Copyright © 2000-2024, PeerView

28. FDA and EMA Regulatory Approvals
of Adjuvant Abemaciclib

FDA Expanded Approval

+ Abemaciclib with ET (tamoxifen or an aromatase inhibitor) is indicated for adjuvant treatment
of adult patients with HR+, HER2-, node-positive EBC at high risk of recurrence

+ Patients defined as high risk include those having either 24 pathologic axillary lymph nodes
or 1-3 pathologic axillary lymph nodes and either tumor grade 3 or a tumor size 250 mm

+ Abemaciclib was previously approved for the above high-risk population with the additional requirement

of having a Ki-67 score 220%; the expanded approval removes the Ki-67 testing requirement

EMA Approval
+ Abemaciclib in combination with ET is indicated for the adjuvant treatment of patients
with HR+, HER2-, node-positive EBC at high risk of recurrence
+ High risk of recurrence in cohort 1 was defined by clinical and pathologic features: either 24 positive
axillary lymph nodes or 1-3 positive axillary lymph nodes, and at least one of the following criteria:
tumor size 25 cm or histological grade 3
+ In pre- or perimenopausal women, Al ET should be combined with a LHRH agonist

PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

29. NATALEE Study Design‘

‘Adult patients with HR+/HER2- EBC Ribociclib 400 mg/day Primary Endpoint:
+ Prior ET allowed up to 12 months weeks on/1 week off) for IDFS (STEEP criteria)
+ Anatomic stage IIA

— NO with grade 2 and evidence of high ri Key Secondary

(Ki-67 220%, oncotype DX breast recurrence score 226, = = RT Endpoints:
‘or high risk via genomic risk profiling) or grade 3 i een See RFS, distant DFS,

a years + goserelin in men and Catone
+ Anatomic stage IIB*: NO or N1 premenopausal women safety/tolerability,

+ Anatomic stage Ill: NO, N1, N2, or N3 and PK
Randomization stratification e Exploratory Endpoints:
Anatomic stage: II vs Ill locoregional RFS
Menopausal status: men and premenopausal women vs and gene expression
postmenopausal women > and alterations in tumor
Prior (neo)adjuvant chemo: yes vs no ctDNA/ctRNA samples

Geographic location: North America/Western
Europe/Oceania vs rest of world

Met its primary endpoint by demonstrating statistically significant and clinically meaningful IDFS benefit with ribociclib + NSAI vs NSAI
alone (HR = 0.748 [95% CI, 0.618-0.906]; P = .0014) in broad population of patients with stage I! or Ill HR+/HER2- EBC at risk of

recurrence, including those with node-negative disease
HR-Qol of patients with HR+/HER2- EBC was maintained with the addition of ribociclib to SOC adjuvant NSAI vs NSAI alone
in this study

*Envolment of paints wih stage Il disease capped at 40%. Open ebel design

8,101 patients randomized trom January 10,2019, to Ap 20,2021. * Per investigator choice. =
41 Slamon DJ etal ASCO 2023, Abstract LBASOO. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

30. NATALEE: Final IDFS*2

100
90 Ribo + NSAI
80 Median follow-up for IDFS was 33.3
70 months (maximum, 51 months), with
60 1 an additional 5.6 months from the
a ! second interim efficacy analysis
2
5 A Absolute IDFS benefit with ribociclib
wo | 0 2262.549(89) 2892,552 (11.1) + NSAI was 3.1% at 3 years
3-year IDFS rate, % 907 876
207 HR (95% cl) 0.749 (0.628-0.892) Risk of invasive disease was
10 4 Nominal 1-sided P 0006 reduced by 25.1% with ribociclib +
o NSAI vs NSAI alone
0 6 12 18 24 30 36 42 48 54
Time, mo
No at Risk

Rbo+NSA 2549 2350 2273 2204 2100 1604 1111 368 21
NSAlalone 2.552 2241 2169 2080 1975 1597 1067 354 26

1. Slamon DJ et al. ASCO 2023, Abstract LBASOO. 2. Hrtobagy G et al. SABCS 2023. Abstract 6503-03. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

31. NATALEE: IDFS by Nodal Status!

+ The risk of invasive disease was reduced by 27.7% for node-negative and by 24.1%
for node-positive disease with ribociclib plus NSAI versus NSAI alone

No

100 Ribo + NSAI
0
80 NSAI alone
7
"o Median follow-up: 38.7 mo
£ so Ribo + NSAI__NSAI Alone
© 40.7 Eventsin 207285 31328
304 (%) m (5)
20 À Sear IDFS rate, % 932 906
10 À HR (95% cl) 0.723 (0.412-1.268)
o

0 6 12 18 24 30 36 42 48 54

ER Time, mo

Rbo+NSN 285 262 258 250 244 235 177 67 5 0
NSA alone 328 300 204 287 276 258 18 80 5 0

1. Hortobagyi Get al. SABCS 2023. Abstract 6503-0,

PeerView.com/WUM827

N1-N3

Ribo + NSAI

NSAI alone”

ye 70

60 Median follow-up: 33.2 mo
¢
55 Ribo +NSAI _ NSAI Alone

Evenisin 2062261 25112219
o) (94) (113)

3-year IDFS rate, %. 90.3 874
HR (95% Cl) 0.759 (0.631-0.912)

0 6 12 18 24 30 36 42 48 54
Pres Time, mo

Rbo+NSAI 2261 2085 2012 1951 1853 1458 934 301 16 0
NSAlalone 2219 1938 1873 1791 1697 1397 877 273 21 0

PeerView.com

Copyright © 2000-2024, PeerView

32. NATALEE: OS!

Ribo + NSAI
80
70
g o Median follow-up for OS
E © was 35.9 months at the final analysis
g Ribo+NSAI NSAÏ Alone
40 OS data require longer-term follow-up,
20 | Fan CAMERA) MEAN as there were fewer than 4% of events
20 | 3-year OS rate, % 7 96.4 in both treatment arms
104 HR (95% cl) 0.892 (0.661-1.203)

0 6 12 18 2 30 36 42 48 54
Time, mo
No. at Risk

Rbo+NSAI 2549 2405 2537 2905 2250 1902 1259 455 2 0
INSAlalone 2552 2902 2256 2209 2158 1815 1207 444 31 0

1, Horobagi G etal. SABCS 2023. Abstract 6503.03. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

33. Returning to Our Case

Tina, a 57-year-old postmenopausal woman, who is a real
estate agent and travels frequently for work, presents to your

clinic with symptomatic mass in the right breast; further
assessment is undertaken followed by surgery, with the
following results:

Mammogram/US showed a 3-cm mass + enlarged,

suspicious axillary LN

Core biopsy: grade 3 ILC, ER 90%, PgR 25%, HER2

nonamplified by FISH

LN biopsy + carcinoma

PET CT staging and germline testing negative

Right mastectomy and axillary LN dissection performed:

2.3 cm, grade 3 UES 1/3 LN+

PeerView.com/WUM827

Let's discuss

V What treatment options would you
recommend to/discuss with her?

Y Would you offer adjuvant CDK4/6i
therapy—does the patient have high
enough risk? If so, what therapy and
why? Which ET would you use?

What if the patient had a grade 2 tumor?
What are the implications of biomarker
data from monarchE on outcomes and
benefit from CDK4/6i therapy?

Is there benefit from adjuvant CDK4/6i
purely in the biologically high-risk
patients?

Can adjuvant CDK4/6i replace chemo
in patients with an Oncotype RS of 27
or 30?

Copyright © 2004

34. Our Case Continues

Tina, a 57-year-old postmenopausal woman, who is a real estate agent and travels frequently for work,
comes to your clinic for a second opinion
+ Started on adjuvant abemaciclib 150 mg BID
+ Has experienced:
- Persistent and recurrent diarrhea after first 2 cycles
- Continuous low-grade fatigue
- Average absolute neutrophil count 1.8
Admits that she has taken two short breaks off abemaciclib therapy, continuing ET alone

Diarrhea and fatigue improved off therapy, but she is concerned about both continuing therapy because
of the AEs and implications on her work/personal life and discontinuing and how that could affect her
risk of recurrence and outcomes

Currently restarted abemaciclib + ET and experiencing grade 2 diarrhea
Dose has remained at 150 mg BID

PeerView.com/WUM827 Copyright

35. ADJUVANT COKA/61 in HR, HER?-, HIGH-RISKEBC | OUTLINE

Safeguarding Patients With HR+,
HER2-, High-Risk, Early Breast Cancer

A Practical Roadmap for CDK4/6 Inhibition in the Adjuvant Setting

1 2 3

Conducting risk Integrating the latest Mitigating AEs, improving

assessment in HR+, evidence to support adherence/persistence,

HER2- EBC to identify multifactorial clinical and maximizing treatment

patients at high risk of decisions about adjuvant benefits from CDK4/6

recurrence CDK4/6 inhibition inhibitors in high-risk HR+
HER2- EBC

PeerView.com/WUM827

36. Mitigating AEs, Improving
Adherence/Persistence,

PeerView.com/WUM827

Patrick Neven, MD, PhD

Professor

Department of Gynaecological Oncology
Multidisciplinary Breast Centre
University Hospitals

Leuven, Belgium

37. monarchE: Safety of Adjuvant Abemaciclib‘

Abemaciclib + ET, % ET Alone, %
(n = 2,791) (n= 2,800)
220% in either arm MG3+ mM G2 u GI G1 MH G2 m G3+

Diarrhea er lo Median duration of abemaciclib: 23.7 months
Fatigue Ie Other Events of Abemaciclib + ET, % ET Alone, %
Interest, Any Grade (n=2,791) (n=2,800)

Arthralgia | | 3% VIE 25 07
Neutropenia 46 Is PE 10 0.1
Leukopenia E io 33 13
‘Abdominal pain > Lo Aberaciól doen scfustants due do ABs
Nausea 30 lo + Dose reductions: 43.6%
eel + Discontinuations 18.5% (8.9% after dose reduction)

E VTE by first endocrine therapy?
Anemia + 17% with Al

+ 4.1% with tamoxifen

100 8 6 40 2 0 2 40 60 80 100

The safety profile of abemaciclib is considered manageable and acceptable for this high-risk population

"Al patents who received atleast one dose of study treatment wer included inthe safety population. a
1. Johnston S et al SABCS 2022. Abstract GS1-09, 2. Toi Met al. ESMO Breast Cancer 2022. Abstract 440.3. Rugo HS et al Ann Oncol 2022:33:616:27. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

38. monarchE: Long-Term Follow-Up
on Safety of Adjuvant Abemaciclib!

Abemaciclib + ET (n = 2,791) ET (n = 2,800)

Patients with 21 TEAE, n (%) 2,746 (98.4) 2,746(98.4) 2.488(88.9) 2,488 (88.9)
Patients with 21 grade 23 TEAE, n (%) 1,393 (49.9) 1,395 (60) 472 (16.9) 474 (16.9)
Patients with 21 SAE, n (%) 433 (15.5) 435 (15.6) 256 (9.1) 258 (9.2)

+ SAEs regardless of causality reported for patients in long-term follow-up are higher in ET alone arm (7.3%)
compared with abemaciclib plus ET (6.5%)

Consistent safety results from prior analyses, as all treated patients have completed treatment

4, Rastogi P et al. J Clin Oncol 2024 00:17. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

39. monarchE: Safety of Adjuvant
Abemaciclib in Older Patients!

+ Older patients often have a higher burden of comorbidities and may be at a higher risk for toxicities

+ In monarchE, AE rates were similar between different age groups, although dose reductions and treatment discontinuations
were higher in older patients

Clinically relevant AES
Gt 45 46 37
Diarrhea 62 31 31 30
63 8 7 12
G1 23 23 21
Fatigue G2 15 14 20
G3 3 2 6
G12 26 27 22
Neutropenia ES 20 20 19
G12 10 10 7
ALT increase u E 5 a
Any 3 2 3
VIE G23 a 1 4:
Any 3 3 3
LD G23 <a <a a

1. Rastogi Pet al. J Cin Oncol. 2024:00:1-7. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

40. NATALEE: Safety Profile
of Adjuvant Ribociclib 400 mg!

EGS Ribociclib + NSAI (n = 2,525) NSAI Alone (n
Any Grade Grade 23 Any Grade

Neutropenia? 625 443 46
Febrile neutropenia 03 03 0

Liver-related AEs” 26.4 86 12

QT interval prolongation® 53 10 14
ECG QT prolonged 43 03 0.7

ILD/pneumonitist 15 o 09

Other clinically relevant AEs, %
Arthralgia 37.3 10 433 13
Nausea 23.3 02 78 0
Headache 2.8 04 17.0 02
Fatigue 223 08 132 02
Diarrhea 14.5 06 55 04
VTE 15 06 0.8 04

+ NoAESIs or clinically relevant AEs increased >1% and only a 0.8% increase in discontinuations was observed

in this updated analysis.

+ _ The most frequent reason for ribociclib discontinuation was liver-related AEs
* Grouped term that combines neutropenia and neutrophil count decreased. ® Grouped term tha includes all prefered tems identified by standardized MedDRA queries for drug related hepatic
disorders. Grouped term. Grouped term that includes all preferred terms identified by standarcized MedDRA queries for ILD. * Grouped term that includes all preferred terms denied by
‘standardized MedDRA queries for VTE. ri
1. Hotobagy! G et al. SABCS 2023. Abstract GS03-03. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

41. Long-Term PROs From monarchE:
AE Burden’

FACT-B GP5 “I am bothered by side effects of treatment”

| — — — Over half of patients in both arms
reported treatment bother at
2 1 eS ee eye baseline
ë During treatment period majority
Ea ee of patients reported being
insta | bothered “Not at al” or A little bit
ET alone Bm | DY AEs within both study arms

-aueast | + Increase in proportion of patients
wen | reporting any bother in the
abemaciclib arm was 14% at

grue wo st me lu us Zen
? month 3, but gradually decreased
ES over the treatment period
2
Largest change in AE burden was
in the response of “A lite bit”
A EA

Month 0)

1. Tolaney SM et al. Eur Cancer, 2024:199:113556. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

42. Long-Term PROs From monarchE:
Focus on Diarrhea’

FACT-ES C5 “I have diarrhea”

1001 Bases ‘On-Study Treatment Post-Treatment Period:

= Not at ail

27 475 802 #48 860 ame
2 = Somewhat
go = Quite a bit
x = Very much

lll
\ PEPE .
= EA

Month 0

Most patients (58% to 69%) reported having “Not at ‘A litle bit" of diarrhea during the treatment per
+ When present, diarrhea was most often reported as “A little bit” or “Somewhat”, and the rates decreased after month 3

A. Tolaney SM ot al Eur Canco.2024:199:113555. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

43. Long-Term PROs From monarchE:
Focus on Fatigue’

FACIT-F An2 “I feel tired”

‘Abemaciclib +ET sere On Sy Temen

Poser Pod
+ 3 out of 4 patients reported

| a a a a |
Le tiredness at baseline
a own | =40% of patients reported
. Awe feeling “A little bit" tired at
° miss | baseline and through the
100, | Pees post-treatment period
zu Ez :
o = |

In the abemaciclib arm,
Moon — à 3

ES
B a a . E EE ea ae
at month 3 increased by 6%,
gradually reverting to
baseline thereafter
se A

+ While patient- and investigator-reported fatigue showed consistent patterns within and across treatment arms, a higher %
of patients reported fatigue vs investigator-reported fatigue — important to use a PRO instrument to assess fatigue in the

adjuvant setting

1. Rastogi P et al. J Cin Oncol 202400:1-7. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

44. monarchE: Treatment Discontinuations in the
Abemaciclib Arm Due to AEs‘ ETA =

‘AES leading to discontinuation

Diarrhea en
MDiarmea Fatigue 56 (2.0)
Fatigue Neutropenia 25 (0.9)
‘Abdominal pain 20 (0.7)
Nausea 11 (0.4)
Leukopenia 1104)
Blood creat 10 (0.4)

Vomiting 7(03)

= Depression 5(02)
a Gamma-glutamyl transferase increased 5 (0.2)
5 Rash 5(02)
3 ‘Anemia 404)
teak Dyspnea 3(0.1)
Dyspepsia 3(0.1)

Anxiety 3(0.1)

‘Composite terms
VTE 14 (0.5)
ID 19 (027)
Increased transaı 24
123 4 5 6 7 8 9 1011 12 13 14 15 16 17 18 19 20 21 22 23 24
Time, mo n
1. Rastogi P etal. J Cin Oncol. 2024:00:1-7. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

45. Abemaciclib: Dose Holds and Reductions‘

Abemaciclib + ET, n (%)
(n=2,791)

Patient with 21 dose hold and/or reduction 1,958 (70.2)

Patients with 21 dose hold 1,844 (66.1)

Reasons leading to dose hold*

AES 1,661 (59.5)
Diarrhea 530 (19.0)
Neutropenia 427 (15.3)
Leukopenia 193 (6.9)

Preplanned surgery 340 (12.2)

‘Scheduling conflict 101 (3.6)

Treatment availability 23 (0.8)

Patients with 21 dose reduction 1,193 (42.7)
Reasons leading to dose reduction*

AES 1,187 (42.5)
Diarrhea 474 (17.0)
Neutropenia 217 (7.8)

Fatigue 124 (4.4)
Patents may be counted in more than one dose hol or doe reduction in subcategon; values not adding up to the total number were due o missing or oer reasons.
1. Rogan MM et a, SABCS 2021. Abstract 652.05.

PeerView.com
PeerView.com/WUM827

Copyright © 2000-2024, PeerView

46. Dose Reductions Do Not Compromise the Efficacy
of Adjuvant Abemaciclib in High-Risk EBC?

IDFS According to RDI in Patients Treated With Abemaciclib in ITT Population

100
———
293% 66%-93%

75

*
g «
i=} Relative Dose
9 re 4-Year IDFS Rates in ITT, % (95% CI 4-Year IDFS Rates in Cohort 1, % (95% C1) | IDES rates were similar
28 | 0%-66% 87.4 (64807) 87.2 (84-898) DET
intensity subgroups
66%-93% 864 (63.6-88.7) 86.1 (83.3-88.5)
o| 2% 83.7 (60.7-86.3) 83.1 (79.9858)
[2 y = 7 a a a à ©
No. at Risk
— ms 1 so HS mm se 4 2 o
Zum mw m gi me 48 oz o
o E o
1. O'Shaughnessy Jet al. ESMO 2023. Poster 274P. 2. Gootz MP et al. NP Breast Cancer. 2024. PMID: 38671001. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

47. Recommended Abemaciclib Dose
Modifications for Adverse Reactions’ C9

Abemaciclib Dose for Combination

Dose Level With Fulvestrant, Tamoxifen, or an Al

Recommended starting dose 150 mg twice daily
First dose reduction 100 mg twice daily
Second dose reduction 50 mg twice daily
1: hpss/www.accessdata. da. gow/drugsatida_docs/tabel2021/2087 160068078008 pa. PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, Peerview

48. What Should the Schedule Be for Monitoring
Patients on Adjuvant Abemaciclib?

Months 1-2 on abemaciclib

Monitor every 2 wk ?
* CBC with differential
+ Electrolytes, LFTs, creatinine level

Months 2-4 on abemaciclib

Monitor every 1 mo Y
+ CBC with differential
+ Electrolytes, LFTs, creatinine level

Months 4+ on abemaciclib

Depends on the patient’s response to therapy and their characteristics (age, comorbidities)
+ If tolerating therapy well, extend monitoring interval to every 2 mo
PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

49. Strategies for Optimizing Adherence
and Persistence

+ Different methods available for measuring adherence: eg, oral therapy checklists, pill counts,
pharmacy and administrative records, medical record review and clinician reports, self or caregiver
reports, electronic medication monitoring systems (MEMS), web-based or mobile applications (apps)

+ Patient education, counseling, and shared decision-making (SDM) are essential

+ Adjuvant abemaciclib: to improve adherence and persistence, educate patients on:

— Features of their disease and risk of recurrence, potential AEs, implications of nonadherence

— Prophylactic measures that can be taken to be better prepared to address potential AEs
(eg, providing patients with a prescription for antidiarrheal medication and suggesting having that
always at hand should an episode of diarrhea occur)

— Possibility of treatment holds and dose modifications/reductions to manage AEs

PeerView.com

PeerView.com/WUM827 Copyright © 2000-2024, PeerView

50. New Tools for Monitoring and Managing
Adverse Events and Adherence/Persistence

montering nd tracking of AEs ond adherenclpersistence

PROS captured using web-based or
mob pps n abemacii cima ils

Copyright © 2000-2024, PeerView

51. Prophylaxis and Management of Diarrhea

Be proactive about patient education and communication

+ Ensure patients have an OTC antidiarrheal (eg, loperamide) on hand before starting therapy
+ Discuss recommended dietary changes

+ Communicate potential for dose modifications and the importance of staying on treatment

Implement strategies for diarrhea management to keep patients on treatment

At the first sign of loose stools, instruct patients to immediately start an antidiarrheal, increase fluids, and notify your office

Follow up after 24 hours: if diarthea has not resolved to < grade 1, suspend abemaciclib until resolution
If necessary, reduce the dose

+ Grade 1: no dose modification required
+ Grade 2: suspend abemaciclib if diarrhea does not improve to grade <1 within 24 h; no dose reduction required
Grade 2 (recurrent/persistent): suspend abemaciclib until toxicity resolves to grade $1; resume at next lower dose
Grade 3-4: suspend abemaciclib until toxicity resolves to grade <1; resume at next lower dose
PeerView.com

PeerView.com/WUM827

Copyright 4, PeerView

52. Returning to Our Case

Tina, a 57-year-old postmenopausal woman, who is a real estate
agent and travels frequently for work, presents to your clinic for a
second opinion:
+ Started on adjuvant abemaciclib 150 mg BID
+ Has experienced:
- Persistent and recurrent diarthea after first 2 cycles
- Continuous low-grade fatigue
- Average absolute neutrophil count 1.8
Admits that she has taken two short breaks off therapy,
continuing ET
Diarrhea and fatigue improved off therapy, but she is concerned
about both continuing therapy because of the AEs and implications
on her work/personal life AND discontinuing and how that could
affect her risk of recurrence and outcomes
Currently restarted abemaciclib + ET and experiencing
grade 2 diarrhea
Dose has remained at 150 mg BID

PeerView.com/WUM827

Let's discuss

What would you recommend to this
patient to manage her diarrhea?
Would you reduce the dose?

How would you manage the fatigue?

What strategies do you use to address
adherence/persistence and help patients
stay on therapy?

How to optimize QoL on abemaciclib
plus adjuvant endocrine therapy?

What if the patient develops DVT, liver
function abnormalities, serum creatinine
elevations, or other AEs?

Copyright © 2000-2024, PeerView

53. Audience Q&A

Copyright © 2000-2024, Peerview

54. Thank You

Copyright © 2000-2024, Peerview