Rising to the Challenges of Early and Advanced HR+ Breast Cancer: Examining Complex Evidence to Inform Clinical Decisions
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Jul 10, 2024
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About This Presentation
Chair and Presenter, Joyce O’Shaughnessy, MD, Javier Cortes, MD, PhD, and Cynthia X. Ma, MD, PhD, discuss breast cancer in this CME/MOC/NCPD/AAPA/IPCE activity titled “Rising to the Challenges of Early and Advanced HR+ Breast Cancer: Examining Complex Evidence to Inform Clinical Decisions.” Fo...
Slide Content
Rising to the Challenges of Early
and Advanced HR+ Breast Cancer
Examining Complex Evidence to Inform Clinical Decisions
Joyce O'Shaughnessy, MD
(BF Celebrating Women Chair in Breast Cancer Research
view Bayior University Medical Center
Texas Oncology
Sarah Cannon Research Institute
Dallas, Texas
Javier Cortes, MD, PhD Cynthia X. Ma, MD, PhD
Head Professor
International Breast Cancer Center (IBCC) Division of Oncology
Barcelona, Spain Department of Medicine
Washington University
St. Louis, Missouri
Ez Es Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, Peerview
and Advanced HR+ Breast Cancer
Examining Complex Evidence to Inform Clinical Decisions
Joyce O'Shaughnessy, MD
(BF Celebrating Women Chair in Breast Cancer Research
view Bayior University Medical Center
Texas Oncology
Sarah Cannon Research Institute
Dallas, Texas
Javier Cortes, MD, PhD Cynthia X. Ma, MD, PhD
Head Professor
International Breast Cancer Center (IBCC) Division of Oncology
Barcelona, Spain Department of Medicine
Washington University
St. Louis, Missouri
Ez Es Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.
Copyright © 2000-2024, Peerview
Our Goals for Today
Augment your knowledge and understanding of the key data
on current and emerging treatment options for patients with HR+,
HER2- EBC and MBC
Equip you with skills to conduct risk assessment and biomarker
testing, and individualize the treatment selection and sequencing in
HR+, HER2- EBC and MBC
Enhance best practices for team-based collaboration to optimize
treatment adherence/persistence and manage AEs associated with
latest therapies for HR+, HER2- EBC and MBC
Copyright © 2000-2024, PeerView
Augment your knowledge and understanding of the key data
on current and emerging treatment options for patients with HR+,
HER2- EBC and MBC
Equip you with skills to conduct risk assessment and biomarker
testing, and individualize the treatment selection and sequencing in
HR+, HER2- EBC and MBC
Enhance best practices for team-based collaboration to optimize
treatment adherence/persistence and manage AEs associated with
latest therapies for HR+, HER2- EBC and MBC
Copyright © 2000-2024, PeerView
We have partnered with GRASP and LBBC in this program
%
LIVING BEYOND
BREAST CANCER’
Please review and download the supplemental resource compendium,
which includes information and educational materials for your patients to
help them become better informed and engaged participants in their care
Copyright © 2000-2024, PeerView
%
LIVING BEYOND
BREAST CANCER’
Please review and download the supplemental resource compendium,
which includes information and educational materials for your patients to
help them become better informed and engaged participants in their care
Copyright © 2000-2024, PeerView
RISING TO THE CHALLENGE OF EARLY AND ADVANCED HR+ BREAST CANCER | OUTLINE
PART 1
PART 2
Candid Conversations & Clinical Consults
HR+, HER2- EBC: Stratifying Risk and
Reducing the Risk of Recurrence With
Adjuvant CDK4/6 Inhibition
Candid Conversations & Clinical Consults
HR+, HER2- MBC: Interpreting the Latest
Evidence and Individualizing Treatment
Selection/Sequencing
Copyright © 200%
PART 1
PART 2
Candid Conversations & Clinical Consults
HR+, HER2- EBC: Stratifying Risk and
Reducing the Risk of Recurrence With
Adjuvant CDK4/6 Inhibition
Candid Conversations & Clinical Consults
HR+, HER2- MBC: Interpreting the Latest
Evidence and Individualizing Treatment
Selection/Sequencing
Copyright © 200%
Let’s Start With a Case
PRE
A 59-year-old postmenopausal woman who is a violinist in an orchestra presents with a mass
in the right breast discovered on routine mammogram; further assessment is undertaken
followed by surgery, with the following results:
Mammogram/US showed a 2.8-cm mass + enlarged, suspicious axillary LN
Core biopsy: grade 3 IDC, ER 90%, PgR 25%, HER2-
LN biopsy + carcinoma
PET CT staging and germline testing negative
Right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3 ILC, 2/3 LN+
PeerView.com/BEX827 Copyright © 2000
PRE
A 59-year-old postmenopausal woman who is a violinist in an orchestra presents with a mass
in the right breast discovered on routine mammogram; further assessment is undertaken
followed by surgery, with the following results:
Mammogram/US showed a 2.8-cm mass + enlarged, suspicious axillary LN
Core biopsy: grade 3 IDC, ER 90%, PgR 25%, HER2-
LN biopsy + carcinoma
PET CT staging and germline testing negative
Right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3 ILC, 2/3 LN+
PeerView.com/BEX827 Copyright © 2000
State of the Science: Assessing Risk
and Integrating Adjuvant CDK4/6
Inhibitor Therapy in HR+, HER2- EBC
Javier Cortes, MD, PhD
Head z
International Breast Cancer Center (IBCC)
Barcelona, Spain E
and Integrating Adjuvant CDK4/6
Inhibitor Therapy in HR+, HER2- EBC
Javier Cortes, MD, PhD
Head z
International Breast Cancer Center (IBCC)
Barcelona, Spain E
What to Consider
in Risk Assessment
in Risk Assessment
os
04
03
02
01
Recurrence Hazard Rate (95% Cl)
pose Ls
1. Colioni M et al. J Cin Oncol. 2016.34:927:935. 2. O'Shaughnessy J et al. SABCS 2022. Oral presentation.
Risk of Recurrence With Early Breast Cancer:
IBCSG Trials | to V'?
Annual Hazard of BC Recurrence for ER+ BC
—+ 24 positive nodes
—— 1-3 positive nodes
=> 0 positive nodes
0 2 4 6 6 0 1 % 16 18 20 2 A
Time, y
M M SE
PeerView.com/BEX827
Invasive Disease-Free Survival of Stage WII
Breast Cancer Patients: RWE US Database 1995-2021
IDFS in Patients With Stage II and Stage III Disease
10
IDFS, Proportion
Stage lll
0 2% 60 75 100 125 180 175 200 225 250 275
cine ie ro
‘Stage m (490) (Gas) (87) (1,179) (1347) (1,484) (1,582) (1,855) (1,707) (1,729) (1,735)
comm 90 0 Sei) Sige” ae CA a V8 NG a
® dan um an am am am am am am am
PeerView.com
Copyright © 2000-2024, PeerView
04
03
02
01
Recurrence Hazard Rate (95% Cl)
pose Ls
1. Colioni M et al. J Cin Oncol. 2016.34:927:935. 2. O'Shaughnessy J et al. SABCS 2022. Oral presentation.
Risk of Recurrence With Early Breast Cancer:
IBCSG Trials | to V'?
Annual Hazard of BC Recurrence for ER+ BC
—+ 24 positive nodes
—— 1-3 positive nodes
=> 0 positive nodes
0 2 4 6 6 0 1 % 16 18 20 2 A
Time, y
M M SE
PeerView.com/BEX827
Invasive Disease-Free Survival of Stage WII
Breast Cancer Patients: RWE US Database 1995-2021
IDFS in Patients With Stage II and Stage III Disease
10
IDFS, Proportion
Stage lll
0 2% 60 75 100 125 180 175 200 225 250 275
cine ie ro
‘Stage m (490) (Gas) (87) (1,179) (1347) (1,484) (1,582) (1,855) (1,707) (1,729) (1,735)
comm 90 0 Sei) Sige” ae CA a V8 NG a
® dan um an am am am am am am am
PeerView.com
Copyright © 2000-2024, PeerView
ET Resistance Increases Risk of Recurrence
n NSABP B-14 Adjuvant Tamoxifen Trial
Proliferation Module vs RS!
‘Spearman's p = 0.36
ER+ Node-Negative EBC: 10-Year Distant
3 H Recurrence Rate by RS Group?
7
A x
ge A 6.8%
8
gs 3 14.3%
2 + E 30.5%
TITS 60] NSABP B-14: tamoxifen x 5 y Hd
Estrogen Module ys RS" A
‘Spearman's p = 079 $
2 oO 40
3 E Multivariate Cox Model
¿o a RS prognostic independent of age and tumor size
5 20] — Low risk (RS <18) 338 patients (51%)
Boe 5 termediate risk (RS 18-30) 149 patients (22%)
ë 3 — High risk (RS >30) 181 patients (27%)
2 0 T T T T T
= AE ie
= Time, y
4, Buus Ret al J Gin Oncol. 2021;30:126-135. 2. Pak Set al N Engl J Med, 2004/351:2817.2826, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
n NSABP B-14 Adjuvant Tamoxifen Trial
Proliferation Module vs RS!
‘Spearman's p = 0.36
ER+ Node-Negative EBC: 10-Year Distant
3 H Recurrence Rate by RS Group?
7
A x
ge A 6.8%
8
gs 3 14.3%
2 + E 30.5%
TITS 60] NSABP B-14: tamoxifen x 5 y Hd
Estrogen Module ys RS" A
‘Spearman's p = 079 $
2 oO 40
3 E Multivariate Cox Model
¿o a RS prognostic independent of age and tumor size
5 20] — Low risk (RS <18) 338 patients (51%)
Boe 5 termediate risk (RS 18-30) 149 patients (22%)
ë 3 — High risk (RS >30) 181 patients (27%)
2 0 T T T T T
= AE ie
= Time, y
4, Buus Ret al J Gin Oncol. 2021;30:126-135. 2. Pak Set al N Engl J Med, 2004/351:2817.2826, PeerView.com
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Which HR+, HER2- EBC Patients Benefit
From Chemotherapy?!
o 70-gene
signature
0-10 11-25 >25 | 040 | 1125 | >25
Clinical high risk +
genomic low risk
P 1145 16-20 21-25 0-3+ nodes
Las ET Er Postmenopausal ET
ET | low Premenopausal CET
risk
0-10 11-25 >25 | 0-10 | 1125 | >25 <20% premen HR+ pts
eee TAILORx, RxPonder
a a = = and MINDACT had
LHRH agonist
R+ and HER2s: endocrine therapy only and ER- HER2+ and TN no chemoRx
insider chemoRx (+ trastuzumab and ET as appropriate)
1. Provided courtesy of Pro: Peter Schmidt, FRCP, MO, PhO. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
From Chemotherapy?!
o 70-gene
signature
0-10 11-25 >25 | 040 | 1125 | >25
Clinical high risk +
genomic low risk
P 1145 16-20 21-25 0-3+ nodes
Las ET Er Postmenopausal ET
ET | low Premenopausal CET
risk
0-10 11-25 >25 | 0-10 | 1125 | >25 <20% premen HR+ pts
eee TAILORx, RxPonder
a a = = and MINDACT had
LHRH agonist
R+ and HER2s: endocrine therapy only and ER- HER2+ and TN no chemoRx
insider chemoRx (+ trastuzumab and ET as appropriate)
1. Provided courtesy of Pro: Peter Schmidt, FRCP, MO, PhO. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
BR009: Schema!
Ovarian function suppression + aromatase inhibitor®
X5 rs
+ Premenopausal; HR+/HER2- BC say
+ pNO with RS 16-20 (high clinical e ¡Siraificalon
N=3,960 + Nodal Status (pNO vs. pN1)
risk) or RS 21-25 + RS (0-15 vs. 16-25)
+ pN1 with RS 0-25
Ovarian function suppression + aromatase inhibitor®
hemotherapy
* Tamouten can be used if Al not tolerated 2
1. ps lasse cnicalras gov/e@showNCTOS879026, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Ovarian function suppression + aromatase inhibitor®
X5 rs
+ Premenopausal; HR+/HER2- BC say
+ pNO with RS 16-20 (high clinical e ¡Siraificalon
N=3,960 + Nodal Status (pNO vs. pN1)
risk) or RS 21-25 + RS (0-15 vs. 16-25)
+ pN1 with RS 0-25
Ovarian function suppression + aromatase inhibitor®
hemotherapy
* Tamouten can be used if Al not tolerated 2
1. ps lasse cnicalras gov/e@showNCTOS879026, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
ADAPT Trial: ER+, HER2-
Pre- and Postmenopausal EBC"
Presentation Surgery
+. Fatty tissue
a, ,
Chemotherapy
n2
NB
RS 12-25, Ki-67 >10%
> ) 3 weeks
2 esten BS 125 KIET OR
Experimental arm
Biopsy or
excision biopsy
4. Kuemmel Set al. SABCS 2020. Abstract 654-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Pre- and Postmenopausal EBC"
Presentation Surgery
+. Fatty tissue
a, ,
Chemotherapy
n2
NB
RS 12-25, Ki-67 >10%
> ) 3 weeks
2 esten BS 125 KIET OR
Experimental arm
Biopsy or
excision biopsy
4. Kuemmel Set al. SABCS 2020. Abstract 654-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Ki67 510%
100
Prognostic Effect of ET Response (4-wk Lead-In)
on IDFS in ADAPT1 (Median Follow-Up: 60 mo)?
Kar 510%
Hey (eT 158%)
——
075 À All patients Ki67 >10% 075 on
oso | Unadiusted: HR 0.59 (0.47.0.75); P < 001 On (CTA 905%)
Ss Adjusted: HR 0.73 (0.56-0.94); P= 017 E
540 y (premenopausal)
Unadjusted: HR 0.59 (0.27-1.30); P= 191
Adjusted: HR 0.63 (0.24-1.65), P= 346
o
° = 2 38 ny y o = 2 20 “ so
Time, mo Time, mo
o. Hoot Risk
ers 4300116 seo ur 763 550 Pr) w m 108 » “e
Ka 2 IR = was m “ ES ES “ ES
100 Ki67 s10% 100
TES) ET
a 167 10% ors | 7% 139%) pere
de cms) 2 CCE
Kos Sos
= 41-50 y (premenopausal) >50 y (postmenopausal)
0.254 Unadjusted: HR 0.51 (0.31-0.84); P=.009 025 | Unadjusted: HR 0.63 (0.46-0.87); P= 005
9 |_Adiusted: HR 063 (037-110) P= 105 9 |_Adiusted: HR 0.78 (0.54-1.12), P= 174
o 2 2 36 y © o 32 2 ES “ o
Time, mo Time, mo
No. ok No. ot sk
Rae Se ss sn zu 1 ao 2 ses se ss ss 5
Karson 8 EJ E] Su Es] ee A a A]
1. Ntz A etal. Gin Oncal.2022:402587-2567. 2 Glitz O et al. ESMO 2022. Abstract LBA PeerView.com
PeerView.com/BEX827
Copyright © 2000-2024, Peerview
100
Prognostic Effect of ET Response (4-wk Lead-In)
on IDFS in ADAPT1 (Median Follow-Up: 60 mo)?
Kar 510%
Hey (eT 158%)
——
075 À All patients Ki67 >10% 075 on
oso | Unadiusted: HR 0.59 (0.47.0.75); P < 001 On (CTA 905%)
Ss Adjusted: HR 0.73 (0.56-0.94); P= 017 E
540 y (premenopausal)
Unadjusted: HR 0.59 (0.27-1.30); P= 191
Adjusted: HR 0.63 (0.24-1.65), P= 346
o
° = 2 38 ny y o = 2 20 “ so
Time, mo Time, mo
o. Hoot Risk
ers 4300116 seo ur 763 550 Pr) w m 108 » “e
Ka 2 IR = was m “ ES ES “ ES
100 Ki67 s10% 100
TES) ET
a 167 10% ors | 7% 139%) pere
de cms) 2 CCE
Kos Sos
= 41-50 y (premenopausal) >50 y (postmenopausal)
0.254 Unadjusted: HR 0.51 (0.31-0.84); P=.009 025 | Unadjusted: HR 0.63 (0.46-0.87); P= 005
9 |_Adiusted: HR 063 (037-110) P= 105 9 |_Adiusted: HR 0.78 (0.54-1.12), P= 174
o 2 2 36 y © o 32 2 ES “ o
Time, mo Time, mo
No. ok No. ot sk
Rae Se ss sn zu 1 ao 2 ses se ss ss 5
Karson 8 EJ E] Su Es] ee A a A]
1. Ntz A etal. Gin Oncal.2022:402587-2567. 2 Glitz O et al. ESMO 2022. Abstract LBA PeerView.com
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How to Interpret the Latest Evidence
on Adjuvant CDK4/6 Inhibition
on Adjuvant CDK4/6 Inhibition
monarchE Study Design‘?
Cohort 4 (91%)
High risk based on
clinical pathological features On-study treatment period
2years
+24 ALN or 1-3 ALN and at least
1 ofthe following
- Grade 3 disease Abemaciclib
- Tumor size 25 om (150 mg twice daily
+ endocrine therapy
Follow-up period
Endoorine therapy
3-8 years as
cinically indicated
HR+/HER2.,
node-positive, ‚Stratifed for prior chemo,
highsisk EBC ‘menopausal status, and region
ITT® includes both
‘cohort 1 and cohort 2
Cohort 2 (9%) Endocrine therapy
High risk based on Ki-67
+ 1-3 ALN and Ki-67 220%
and grade <3 and tumor size
Sem
+ Primary objective: IDFS
+ Secondary objectives: IDFS in high Ki-67 populations, DRFS, OS,
safety, PK, and PROS
|" Recruitment from July 2017 to August 2019. ® Endocrine therapy of physician's choice (eg, aromatase inhibitors, tamosifen, LHRH agonist). 7
1. Harbeck N. ESMO 2023, Abstract LBA17. 2. Rastogi et al y Cin Oncol 2024:42987.903. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
Cohort 4 (91%)
High risk based on
clinical pathological features On-study treatment period
2years
+24 ALN or 1-3 ALN and at least
1 ofthe following
- Grade 3 disease Abemaciclib
- Tumor size 25 om (150 mg twice daily
+ endocrine therapy
Follow-up period
Endoorine therapy
3-8 years as
cinically indicated
HR+/HER2.,
node-positive, ‚Stratifed for prior chemo,
highsisk EBC ‘menopausal status, and region
ITT® includes both
‘cohort 1 and cohort 2
Cohort 2 (9%) Endocrine therapy
High risk based on Ki-67
+ 1-3 ALN and Ki-67 220%
and grade <3 and tumor size
Sem
+ Primary objective: IDFS
+ Secondary objectives: IDFS in high Ki-67 populations, DRFS, OS,
safety, PK, and PROS
|" Recruitment from July 2017 to August 2019. ® Endocrine therapy of physician's choice (eg, aromatase inhibitors, tamosifen, LHRH agonist). 7
1. Harbeck N. ESMO 2023, Abstract LBA17. 2. Rastogi et al y Cin Oncol 2024:42987.903. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
monarchE 5-Year Update:
Sustained IDFS Benefit in ITT‘
927 (0=28)
100
£92 (4 =48) 96.0(a=60)
836 (a=70)
Abemaci + ET
Cy
® o ET Alone
Eo IDFS events, n 407 585
” HR = 0.680 (95% Cl, 0.599-0.772); nominal P < .001
a
10] 2,yoar abemeciolo + 32% reduction in the risk of developing
QT an IDFS event
0 8 2 8 À 0 % 2 4% À
PAS PI RSS + KM curves continue to separate; absolute
No. at Risk > difference in the IDFS rates between arms
Abemacielb +ET 2808 2621 2549 2479 2408 2,347 2264 2220 2005 1.175 was ze ats years)
ETolone 2820 2653 2573 2474 2374 2281 2,195 2,125 1974 1,124
Data cutftJuy 3, 2023,
1. Rastogi etal. J Cin Oncol2024:42:987-003,
PeerView.com
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Sustained IDFS Benefit in ITT‘
927 (0=28)
100
£92 (4 =48) 96.0(a=60)
836 (a=70)
Abemaci + ET
Cy
® o ET Alone
Eo IDFS events, n 407 585
” HR = 0.680 (95% Cl, 0.599-0.772); nominal P < .001
a
10] 2,yoar abemeciolo + 32% reduction in the risk of developing
QT an IDFS event
0 8 2 8 À 0 % 2 4% À
PAS PI RSS + KM curves continue to separate; absolute
No. at Risk > difference in the IDFS rates between arms
Abemacielb +ET 2808 2621 2549 2479 2408 2,347 2264 2220 2005 1.175 was ze ats years)
ETolone 2820 2653 2573 2474 2374 2281 2,195 2,125 1974 1,124
Data cutftJuy 3, 2023,
1. Rastogi etal. J Cin Oncol2024:42:987-003,
PeerView.com
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monarchE 5-Year Update:
Observed i
Consistent IDFS Bene Subgroups'
i STOW OTE tens STE al ld
PEA PAGAN oma
TT IT) IS SM REA
vum magie Una wemenn oem 05750175
Sue o om man Separa
yours Osa mans Trasse a
save wımımn mar wımon ar oaranı
a Mie Ve Her pesima
¡pum amino 10e roman coe 050.0770
Vetoes ales Mudo Biei cesses
zu sanasson2, zum 94707209) asomar
e Samos “awe “Teaser e
2405007 0049) 220400 991704817 ost osmorsn
‘Sine’ Gromer) um mie EE)
me ems m1 3083849 osıromsoom
nz non tao MINS Sn oo
ane dou Yin MAT DEC
sue m20000 14010 mins gra etes
ion mambo Ya MIEDO su Dear
nor Matos ‘wars memes) on
zo mm zus 995009009 oom ours: 170
sarin VOST re named EE)
au serian ando mananz Some
Re MU su.
di Mein He ITR sen
mem mimsun mom sam green
ale DESSUS) Jam Tie ty an
wm TEO wow mouse ss omsareı
an BASS taro MOST DE
1. Rastogi Pet al. J Clin Oncol 2024:42987-993. PeerView.com
PeerView.com/BEX827
Copyright © 2000-2024, PeerView
Observed i
Consistent IDFS Bene Subgroups'
i STOW OTE tens STE al ld
PEA PAGAN oma
TT IT) IS SM REA
vum magie Una wemenn oem 05750175
Sue o om man Separa
yours Osa mans Trasse a
save wımımn mar wımon ar oaranı
a Mie Ve Her pesima
¡pum amino 10e roman coe 050.0770
Vetoes ales Mudo Biei cesses
zu sanasson2, zum 94707209) asomar
e Samos “awe “Teaser e
2405007 0049) 220400 991704817 ost osmorsn
‘Sine’ Gromer) um mie EE)
me ems m1 3083849 osıromsoom
nz non tao MINS Sn oo
ane dou Yin MAT DEC
sue m20000 14010 mins gra etes
ion mambo Ya MIEDO su Dear
nor Matos ‘wars memes) on
zo mm zus 995009009 oom ours: 170
sarin VOST re named EE)
au serian ando mananz Some
Re MU su.
di Mein He ITR sen
mem mimsun mom sam green
ale DESSUS) Jam Tie ty an
wm TEO wow mouse ss omsareı
an BASS taro MOST DE
1. Rastogi Pet al. J Clin Oncol 2024:42987-993. PeerView.com
PeerView.com/BEX827
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monarchE 5-Year Update:
Sustained DRFS Benefit in ITT!
100 940(0=25)
$09(0=41) 004(8=52) 580
n
Abemacicib + ET
ET alone
DRFS, %
8
HR = 0,675 (95% Cl, 0.588-0.774)
‘Nominal P < 001
+ 32.5% reduction in the risk
of developing a DRFS event
+ KM curves continue to separate and
r 0 7 absolute difference in DRFS rates
No. at Risk Time, mo between arms was 6.7% at 5 years
‘Avemacicld + ET 2800 2690 2507 2500 2494 2375 2319 2259 2141 1202 500 75 0
J
0 6 2 1 2 % % 42 4 ©
ET alene 2829 2660 2590 2499 2410 2327 2243 2178 2032 1,161 488 72 0
1. Rastogi Pet al. Ci Oncol 2024 42:987-003, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
Sustained DRFS Benefit in ITT!
100 940(0=25)
$09(0=41) 004(8=52) 580
n
Abemacicib + ET
ET alone
DRFS, %
8
HR = 0,675 (95% Cl, 0.588-0.774)
‘Nominal P < 001
+ 32.5% reduction in the risk
of developing a DRFS event
+ KM curves continue to separate and
r 0 7 absolute difference in DRFS rates
No. at Risk Time, mo between arms was 6.7% at 5 years
‘Avemacicld + ET 2800 2690 2507 2500 2494 2375 2319 2259 2141 1202 500 75 0
J
0 6 2 1 2 % % 42 4 ©
ET alene 2829 2660 2590 2499 2410 2327 2243 2178 2032 1,161 488 72 0
1. Rastogi Pet al. Ci Oncol 2024 42:987-003, PeerView.com
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monarchE 5-Year Update: OS in ITT’
100
90 i} ET alone
80 1 Abemaciclib + ET
70 H
= 6 i Abemaciclib + ET ET Alone
ge © H (n=208) (n=234)
Cu |
A HR = 0.903 (95% Cl, 0.749-1.088)
30 H Nominal P< 284
20 i
10 4 2ear abemacicib, H
o Hamm > — i
0 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
No. at Risk
Abemaciib + ET 2908 2666 2614 2568 2518 2485 2407 2373 2260 1271 528 80 0
ET sens 2829 2705 2064 2500 2545 2408 2440 2382 2243 1279 538 77 0
1. Raslog P tal. J Cin Oncol 2024:42997-999, PeerView.com
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100
90 i} ET alone
80 1 Abemaciclib + ET
70 H
= 6 i Abemaciclib + ET ET Alone
ge © H (n=208) (n=234)
Cu |
A HR = 0.903 (95% Cl, 0.749-1.088)
30 H Nominal P< 284
20 i
10 4 2ear abemacicib, H
o Hamm > — i
0 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
No. at Risk
Abemaciib + ET 2908 2666 2614 2568 2518 2485 2407 2373 2260 1271 528 80 0
ET sens 2829 2705 2064 2500 2545 2408 2440 2382 2243 1279 538 77 0
1. Raslog P tal. J Cin Oncol 2024:42997-999, PeerView.com
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Fewer Patients With Metastatic Disease
the Abemaciclib Arm!
Additional Follow-Up 1 (ITT) OS 1A2 (ITT) OS IAS (ITT)
Data cut: Apel 1,2021
Survol Status
Hi Ave with metastatic disease
A Dent due ©
M Deaths not related to BC
Patients, n
Abemaciclib + ET
Abemaciclib + ET Abemaciclib + ET ET
Imbalance of incurable metastatic recurrence continues to be substantial at OS IA3
PeerView.com
1. Harbeck N. ESMO 2023. Abstract LBAIT.
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the Abemaciclib Arm!
Additional Follow-Up 1 (ITT) OS 1A2 (ITT) OS IAS (ITT)
Data cut: Apel 1,2021
Survol Status
Hi Ave with metastatic disease
A Dent due ©
M Deaths not related to BC
Patients, n
Abemaciclib + ET
Abemaciclib + ET Abemaciclib + ET ET
Imbalance of incurable metastatic recurrence continues to be substantial at OS IA3
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1. Harbeck N. ESMO 2023. Abstract LBAIT.
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monarchE: Inferred 21-Gene Oncotype Risk Scores!
21-Gene Oncotype Expression Signature er pro Pe Trans
Score Inferred From RNAseq
Events DESTE events (yy DES Rate 5 cn
[con } pS 138/605(23) 774(741-809) 182585(31) 69.8 (66.1-73.7) 0.70(0.56-0.88) —
subset
Inferes
oncotypeRNA ATS) 902(858949) 2865(17) 242787901) 050(033.110)
sore 25
ca Interes
ONCONPeRNA — 120M32(28) — 723(68.1768) MEET) 64.1(696-600) OTMOSTO9) e
ET Alone Abema + ET sere 25,
001 050 100 130
Interaction P (inferred oncotype scores high and low) = .532
+ The selected biomarker subset is enriched for IDFS events using case-cohort design
+ 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
(Observed high percentage of tumors with RS >25
risk score, reflective of high-risk patient population
41. Tumer N etal. SABCS 2023, Abstract GS 03-08. PeerView.com
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21-Gene Oncotype Expression Signature er pro Pe Trans
Score Inferred From RNAseq
Events DESTE events (yy DES Rate 5 cn
[con } pS 138/605(23) 774(741-809) 182585(31) 69.8 (66.1-73.7) 0.70(0.56-0.88) —
subset
Inferes
oncotypeRNA ATS) 902(858949) 2865(17) 242787901) 050(033.110)
sore 25
ca Interes
ONCONPeRNA — 120M32(28) — 723(68.1768) MEET) 64.1(696-600) OTMOSTO9) e
ET Alone Abema + ET sere 25,
001 050 100 130
Interaction P (inferred oncotype scores high and low) = .532
+ The selected biomarker subset is enriched for IDFS events using case-cohort design
+ 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
(Observed high percentage of tumors with RS >25
risk score, reflective of high-risk patient population
41. Tumer N etal. SABCS 2023, Abstract GS 03-08. PeerView.com
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Consistent Abemaciclib Treatment Benefit Across
All Intrinsic Molecular Subtypes'
Abemaciclib + ET ET Alone Abema+ET ET Alone
Eventsin (%) — 4-Y IDFS Rate (95% CI) Eventsin(%) — 4-Y IDFS Rate (95% CI) HR (95% CI)
oT 407/2,808 (14) 86 (84.7-87.3) 585/2,829 (21) 80 (78.5-81.6) 0.68 (0.60-0.77) -
een 1381605 (23) 77.4 (74.1-80.9) 182/585 (31) 69.8 (66.1-73.7) 0.70 (0.56-0.88)
Luma 28/230 (12) 87.5 (83.2:92.0) 451228 (20) 814(763-868) 0.59(0.37-0.95)
Lume, 65/265 (25) 76.3 (71.2-81.7) 881262 (34) 66.6 (61.1-72.7) 0.70 (0.51-0.97)
HER2E 32/69 (46) 52.6 (41.8-66.2) 34/59 (58) 425(814575) 0.74 (0.46-1.20)
Basal 9721 (43) 57.1(39.5-82.8) 8/15 (63) 467 (27.2802) 0.75(029-190)
Interaction P (all subtypes) = 0.621 a age
+ The selected biomarker subset is enriched for IDFS events using case-cohort design
+ 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 event enrichment
1. TumerN et al SABCS 2023, Abstract 6502-06, PeerView.com
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All Intrinsic Molecular Subtypes'
Abemaciclib + ET ET Alone Abema+ET ET Alone
Eventsin (%) — 4-Y IDFS Rate (95% CI) Eventsin(%) — 4-Y IDFS Rate (95% CI) HR (95% CI)
oT 407/2,808 (14) 86 (84.7-87.3) 585/2,829 (21) 80 (78.5-81.6) 0.68 (0.60-0.77) -
een 1381605 (23) 77.4 (74.1-80.9) 182/585 (31) 69.8 (66.1-73.7) 0.70 (0.56-0.88)
Luma 28/230 (12) 87.5 (83.2:92.0) 451228 (20) 814(763-868) 0.59(0.37-0.95)
Lume, 65/265 (25) 76.3 (71.2-81.7) 881262 (34) 66.6 (61.1-72.7) 0.70 (0.51-0.97)
HER2E 32/69 (46) 52.6 (41.8-66.2) 34/59 (58) 425(814575) 0.74 (0.46-1.20)
Basal 9721 (43) 57.1(39.5-82.8) 8/15 (63) 467 (27.2802) 0.75(029-190)
Interaction P (all subtypes) = 0.621 a age
+ The selected biomarker subset is enriched for IDFS events using case-cohort design
+ 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 event enrichment
1. TumerN et al SABCS 2023, Abstract 6502-06, PeerView.com
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monarchE: Prognostic Utility of ctDNA Detection}
+ This is the largest study evaluating ctDNA in the adjuvant setting in high-risk HR+, HER2- EBC
+ Despite enrolling a high-risk population to monarchE and confining biomarker analysis to a patient
subset enriched for IDFS events, ctDNA detection was relatively infrequent (<10% at baseline;
17% at any time)
+ ctDNA detection was highly prognostic of worse outcomes, particularly for patients who were
persistently positive
— Further intensification of treatment with novel therapeutics should be evaluated for these patients
— Itis notable that patients who were ctDNA- tended to develop local/regional/contralateral forms of
recurrence whereas those who were ctDNA+ had more distant recurrences
+ Lead time from first ctDNA detection to IDFS event was relatively short
+ Although recurrence rate was high among patients who were ctDNA+ at baseline, =40% became
ctDNA- (undetected) on monarchE (ET +/- abemaciclib), and outcomes appeared more favorable
in this subgroup
1. LoiS et al ASCO 2024. Abstract LBASO7. PeerView.com
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+ This is the largest study evaluating ctDNA in the adjuvant setting in high-risk HR+, HER2- EBC
+ Despite enrolling a high-risk population to monarchE and confining biomarker analysis to a patient
subset enriched for IDFS events, ctDNA detection was relatively infrequent (<10% at baseline;
17% at any time)
+ ctDNA detection was highly prognostic of worse outcomes, particularly for patients who were
persistently positive
— Further intensification of treatment with novel therapeutics should be evaluated for these patients
— Itis notable that patients who were ctDNA- tended to develop local/regional/contralateral forms of
recurrence whereas those who were ctDNA+ had more distant recurrences
+ Lead time from first ctDNA detection to IDFS event was relatively short
+ Although recurrence rate was high among patients who were ctDNA+ at baseline, =40% became
ctDNA- (undetected) on monarchE (ET +/- abemaciclib), and outcomes appeared more favorable
in this subgroup
1. LoiS et al ASCO 2024. Abstract LBASO7. PeerView.com
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monarchE: Treatment Discontinuations
in the Abemaciclib Arm Due to AEs!
Abemaciclib + ET (N
‘AES leading to discontinuation
Diarrhea 147 (53)
are Fatigue 56 (2.0)
30 Hi Neutropenia Newtiopenia 25 (09)
other ‘Abdominal pain 20(0.7)
Nausea 1104)
25 Leukopenia 11 (0.4)
Blood creatinine increased 10 (0.4)
20 Vomiting 703)
= Depression 502)
E 'Gamma-glutamy!transferase increased 5(0.2)
315 Rash 5(0.2)
& Anemia 401)
10 Dyspnea 3(0.1)
Dyspepsia 30.1)
a5 Anxiety 301)
Composite terms
VIE 14/05)
o ILD 19
123 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Increased transaminases 24 (09
Time, mo
1, Rugo HS et a. Ann Oncol 2022:3:616-627 PeerView.com
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in the Abemaciclib Arm Due to AEs!
Abemaciclib + ET (N
‘AES leading to discontinuation
Diarrhea 147 (53)
are Fatigue 56 (2.0)
30 Hi Neutropenia Newtiopenia 25 (09)
other ‘Abdominal pain 20(0.7)
Nausea 1104)
25 Leukopenia 11 (0.4)
Blood creatinine increased 10 (0.4)
20 Vomiting 703)
= Depression 502)
E 'Gamma-glutamy!transferase increased 5(0.2)
315 Rash 5(0.2)
& Anemia 401)
10 Dyspnea 3(0.1)
Dyspepsia 30.1)
a5 Anxiety 301)
Composite terms
VIE 14/05)
o ILD 19
123 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Increased transaminases 24 (09
Time, mo
1, Rugo HS et a. Ann Oncol 2022:3:616-627 PeerView.com
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Abemaciclib: Dose Holds and Reductions’
+ 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)
Patients may be counted in more than one dose hold or dose reduction in subcategory; values not adding up to the total number were due to missing or aher reasons.
1. Regan MM et al SABCS 2021. Abstract 682.05.
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+ 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)
Patients may be counted in more than one dose hold or dose reduction in subcategory; values not adding up to the total number were due to missing or aher reasons.
1. Regan MM et al SABCS 2021. Abstract 682.05.
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Dose Reductions Do Not Compromise the Efficacy
of Adjuvant Abemaciclib in High-Risk EBC*2
IDFS According to RDI in Patients Treated With Abemaciclib in ITT Population
so
—— 0%-56%
a 293% 66%-93%
x
do
a Relative De
S | Rue Dove gsyeariOFS Rates inITT, 4 (95% Cl) 4:YearIDFS Rates In Cohort 1, % (95% Cl)
2 | onen Sra 64897) 372 (64898)
na 864 636887) 861 (633885)
o| sos 8707303) 031199958)
D € à ss *
No. at Risk Time, mo
mm m m M 0
oe teeter Om JD eG A ©
= CS
41. O'Shaughnessy J etal. ESMO 2023. Poster 274P. 2. Goetz MP et al. NPJ Breast Cancer. 2024:10:34
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IDFS rates were similar
across relative dose
intensity subgroups
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of Adjuvant Abemaciclib in High-Risk EBC*2
IDFS According to RDI in Patients Treated With Abemaciclib in ITT Population
so
—— 0%-56%
a 293% 66%-93%
x
do
a Relative De
S | Rue Dove gsyeariOFS Rates inITT, 4 (95% Cl) 4:YearIDFS Rates In Cohort 1, % (95% Cl)
2 | onen Sra 64897) 372 (64898)
na 864 636887) 861 (633885)
o| sos 8707303) 031199958)
D € à ss *
No. at Risk Time, mo
mm m m M 0
oe teeter Om JD eG A ©
= CS
41. O'Shaughnessy J etal. ESMO 2023. Poster 274P. 2. Goetz MP et al. NPJ Breast Cancer. 2024:10:34
PeerView.com/BEX827
IDFS rates were similar
across relative dose
intensity subgroups
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FDA and EMA Regulatory Approvals
of Adjuvant Abemacic
~
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
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of Adjuvant Abemacic
~
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
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NATALEE Study Design!
‘Adult patients with HR+/HER2- EBC.
+ Prior ET allowed up to 12 months o Done ce’ Primary Endpoint:
ESTA IDFS (STEEP criteria)
— NO with grade 2 and evidence of high ri Key Secondary
(Ki-67 220%, oncotype DX breast recurrence score 226, Endpoints:
or high risk via genomic risk profiling) or grade 3 > RFS, distant DFS,
- M OS, HRQO!
+ Anatomic stage IIB: NO or N1 safety/tolerabilty,
+ Anatomic stage Ill: NO, N1, N2, or N3 and PK
Randomization stratification á Exploratory Endpoints:
‘Anatomic stage: Il 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% Cl, 0.618-0.906]; P = .0014) in broad population of patients with stage Il or Ill HR+/HER2- EBC at risk of
recurrence, including those with node-negative disease
HRQOL of patients with HR+/HER2- EBC was maintained with the addition of ribociclib to SOC adjuvant NSAI vs NSAI alone
in this study
‘Enrolment of patents with stage 1 disease capped at 40%. > Operiabel design
8101 patents randomized fem January 10,2019, 1 Apr 20,2021. Pr investigator choice. >
1. Slamon D et al ASCO 2023, Abstract LBASOO) PeerView.com
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‘Adult patients with HR+/HER2- EBC.
+ Prior ET allowed up to 12 months o Done ce’ Primary Endpoint:
ESTA IDFS (STEEP criteria)
— NO with grade 2 and evidence of high ri Key Secondary
(Ki-67 220%, oncotype DX breast recurrence score 226, Endpoints:
or high risk via genomic risk profiling) or grade 3 > RFS, distant DFS,
- M OS, HRQO!
+ Anatomic stage IIB: NO or N1 safety/tolerabilty,
+ Anatomic stage Ill: NO, N1, N2, or N3 and PK
Randomization stratification á Exploratory Endpoints:
‘Anatomic stage: Il 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% Cl, 0.618-0.906]; P = .0014) in broad population of patients with stage Il or Ill HR+/HER2- EBC at risk of
recurrence, including those with node-negative disease
HRQOL of patients with HR+/HER2- EBC was maintained with the addition of ribociclib to SOC adjuvant NSAI vs NSAI alone
in this study
‘Enrolment of patents with stage 1 disease capped at 40%. > Operiabel design
8101 patents randomized fem January 10,2019, 1 Apr 20,2021. Pr investigator choice. >
1. Slamon D et al ASCO 2023, Abstract LBASOO) PeerView.com
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NATALEE: Final IDFS?2
100
90
80
Ribo + NSAI
876
Median follow-up for IDFS was 33.3
NSAI alone
70 months (maximum, 51 months), with
oo an additional 5.6 months from the
= En second interim efficacy analysis
a Ribo+NSAI NSAIA P 5
So = 2 Absolute IDFS benefit with ribociclib
Eventsin (%) 226/2,549 (8.9) 2832,552(11.1) + NSAI was 3.1% at 3 years
307 a year IDFS rate, % 907 876
20 À hr (05% cl) 0.749 (0.628-0.892) Risk of invasive disease was
D ee reduced by 25.1% with ribociclib +
9 NSAI vs NSAI alone
0 6 12 18 2 30 36 42 48 54
Time, mo
No. atRisk
Rbo+NSAl 2549 2350 2273 2204 2100 180% 1111 308 21 0
NSAlalone 2552 2241 2160 2080 1978 1507 1067 35 2% 0
1. Slamon DJ et al ASCO 2023. Abstract LBASOO. 2. Hortobagy G et al. SABCS 2023. Abstract 6803-03 PeerView.com
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100
90
80
Ribo + NSAI
876
Median follow-up for IDFS was 33.3
NSAI alone
70 months (maximum, 51 months), with
oo an additional 5.6 months from the
= En second interim efficacy analysis
a Ribo+NSAI NSAIA P 5
So = 2 Absolute IDFS benefit with ribociclib
Eventsin (%) 226/2,549 (8.9) 2832,552(11.1) + NSAI was 3.1% at 3 years
307 a year IDFS rate, % 907 876
20 À hr (05% cl) 0.749 (0.628-0.892) Risk of invasive disease was
D ee reduced by 25.1% with ribociclib +
9 NSAI vs NSAI alone
0 6 12 18 2 30 36 42 48 54
Time, mo
No. atRisk
Rbo+NSAl 2549 2350 2273 2204 2100 180% 1111 308 21 0
NSAlalone 2552 2241 2160 2080 1978 1507 1067 35 2% 0
1. Slamon DJ et al ASCO 2023. Abstract LBASOO. 2. Hortobagy G et al. SABCS 2023. Abstract 6803-03 PeerView.com
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NATALEE: Distant Disease-Free Survival!
The absolute DDFS? benefit with
Es On ribociclib plus NSAI was 2.7% at 3
Es Ribo+NSAl__NSAIAlone years
© 40] ESTO 2012,540 (8) 256/2,562 (10) The risk of distant disease was
30 À 3-year DDFS rate, % 929 90.2 reduced by 25.1% with ribociclib plus
20 À HR (95% cl) 0.749 (0.623-0.900) NSAI vs NSAI alone at the final
10 7 Nominal 1-sided P 0010 analysis
Vo os D 1 à © 0 a 4 à
No. ot Risk (Time, mo
RIBSNSAI 2540 2352 2200 2212 2119 1706 1.119 20 28 0
NSAlalone 2552 2245 2171 2001 1,900 1609 1080 358 28 0
"DDFS is he time from randomization tothe date ofthe st event of stat recurrence, death by any cause, of second primary nonbreast invasive cancer,
‘cng basal and squamous cel earcnomas ofthe shins, a
1 Hotobapy O etal SABES 2023 Ata 020308 PeerView.com
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The absolute DDFS? benefit with
Es On ribociclib plus NSAI was 2.7% at 3
Es Ribo+NSAl__NSAIAlone years
© 40] ESTO 2012,540 (8) 256/2,562 (10) The risk of distant disease was
30 À 3-year DDFS rate, % 929 90.2 reduced by 25.1% with ribociclib plus
20 À HR (95% cl) 0.749 (0.623-0.900) NSAI vs NSAI alone at the final
10 7 Nominal 1-sided P 0010 analysis
Vo os D 1 à © 0 a 4 à
No. ot Risk (Time, mo
RIBSNSAI 2540 2352 2200 2212 2119 1706 1.119 20 28 0
NSAlalone 2552 2245 2171 2001 1,900 1609 1080 358 28 0
"DDFS is he time from randomization tothe date ofthe st event of stat recurrence, death by any cause, of second primary nonbreast invasive cancer,
‘cng basal and squamous cel earcnomas ofthe shins, a
1 Hotobapy O etal SABES 2023 Ata 020308 PeerView.com
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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
N1-N3
NO
100 Ribo + NSAI
90
80 NSAI alone
70
* o Median follow-up: 38.7 mo
go Ribo+NSAI NSAI Alone
40] Eventsin 20/285 311328
304 (0%) @ (95)
20 | 3-yearIDFS rate, % 932 906
10 À HR (85% cl 0.723 (0412-1268)
Te DE 28m 36 0 € à
No, at Risk ‚Time, mo,
Ribo + NSAI 285 262 258
NSAlalone 328 300 204 287
250 24 295 17 8 5 0
216 26 188 80 5 0
1. Hortobagyi Get al. SABCS 2023. Abstract 6503-03,
PeerView.com/BEX827
No. at Risk
Ribo + NSAI
NSAI alone”
Median follow-up: 33.2 mo
o
Ribo +NSAI NSAI Alone
Eventsin 2062261 25112219
(%) (01) (11.3)
year IDFS rate, % 90.3 874
HR (95% Cl)
6
12
0.759 (0.631-0.912)
18 24 30 36 42 48 54
Time, mo
Rbo+ NSAI 2261 2085 2012 1.951 1853 1458 934 301 18 0
NSAlalone 2210 1938 1873 1791 1607 1337 877 273 21 0
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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
N1-N3
NO
100 Ribo + NSAI
90
80 NSAI alone
70
* o Median follow-up: 38.7 mo
go Ribo+NSAI NSAI Alone
40] Eventsin 20/285 311328
304 (0%) @ (95)
20 | 3-yearIDFS rate, % 932 906
10 À HR (85% cl 0.723 (0412-1268)
Te DE 28m 36 0 € à
No, at Risk ‚Time, mo,
Ribo + NSAI 285 262 258
NSAlalone 328 300 204 287
250 24 295 17 8 5 0
216 26 188 80 5 0
1. Hortobagyi Get al. SABCS 2023. Abstract 6503-03,
PeerView.com/BEX827
No. at Risk
Ribo + NSAI
NSAI alone”
Median follow-up: 33.2 mo
o
Ribo +NSAI NSAI Alone
Eventsin 2062261 25112219
(%) (01) (11.3)
year IDFS rate, % 90.3 874
HR (95% Cl)
6
12
0.759 (0.631-0.912)
18 24 30 36 42 48 54
Time, mo
Rbo+ NSAI 2261 2085 2012 1.951 1853 1458 934 301 18 0
NSAlalone 2210 1938 1873 1791 1607 1337 877 273 21 0
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NATALEE: IDFS by Anatomical Stage’
The risk of invasive disease was reduced by 30% for stage Il and
by 24.5% for stage III disease with ribociclib + NSAI vs NSAI alone
Stage Il Stage III
00 Ribo + NSAI 100
2 20 Rito + NSAI
80 NSAI alone had
70 70 REA alone
zo ©
ds Mecianfolowup: 38.6 mo E Median follow-up: 33.1 mo
So Ribo+NSAI___NSAI Alone 5 4 Ribo+NSAl__NSAI Alone
30 4” Eventsin (%) 55/1,011 (5.44) — 80/1,034 (7.74) 30 4 Eventsin (%) 170/1,528 (111) 201,512 (13.4)
20 | 3-year IDFS rate, % 42 926 204 3:yeariDFS 881 838
10 1 Hr (95% Cl) 0.700 (0.496-0.986) 101 Hr (95% Cl) 0.755 (0.616-0.926)
o
E EE % 4 4% OM EE a 48 à
Time, mo Time, mo
No. at Risk a Ro
Re NEA 1011 929 902 89 850 Mu em 104 15 0 RE SNSAL 1528 1411 1362 1312 1202 844 ae 14 0 0
NsAlaione 1004 048 G24 803 G72 840 00 203 1 0 NSAI atone 1812 1280 1241 1.183 1099 793 458 151 BD
1. Hortobagyi G et al, SABCS 2023. Abstract 650303. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
The risk of invasive disease was reduced by 30% for stage Il and
by 24.5% for stage III disease with ribociclib + NSAI vs NSAI alone
Stage Il Stage III
00 Ribo + NSAI 100
2 20 Rito + NSAI
80 NSAI alone had
70 70 REA alone
zo ©
ds Mecianfolowup: 38.6 mo E Median follow-up: 33.1 mo
So Ribo+NSAI___NSAI Alone 5 4 Ribo+NSAl__NSAI Alone
30 4” Eventsin (%) 55/1,011 (5.44) — 80/1,034 (7.74) 30 4 Eventsin (%) 170/1,528 (111) 201,512 (13.4)
20 | 3-year IDFS rate, % 42 926 204 3:yeariDFS 881 838
10 1 Hr (95% Cl) 0.700 (0.496-0.986) 101 Hr (95% Cl) 0.755 (0.616-0.926)
o
E EE % 4 4% OM EE a 48 à
Time, mo Time, mo
No. at Risk a Ro
Re NEA 1011 929 902 89 850 Mu em 104 15 0 RE SNSAL 1528 1411 1362 1312 1202 844 ae 14 0 0
NsAlaione 1004 048 G24 803 G72 840 00 203 1 0 NSAI atone 1812 1280 1241 1.183 1099 793 458 151 BD
1. Hortobagyi G et al, SABCS 2023. Abstract 650303. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
NATALEE: OS!
2 Ribo + NSAI
35 Median follow-up for OS
= was 35.9 months at the
= 50 final analysis
8 Ribo+NSAI NSAI Alone
40 i x
Eventsin (%) 8412,549 (3.3) 88/2,552 (3.4) esate require longer En
30 follow-up, as there were fewer
20 e Ce tales v7 oe than 4% of events in both
10 7 HR (95% CI) 0.892 (0.661-1.203) treatment arms
0
0 6 12 18 24 30 36 42 48 54
Time, mo
No, at Risk
Ribo+NSAl 2549 2405 2397 2305 2250 1002 1259 455 24 0
NSAlalone 2552 2302 2256 2200 2158 1815 1207 44 31 0
1. Hodobagyi Ge al SABCS 2023, Abstract 6503-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
2 Ribo + NSAI
35 Median follow-up for OS
= was 35.9 months at the
= 50 final analysis
8 Ribo+NSAI NSAI Alone
40 i x
Eventsin (%) 8412,549 (3.3) 88/2,552 (3.4) esate require longer En
30 follow-up, as there were fewer
20 e Ce tales v7 oe than 4% of events in both
10 7 HR (95% CI) 0.892 (0.661-1.203) treatment arms
0
0 6 12 18 24 30 36 42 48 54
Time, mo
No, at Risk
Ribo+NSAl 2549 2405 2397 2305 2250 1002 1259 455 24 0
NSAlalone 2552 2302 2256 2200 2158 1815 1207 44 31 0
1. Hodobagyi Ge al SABCS 2023, Abstract 6503-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
NATALEE: Safety Profile of Adjuvant Ribociclib 400 mg!
Ribocicl
DESI Any Grade
Neutropenia 625
Febrile neutropenia 03
Liver-related AEs® 264
QT interval prolongation* 53
ECG QT prolonged 43
ILD/pneumonitiss 15
Other clinically relevant AEs
Arthralgia 373
Nausea 233
Headache 28
Fatigue 23
Diarrhea 145
vie 15
1.0
0.2
0.4
0.8
0.6
06
NSAI Alone (n
Any Grade
46
o
112
14
0.7
09
433
78
17.0
132
13
02
02
01
04
+ NoAESIis 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 neutophi count decreased. ® Grouped term thal includes al referred terms identified by standardized MegORA quenes
{or drug-related hepatic disorders.‘ Grouped term. Grouped term that includes al preferred terms dented by standardized MedDRA queries for ILD. * Grouped tam
that includes al preferred terms identified by standardized MedDRA queries fr VTE.
1. Hodobagy G et al SABCS 2023. Abstract 6803.03.
PeerView.com/BEX827
PeerView.com
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Ribocicl
DESI Any Grade
Neutropenia 625
Febrile neutropenia 03
Liver-related AEs® 264
QT interval prolongation* 53
ECG QT prolonged 43
ILD/pneumonitiss 15
Other clinically relevant AEs
Arthralgia 373
Nausea 233
Headache 28
Fatigue 23
Diarrhea 145
vie 15
1.0
0.2
0.4
0.8
0.6
06
NSAI Alone (n
Any Grade
46
o
112
14
0.7
09
433
78
17.0
132
13
02
02
01
04
+ NoAESIis 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 neutophi count decreased. ® Grouped term thal includes al referred terms identified by standardized MegORA quenes
{or drug-related hepatic disorders.‘ Grouped term. Grouped term that includes al preferred terms dented by standardized MedDRA queries for ILD. * Grouped tam
that includes al preferred terms identified by standardized MedDRA queries fr VTE.
1. Hodobagy G et al SABCS 2023. Abstract 6803.03.
PeerView.com/BEX827
PeerView.com
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NATALEE: IDFS by Dose Reductions‘
Landmark analysis revealed that ribociclib dose reduction due to AEs did not impact efficacy
IDFS by Dose Reduction at 25th Percentile”
(1.87 mo)
Time, mo
* Of dose reduction tine, calculated trom randomization
1. Barros C. ESMO 2024, Abstract 11310.
PeerView.com/BEX827
o
[(REFFEFETETI
IDFS by Dose Reduction at 50th Percentile®
(3.17 mo)
1DFS, %
Time, mo
o
BERETELTT
IDFS by Dose Reduction at 75th Percentile®
(7.28 mo)
06 a em 0 me a we
Time, mo
PeerView.com
Copyright © 2000-2024, PeerView
Landmark analysis revealed that ribociclib dose reduction due to AEs did not impact efficacy
IDFS by Dose Reduction at 25th Percentile”
(1.87 mo)
Time, mo
* Of dose reduction tine, calculated trom randomization
1. Barros C. ESMO 2024, Abstract 11310.
PeerView.com/BEX827
o
[(REFFEFETETI
IDFS by Dose Reduction at 50th Percentile®
(3.17 mo)
1DFS, %
Time, mo
o
BERETELTT
IDFS by Dose Reduction at 75th Percentile®
(7.28 mo)
06 a em 0 me a we
Time, mo
PeerView.com
Copyright © 2000-2024, PeerView
NATALEE: Efficacy in Node-Negative (NO)
HR+, HER2- EBC’
IDFS in Node-Negative Subgroup DDFS and DRFS in Node-Negative Subgroup
100 Ribo + NSAI ae RIB + NSAI NSAI Alone
90 acy (n= 285) (n = 328)
80 NSAI alone DDFS
aw Events, n 17 27
Een Median follow-up: 38.7 mo
ge 3-year rate (95% Cl), % 94.3(90.6-96.6) 91.5 (87.6-94.2)
El RO NEN NSA Alone: HR (95% Cl) 0.703 (0.383-1.290)
40 1 Eventsn 20/285 31/328
30 À (%) Mm (05) PRES]
20 | 3-year IDFS rate, % 93.2 90.6 Events, n 12 2
10 À HR (95% cl 0.723 (0.412-1.268) Syear rate (95% Cl),% 96.3 (93.0-98.1) 92.5 (88.8-95.1)
0 HR (95% Cl) 0.580 (0.289-1.170)
0 6 12 18 24 30 36 42 48 54
Add Time, mo
RbosNSAl 285 262 258 250 24% 235 177 oF 5 0
NEA ane 328 300 20s 287 270 288 188 80 5 0
1 Vardey Data. ASCO 2028 Ana S12 ne PeerView.com
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HR+, HER2- EBC’
IDFS in Node-Negative Subgroup DDFS and DRFS in Node-Negative Subgroup
100 Ribo + NSAI ae RIB + NSAI NSAI Alone
90 acy (n= 285) (n = 328)
80 NSAI alone DDFS
aw Events, n 17 27
Een Median follow-up: 38.7 mo
ge 3-year rate (95% Cl), % 94.3(90.6-96.6) 91.5 (87.6-94.2)
El RO NEN NSA Alone: HR (95% Cl) 0.703 (0.383-1.290)
40 1 Eventsn 20/285 31/328
30 À (%) Mm (05) PRES]
20 | 3-year IDFS rate, % 93.2 90.6 Events, n 12 2
10 À HR (95% cl 0.723 (0.412-1.268) Syear rate (95% Cl),% 96.3 (93.0-98.1) 92.5 (88.8-95.1)
0 HR (95% Cl) 0.580 (0.289-1.170)
0 6 12 18 24 30 36 42 48 54
Add Time, mo
RbosNSAl 285 262 258 250 24% 235 177 oF 5 0
NEA ane 328 300 20s 287 270 288 188 80 5 0
1 Vardey Data. ASCO 2028 Ana S12 ne PeerView.com
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Returning to Our Case
+ 59-year-old postmenopausal woman, a violinist in an orchestra, presents with a mass in the right breast,
diagnosed with HR+, HER2- EBC
+ Right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3 ILC, 2/3 LN+
Let’s discuss:
How would you categorize her risk of recurrence based on the available info?
How would you explain her risk of recurrence to the patient in an easy to understand way?
Would you offer adjuvant CDK4/6i therapy to this patient, and if so, what?
Would additional testing results (eg, Oncotype DX RS, Ki-67, ctDNA) influence your risk
assessment and treatment decisions?
Is there benefit from adjuvant CDK4/6i purely in the biologically high-risk patients?
Can adjuvant CDK4/6i replace chemotherapy in patients with an Oncotype RS of 27 or 30?
Copyright © 2000-2024, PeerView
+ 59-year-old postmenopausal woman, a violinist in an orchestra, presents with a mass in the right breast,
diagnosed with HR+, HER2- EBC
+ Right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3 ILC, 2/3 LN+
Let’s discuss:
How would you categorize her risk of recurrence based on the available info?
How would you explain her risk of recurrence to the patient in an easy to understand way?
Would you offer adjuvant CDK4/6i therapy to this patient, and if so, what?
Would additional testing results (eg, Oncotype DX RS, Ki-67, ctDNA) influence your risk
assessment and treatment decisions?
Is there benefit from adjuvant CDK4/6i purely in the biologically high-risk patients?
Can adjuvant CDK4/6i replace chemotherapy in patients with an Oncotype RS of 27 or 30?
Copyright © 2000-2024, PeerView
Our Case Continues
pr ar
A 59-year-old postmenopausal woman, a violinist in an orchestra, presents with a mass in right breast >
diagnosed with HR+, HER2- EBC > right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3
ILC, 2/3 LN+ > started on adjuvant ET + abemaciclib 150 mg BID
Has experienced:
+ Persistent and recurrent diarthea after first 2 cycles; has taken a few treatment breaks, but restarted
abemaciclib + ET and currently experiencing grade 2 diarrhea
Let’s discuss:
> What would you recommend to manage her diarrhea? Would you reduce the dose?
What strategies do you use to improve adherence/persistence and help patients stay on
therapy with adjuvant abemaciclib and reduce their risk of recurrence?
What if the patient develops persistent low-grade fatigue, DVT, liver function abnormalities,
serum creatinine elevations, or other AEs?
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
pr ar
A 59-year-old postmenopausal woman, a violinist in an orchestra, presents with a mass in right breast >
diagnosed with HR+, HER2- EBC > right mastectomy and axillary LN dissection performed: 2.6 cm, grade 3
ILC, 2/3 LN+ > started on adjuvant ET + abemaciclib 150 mg BID
Has experienced:
+ Persistent and recurrent diarthea after first 2 cycles; has taken a few treatment breaks, but restarted
abemaciclib + ET and currently experiencing grade 2 diarrhea
Let’s discuss:
> What would you recommend to manage her diarrhea? Would you reduce the dose?
What strategies do you use to improve adherence/persistence and help patients stay on
therapy with adjuvant abemaciclib and reduce their risk of recurrence?
What if the patient develops persistent low-grade fatigue, DVT, liver function abnormalities,
serum creatinine elevations, or other AEs?
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
RISING TO THE CHALLENGE OF EARLY AND ADVANCED HR+ BREAST CANCER | OUTLINE
PART 1 PART 2
Candid Conversations € Clinical Consults Candid Conversations & Clinical Consults
HR+, HER2- EBC: Stratifying Risk and HR+, HER2- MBC: Interpreting the Latest
Reducing the Risk of Recurrence With Evidence and Individualizing Treatment
Adjuvant CDK4/6 Inhibition Selection/Sequencing
Copyright €
PART 1 PART 2
Candid Conversations € Clinical Consults Candid Conversations & Clinical Consults
HR+, HER2- EBC: Stratifying Risk and HR+, HER2- MBC: Interpreting the Latest
Reducing the Risk of Recurrence With Evidence and Individualizing Treatment
Adjuvant CDK4/6 Inhibition Selection/Sequencing
Copyright €
Let’s Start With a Case
—
A 64-year-old postmenopausal woman, a gastroenterologist, has a history of invasive
carcinoma of the breast (ductal), pT2NO, grade 3, ER+ (90%), PgR+ (50%), HER2-
Mammogram/US showed a 2.8-cm mass + enlarged, suspicious axillary LN
Underwent lumpectomy > adjuvant chemotherapy (TC) > breast RT > adjuvant Al
Two years after starting Al develops right hip pain > imaging reveals lytic bone lesions
Staging scans reveal extensive liver metastases and bony metastases involving spine, hip,
and ribs
Biopsy of the liver shows ER+, PgR+, HER2-; BRCA1/2-
PeerView.com/BEX827 Copyright ©
—
A 64-year-old postmenopausal woman, a gastroenterologist, has a history of invasive
carcinoma of the breast (ductal), pT2NO, grade 3, ER+ (90%), PgR+ (50%), HER2-
Mammogram/US showed a 2.8-cm mass + enlarged, suspicious axillary LN
Underwent lumpectomy > adjuvant chemotherapy (TC) > breast RT > adjuvant Al
Two years after starting Al develops right hip pain > imaging reveals lytic bone lesions
Staging scans reveal extensive liver metastases and bony metastases involving spine, hip,
and ribs
Biopsy of the liver shows ER+, PgR+, HER2-; BRCA1/2-
PeerView.com/BEX827 Copyright ©
Latest Evidence on CDK4/6 Inhibitors
and Oral SERDs in HR+, HER2- MBC
Joyce O’Shaughnessy, MD
Celebrating Women Chair in Breast Cancer Research |
e
Baylor University Medical Center | y
Texas Oncology |
Sarah Cannon Research Institute ”
Dallas, Texas
Copyright © 2000-2024, PeerView
and Oral SERDs in HR+, HER2- MBC
Joyce O’Shaughnessy, MD
Celebrating Women Chair in Breast Cancer Research |
e
Baylor University Medical Center | y
Texas Oncology |
Sarah Cannon Research Institute ”
Dallas, Texas
Copyright © 2000-2024, PeerView
CDK4/6 Inhibitors in the First-Line
Setting and Beyond
Setting and Beyond
Overall Survival in MBC Patients Treated With CDK4/6i'-”
Treatment Arm: Placebo Arm
OS, Median, Mo OS, Median, Mo
PALOMA.2! 0.956
Z Palbociclb + letrozole ay e oran 87
PALOMA? 081
Palbociclib + fulvestrant se) 730 (054-103) % 2
wu MONARCH 2° 076
D Abemaciclib + fulvestrant I ES Ostos 21 VA
MONARCH 3 0.804
Abemacicli + NSAI Ge Se or 6X
MONALEESA-245 076
Riboeiclib + letrozole es aA (063-093, 0% =
Q MoNALEESA 7e om
& Ribociclib + goserelin + NR 409 (054-095) 073 YA
tamoxifen/NSAI 2
MONALEESA-3” 072
Ribociclib + fulvestrant NR 409 or 00455 Y
a =
04 06 08 10 12
E
‘The red» denotes tial rt not report sgicat mean 05 compared wih placebo. Pavers CORA ~ Favors PO
4. Finn RS etal J Cin Oncol, 2022: 40 (suppl 17: abst LBA10O3). 2. Tumer NC et al. Eng J Med.2018:378:1926-1996, 3. Siedge GW et al, JAMA Oncol. 20208:118-124
4. Hortobagy GN et al. N Engl J Med, 2022:386:042-980. 5. Horobagyi GN et al ESMO 2021. Oral LBA17_PR. 6. Im SA et al. N Engl J Med, 2019:381:307-516. =,
7. Slamon DA et al. N Engl Med. 2020:382 514-524 PeerView.com
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Treatment Arm: Placebo Arm
OS, Median, Mo OS, Median, Mo
PALOMA.2! 0.956
Z Palbociclb + letrozole ay e oran 87
PALOMA? 081
Palbociclib + fulvestrant se) 730 (054-103) % 2
wu MONARCH 2° 076
D Abemaciclib + fulvestrant I ES Ostos 21 VA
MONARCH 3 0.804
Abemacicli + NSAI Ge Se or 6X
MONALEESA-245 076
Riboeiclib + letrozole es aA (063-093, 0% =
Q MoNALEESA 7e om
& Ribociclib + goserelin + NR 409 (054-095) 073 YA
tamoxifen/NSAI 2
MONALEESA-3” 072
Ribociclib + fulvestrant NR 409 or 00455 Y
a =
04 06 08 10 12
E
‘The red» denotes tial rt not report sgicat mean 05 compared wih placebo. Pavers CORA ~ Favors PO
4. Finn RS etal J Cin Oncol, 2022: 40 (suppl 17: abst LBA10O3). 2. Tumer NC et al. Eng J Med.2018:378:1926-1996, 3. Siedge GW et al, JAMA Oncol. 20208:118-124
4. Hortobagy GN et al. N Engl J Med, 2022:386:042-980. 5. Horobagyi GN et al ESMO 2021. Oral LBA17_PR. 6. Im SA et al. N Engl J Med, 2019:381:307-516. =,
7. Slamon DA et al. N Engl Med. 2020:382 514-524 PeerView.com
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Phase 3 MONALEESA-2: First-Line Al + Ribociclib
HR+/HER2- MBC"
Median OS, mo (95% Cl)
Ribociclib (n = 334): 63.9
Placebo (n = 334): 51.4
HR = 0.76 (95% CI, 0.63-0.93)
P=.008
Ribociclib
OS, %
g
Placebo
6 4 5 12 16 20 Ze 28 32 36 do da de 82 56 60 64 6B 72 76 80 84 88
Time, mo
Ribociclib + letrozole showed a significant OS benefit, with a 1-year improvement over placebo in
dvanced breast cancer > new benchmark for OS in the first-line setting of over 5 years
1. Horobagyi GN et al N Engl Med. 2022:386:942:950, PeerView.com
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HR+/HER2- MBC"
Median OS, mo (95% Cl)
Ribociclib (n = 334): 63.9
Placebo (n = 334): 51.4
HR = 0.76 (95% CI, 0.63-0.93)
P=.008
Ribociclib
OS, %
g
Placebo
6 4 5 12 16 20 Ze 28 32 36 do da de 82 56 60 64 6B 72 76 80 84 88
Time, mo
Ribociclib + letrozole showed a significant OS benefit, with a 1-year improvement over placebo in
dvanced breast cancer > new benchmark for OS in the first-line setting of over 5 years
1. Horobagyi GN et al N Engl Med. 2022:386:942:950, PeerView.com
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PALOMA-2 First-Line Letrozole + Palbociclib:
Overall Survival Analysis!
OS: ITT
100
oxen eo Kran
x Seated ur ose a
2 (95% CI) (0.774.177) 5
E traded P re E
3 5 ©
2 «0 PAL+ LET 3
é Es
Si DE
o o
me Sa
Post-Hoc Sensitivity Analysis: Excluding
Patients With Survival Data Not Available
Medan 05, me
(95% Ci) Ws 670823)
Unstatied HR 0.260
esc» (0708-1069)
Time, mo
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%
10% of patients continued on palbociclib and letrozole at 7.5-year follow-up
1. Finn RS et al J Cin Oncol, 2022; 4O(supp 17) LBA1003-LBA 1005.
PeerView.com/BEX827
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Overall Survival Analysis!
OS: ITT
100
oxen eo Kran
x Seated ur ose a
2 (95% CI) (0.774.177) 5
E traded P re E
3 5 ©
2 «0 PAL+ LET 3
é Es
Si DE
o o
me Sa
Post-Hoc Sensitivity Analysis: Excluding
Patients With Survival Data Not Available
Medan 05, me
(95% Ci) Ws 670823)
Unstatied HR 0.260
esc» (0708-1069)
Time, mo
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%
10% of patients continued on palbociclib and letrozole at 7.5-year follow-up
1. Finn RS et al J Cin Oncol, 2022; 4O(supp 17) LBA1003-LBA 1005.
PeerView.com/BEX827
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Real-World Overall Survival Data for Palbociclib
Before and After sIPTW and PSM: P-REALITY X!
Pe Unadjusted Analysis SIPTW = PSM
o ° “
* prea À CICR PAL + Al
8 de 8.
mr, ms slam 2 lim ma as
(exc) wre cases) Gee) stern area) Gorey” CRE
MR 067 (GE O0 7 P< O00 ots 070 gs 01 088067: oo HR RO 725% 01062089; 001
0 6 a ES 0 6 2 8 À © a à à © @ 0 6 2 10 24 30 % 42 40 % © &
Time, mo Time, mo Time, mo
TOP soma) zus) D monzesen 2451120429) MO ano 249 (124400
Median OS* was significantly longer among p:
nts who received PAL + Al vs Al alone before and after sIPTW and PSM
Note: Observational retrospective analyses are designed to evaluate associations among variables and cannot establish causality;
they are not intended for direct comparison with clinical trials.
205 was defined as the time in months rom the index date to death ram any cause 7
1. Rugo H et al ESMO BC 2022. Poster 169P PeerView.com
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Before and After sIPTW and PSM: P-REALITY X!
Pe Unadjusted Analysis SIPTW = PSM
o ° “
* prea À CICR PAL + Al
8 de 8.
mr, ms slam 2 lim ma as
(exc) wre cases) Gee) stern area) Gorey” CRE
MR 067 (GE O0 7 P< O00 ots 070 gs 01 088067: oo HR RO 725% 01062089; 001
0 6 a ES 0 6 2 8 À © a à à © @ 0 6 2 10 24 30 % 42 40 % © &
Time, mo Time, mo Time, mo
TOP soma) zus) D monzesen 2451120429) MO ano 249 (124400
Median OS* was significantly longer among p:
nts who received PAL + Al vs Al alone before and after sIPTW and PSM
Note: Observational retrospective analyses are designed to evaluate associations among variables and cannot establish causality;
they are not intended for direct comparison with clinical trials.
205 was defined as the time in months rom the index date to death ram any cause 7
1. Rugo H et al ESMO BC 2022. Poster 169P PeerView.com
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MONARCH-3: First-Line Al + Abemaciclib*!
HR+/HER2- advanced BC
Abemaciclib 150 mg PO BID +
+ Postmenopausal
anastrozole 1 mg or letrozole 2
PO QD until PD
mg
+ Metastatic or locoregionally recurrent disease
with no prior systemic therapy in this setting
If (neo)adjuvant ET administered, a disease-
free interval of >12 months since completion
of ET
+ ECOG PS 0-1
Stratified by
+ Metastatic site (visceral, bone only, or other)
+ Prior ET (Al, no ET, or other)
(N = 493)
Placebo PO BID + anastrozole 1 mg
or letrozole 2.5 mg PO QD until PD
+ Primary endpoint: investigator-assessed PFS.
+ Key secondary endpoints: OS, response
rates, and safety
1. Goetz MP et al. Ann Oncol 2022:38:5808-$869, PeerView.com
Copyright © 2000-2024, PeerView
MONARCH-3: First-Line Al + Abemaciclib*!
HR+/HER2- advanced BC
Abemaciclib 150 mg PO BID +
+ Postmenopausal
anastrozole 1 mg or letrozole 2
PO QD until PD
mg
+ Metastatic or locoregionally recurrent disease
with no prior systemic therapy in this setting
If (neo)adjuvant ET administered, a disease-
free interval of >12 months since completion
of ET
+ ECOG PS 0-1
Stratified by
+ Metastatic site (visceral, bone only, or other)
+ Prior ET (Al, no ET, or other)
(N = 493)
Placebo PO BID + anastrozole 1 mg
or letrozole 2.5 mg PO QD until PD
+ Primary endpoint: investigator-assessed PFS.
+ Key secondary endpoints: OS, response
rates, and safety
1. Goetz MP et al. Ann Oncol 2022:38:5808-$869, PeerView.com
Copyright © 2000-2024, PeerView
MONARCH-3: Final OS in the ITT Population!
08, %
Nat Risk
Abemaciclib + Placebo +
2: NSAI NSAI
bes Median OS, mo 66.8 53.7
70 Abemaciclib + NSAI
HR (95%) 0.804 (0.637-1.015)
66.8 mo
Placebo + NSAI (a=131) 2-sided P 0664
Patents Events
Abemacil + NSAI 328 108(60%)
Placebo + NSAI 165 116,70%)
0 6 12 18 A 30 36 42 48 54 60 66 72 78 84 90 98 102
Time, mo
Abaco NEN 328 304 281 206 247 229 211 100 197 174 180 14% 191 117 100 90 06 €
Preplanned OS analysis
Data cut: Sept 29, 2023
Abemaciclib + NSAI resulted in a numerically longer OS vs NSAI alone; clinically significant
but statistical significance was not reached; the observed improvement in median OS was 13.1 months
2 Did not reach threshold (0.034) or statistical significance a this final analysis
1. Goetz MP et a
PeerView.com/BEX827
'SABCS 2023, Abstract GS01-12.
PeerView.com
Copyright © 2000-2024, PeerView
08, %
Nat Risk
Abemaciclib + Placebo +
2: NSAI NSAI
bes Median OS, mo 66.8 53.7
70 Abemaciclib + NSAI
HR (95%) 0.804 (0.637-1.015)
66.8 mo
Placebo + NSAI (a=131) 2-sided P 0664
Patents Events
Abemacil + NSAI 328 108(60%)
Placebo + NSAI 165 116,70%)
0 6 12 18 A 30 36 42 48 54 60 66 72 78 84 90 98 102
Time, mo
Abaco NEN 328 304 281 206 247 229 211 100 197 174 180 14% 191 117 100 90 06 €
Preplanned OS analysis
Data cut: Sept 29, 2023
Abemaciclib + NSAI resulted in a numerically longer OS vs NSAI alone; clinically significant
but statistical significance was not reached; the observed improvement in median OS was 13.1 months
2 Did not reach threshold (0.034) or statistical significance a this final analysis
1. Goetz MP et a
PeerView.com/BEX827
'SABCS 2023, Abstract GS01-12.
PeerView.com
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MONARCH-3: OS in the Subgroup With
Visceral Disease!
100 Abemaciclib + NSAI Placebo + NSAI
E Median OS, mo 637 488
e HR (95%) 0.758 (0.558-1.030)
e 2-sided P 0757»
60
e 63.7 mo (A = 14.9)
a) >
pa 48.8 mo
Sw
= Abe ic
Paionts,n Events, 00 emaciclib + NSAI
27 avemaci + NSAL m 113.65) Placebo + NSAI
107 Placebo + NSAL so 65.72)
ol
0 6 2 18 M 20 % 42 de 54 © 66 72 78 84 90 9
No. at Risk Time, mo
Avemaciit +NSAI 173 161 147 128 120 118 107 100 95 00 78 72 60 59 40 45 27 0
Abemaciclib + NSAI resulted in a numerically longer OS compared with NSAI alone in the sVD; clinically significant
but statistical significance was not reached; the observed improvement in median OS was 14.9 months
Di ot reac threshold (0.009) for satstea signfcance at hs fra ana =
1. Gotz MP et al SABCS 2023, Abatct 050112 - PeerView.com
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Visceral Disease!
100 Abemaciclib + NSAI Placebo + NSAI
E Median OS, mo 637 488
e HR (95%) 0.758 (0.558-1.030)
e 2-sided P 0757»
60
e 63.7 mo (A = 14.9)
a) >
pa 48.8 mo
Sw
= Abe ic
Paionts,n Events, 00 emaciclib + NSAI
27 avemaci + NSAL m 113.65) Placebo + NSAI
107 Placebo + NSAL so 65.72)
ol
0 6 2 18 M 20 % 42 de 54 © 66 72 78 84 90 9
No. at Risk Time, mo
Avemaciit +NSAI 173 161 147 128 120 118 107 100 95 00 78 72 60 59 40 45 27 0
Abemaciclib + NSAI resulted in a numerically longer OS compared with NSAI alone in the sVD; clinically significant
but statistical significance was not reached; the observed improvement in median OS was 14.9 months
Di ot reac threshold (0.009) for satstea signfcance at hs fra ana =
1. Gotz MP et al SABCS 2023, Abatct 050112 - PeerView.com
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MONARCH-3: Updated PFS in the ITT Population!
100
2 Abemaciclib+NSAl Placebo + NSAI
= Median PFS, mo 29.0 148
2 2 HR (95%) 0.535 (0.535 (0.429-0.668)
gs 29.0 mo (A = 14.3) Nominal P 00012
a 40
30
20 ‘Abemaciclib + NSAI
i Pisa + A
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Pa Time, mo
Abemacilb + NSAI 328 251 209 173 143 121 99 88 76 61 54 45 41 30 31 25 10
Placebo +NSAI 165114 84 61 St 31 21 19 15 13 11 7 5 5 5 3 0
The addition of abemaciclib to NSAI resulted in a 14.3-month improvement in median PFS
with continued separation of the curves at longer follow-up
Statista signiicance was reached ate interim PFS analysis 7
1. Goetz MP et al SABCS 2023, Abstract 6801.12. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
100
2 Abemaciclib+NSAl Placebo + NSAI
= Median PFS, mo 29.0 148
2 2 HR (95%) 0.535 (0.535 (0.429-0.668)
gs 29.0 mo (A = 14.3) Nominal P 00012
a 40
30
20 ‘Abemaciclib + NSAI
i Pisa + A
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Pa Time, mo
Abemacilb + NSAI 328 251 209 173 143 121 99 88 76 61 54 45 41 30 31 25 10
Placebo +NSAI 165114 84 61 St 31 21 19 15 13 11 7 5 5 5 3 0
The addition of abemaciclib to NSAI resulted in a 14.3-month improvement in median PFS
with continued separation of the curves at longer follow-up
Statista signiicance was reached ate interim PFS analysis 7
1. Goetz MP et al SABCS 2023, Abstract 6801.12. PeerView.com
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MONARCH-3: Updated PFS in Subgroups’
EventsiN HR (95% CI) P Median, mo
‘Abema+Al Placebo + Al
mr 293493 0.525 (0.415.0.665) 282 148
Baseline ECOG PS
o 1787296 051200281068) — 798 282 157
1 118/197 0.546 (0.373-0.798) 290 142
Bone-only metastasis.
Yes 57/109 171 (0280-0793) 79 389 266
393.0 665)
‘Liver metasiasis
Fe 5 OSRAM gg St “|
ln sone, zer i u!
nn |
1 Positive 2217983 05860424072) yg 204 156 1
"Negative 701106 0.427 (0.265-0.687) 270 94 1
1 Tumor grade 1
arts mars 054s.0400a7s7) m 210 us |
High 56/97 0.322 (0.190-0.546) 353 90 1
essen i
AS same on so ar ml
92 04 06 08 10
Favors abemaciclib+Al Favors placebo + AI
Treatment benefit observed across all subgroups, with the largest effects observed in patients with liver metastases,
progesterone receptor-negative tumors, high-grade tumors, or TFI <36 months
1. Goetz MP et a. SABCS 2023, Abstract 6801-12. PeerView.com
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EventsiN HR (95% CI) P Median, mo
‘Abema+Al Placebo + Al
mr 293493 0.525 (0.415.0.665) 282 148
Baseline ECOG PS
o 1787296 051200281068) — 798 282 157
1 118/197 0.546 (0.373-0.798) 290 142
Bone-only metastasis.
Yes 57/109 171 (0280-0793) 79 389 266
393.0 665)
‘Liver metasiasis
Fe 5 OSRAM gg St “|
ln sone, zer i u!
nn |
1 Positive 2217983 05860424072) yg 204 156 1
"Negative 701106 0.427 (0.265-0.687) 270 94 1
1 Tumor grade 1
arts mars 054s.0400a7s7) m 210 us |
High 56/97 0.322 (0.190-0.546) 353 90 1
essen i
AS same on so ar ml
92 04 06 08 10
Favors abemaciclib+Al Favors placebo + AI
Treatment benefit observed across all subgroups, with the largest effects observed in patients with liver metastases,
progesterone receptor-negative tumors, high-grade tumors, or TFI <36 months
1. Goetz MP et a. SABCS 2023, Abstract 6801-12. PeerView.com
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Coming Back to Our Case
ao
A 64-year-old postmenopausal woman, a gastroenterologist, with a history of invasive carcinoma of the
breast (ductal), pT2NO, grade 3, ER+ (90%), PgR+ (50%), HER2-; 2.8-cm mass + enlarged, suspicious
axillary LN > received lumpectomy, adjuvant TC, breast RT, adjuvant Al > 2 years after starting Al develops
right hip pain > imaging reveals lytic bone lesions > staging scans reveal extensive liver metastases and
bony metastases involving spine, hip, and ribs > biopsy of the liver shows ER+, PgR+, HER2-; BRCA1/2-
Let’s discuss:
> What treatment would you recommend to this patient?
> What would you recommend if instead of the current presentation the patient:
= Had developed recurrence 2 years after completing 5 years of adjuvant Al with bone only disease?
= Had specific comorbidities such as cardiac disease?
= Other considerations for treatment selection (PR-, tumor grade, short treatment-free interval)?
Copyright © 2000-2024, PeerView
ao
A 64-year-old postmenopausal woman, a gastroenterologist, with a history of invasive carcinoma of the
breast (ductal), pT2NO, grade 3, ER+ (90%), PgR+ (50%), HER2-; 2.8-cm mass + enlarged, suspicious
axillary LN > received lumpectomy, adjuvant TC, breast RT, adjuvant Al > 2 years after starting Al develops
right hip pain > imaging reveals lytic bone lesions > staging scans reveal extensive liver metastases and
bony metastases involving spine, hip, and ribs > biopsy of the liver shows ER+, PgR+, HER2-; BRCA1/2-
Let’s discuss:
> What treatment would you recommend to this patient?
> What would you recommend if instead of the current presentation the patient:
= Had developed recurrence 2 years after completing 5 years of adjuvant Al with bone only disease?
= Had specific comorbidities such as cardiac disease?
= Other considerations for treatment selection (PR-, tumor grade, short treatment-free interval)?
Copyright © 2000-2024, PeerView
Let’s Consider Another Case (S)
f
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC.
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 18 months develops
asymptomatic progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals no ESR1 mutations, gBRCA1/2 mutations, or
PIK3CA/AKT/PTEN pathway alterations
PeerView.com/BEX827 Copyright
f
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC.
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 18 months develops
asymptomatic progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals no ESR1 mutations, gBRCA1/2 mutations, or
PIK3CA/AKT/PTEN pathway alterations
PeerView.com/BEX827 Copyright
Therapeutic Advances in the
Second-Line Setting and Beyond
Second-Line Setting and Beyond
HR+/HER2- Advanced Breast Cancer After First-Line
CDKi Progression (Randomized Data)
Drug Trial r CDKi mPFS, mo
Amcenestrant AMEERA-3? 80 3.6 (independent of ESR1 mutation)
Camizestrant SERENA-2* (phase 2) 50 9.2 (150 mg and ESR1 mutation)
Vepdegestrant VERITAC-2° (phase 2) 100 5.5 (ESR1 mutation)
Venetoclax VERONICA’ (phase 2) 100 2.69
Fulvestrant VERONICA’ (phase 2) 100 1.94
Ribociclib MAINTAINS (phase 2) 100 53
Palbociclib PACE® (phase 2) 100 46
Palbociclib PALMIRA' (phase 2) 100 49
Capivasertib CAPltello-2911! (phase 3) 70 7.3 (pathway altered)
_Alpelisib______ BYLieve12 (nonrandomized) 100 73(cohortA)
1. Martin M. Gin Oncol. Published online March 2, 2024 do: 10.1200/JCO.28 01500. 2 Tolaney Set al. Cin Oncol. 2023:41:014-4024.
3 Bardia À Future Oncol 2019:15:3200-3218. 4. Olvera Metal. SABCS 2022. Abstract GS3-02 5, Goetz Met al Ann Oncol, 2023/34: 1141-1151
8. Hurviz Seta. SABCS 2022. Abstract G53-03. 7. Lindeman GJ ta. Cin Cancer Res. 202228:3258-3267. 8, Kalnaky K et al. J Cin Oncol 2023:41:4004-4013.
8 Mayer EL tal J Ci Orel Putas ening March 21 204. do: 101200400 23 0104010 Cssac A tal Anal Ona 2019305 (upp abs VIA) 7
11. Tumer NC et al. N Eng Med. 2023:3882058-2070. 12. Rugo HS etal. Lancet Oncol, 2021;22 480-4 PeerView.com
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CDKi Progression (Randomized Data)
Drug Trial r CDKi mPFS, mo
Amcenestrant AMEERA-3? 80 3.6 (independent of ESR1 mutation)
Camizestrant SERENA-2* (phase 2) 50 9.2 (150 mg and ESR1 mutation)
Vepdegestrant VERITAC-2° (phase 2) 100 5.5 (ESR1 mutation)
Venetoclax VERONICA’ (phase 2) 100 2.69
Fulvestrant VERONICA’ (phase 2) 100 1.94
Ribociclib MAINTAINS (phase 2) 100 53
Palbociclib PACE® (phase 2) 100 46
Palbociclib PALMIRA' (phase 2) 100 49
Capivasertib CAPltello-2911! (phase 3) 70 7.3 (pathway altered)
_Alpelisib______ BYLieve12 (nonrandomized) 100 73(cohortA)
1. Martin M. Gin Oncol. Published online March 2, 2024 do: 10.1200/JCO.28 01500. 2 Tolaney Set al. Cin Oncol. 2023:41:014-4024.
3 Bardia À Future Oncol 2019:15:3200-3218. 4. Olvera Metal. SABCS 2022. Abstract GS3-02 5, Goetz Met al Ann Oncol, 2023/34: 1141-1151
8. Hurviz Seta. SABCS 2022. Abstract G53-03. 7. Lindeman GJ ta. Cin Cancer Res. 202228:3258-3267. 8, Kalnaky K et al. J Cin Oncol 2023:41:4004-4013.
8 Mayer EL tal J Ci Orel Putas ening March 21 204. do: 101200400 23 0104010 Cssac A tal Anal Ona 2019305 (upp abs VIA) 7
11. Tumer NC et al. N Eng Med. 2023:3882058-2070. 12. Rugo HS etal. Lancet Oncol, 2021;22 480-4 PeerView.com
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What About 2L CDKi Post-Progression on 1L CDKi?1+3
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
“Continuation” CDK4/6i Ribociclib Palbociclib Palbociclib
letrozole
PFS ET only, mo
PFS fulvestrant + CDK4/6i, mo
Different studies, designs, study populations, and subgroup definitions
1. Kaïnsky K et al J Clin Oncol. 2023;41:4004-4013, 2. Mayer EL et al. SABCS 2022. Abstract GS3-0. 3, Liombar-Cussae A et a. ASCO 2023, Abstract 1001 PeerView.com
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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
“Continuation” CDK4/6i Ribociclib Palbociclib Palbociclib
letrozole
PFS ET only, mo
PFS fulvestrant + CDK4/6i, mo
Different studies, designs, study populations, and subgroup definitions
1. Kaïnsky K et al J Clin Oncol. 2023;41:4004-4013, 2. Mayer EL et al. SABCS 2022. Abstract GS3-0. 3, Liombar-Cussae A et a. ASCO 2023, Abstract 1001 PeerView.com
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Does abemaciclib + fulvestrant improve outcomes
after adjuvant or first-line CDK4/6i + ET?
1. MipsIcicatiis govstudyINCTOS169567. 2. htps/clnicalirials govlstudyINCTO497S308,
PeerView.com/BEX827
+ HR#/HER2- MBC pre-
and postmenopausal
adults (women and men)
+ Prior therapy:
= Advanced setting:
Disease progression
on CDK4/6i plus an Al
as initial therapy, or
— Adjuvant setting:
Disease recurrence on
or after CDK4/6i + ET
(N=350)
Other Key Studies Assessing Continuation
of CDK4/6 Inhibition Beyond Progression
postMONARCH (NCT05169567)*
Abemaciclib + fulvestrant
Placebo + fulvestrant
EMBER-3 (NCT04975308)?
How well does imlunestrant + abemaciclib work
compared with standard hormone therapy?
HR+, HER2- locally
ABC or MBC.
+ Iffemale,
postmenopausal
+ ECOG PS 0or1
+ Measurable disease
(per RECIST v1.1)
+ Adequate organ
function
Imlunestrant +
abemaciclib
Exemestane or
fulvestrant
Imlunestrant
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after adjuvant or first-line CDK4/6i + ET?
1. MipsIcicatiis govstudyINCTOS169567. 2. htps/clnicalirials govlstudyINCTO497S308,
PeerView.com/BEX827
+ HR#/HER2- MBC pre-
and postmenopausal
adults (women and men)
+ Prior therapy:
= Advanced setting:
Disease progression
on CDK4/6i plus an Al
as initial therapy, or
— Adjuvant setting:
Disease recurrence on
or after CDK4/6i + ET
(N=350)
Other Key Studies Assessing Continuation
of CDK4/6 Inhibition Beyond Progression
postMONARCH (NCT05169567)*
Abemaciclib + fulvestrant
Placebo + fulvestrant
EMBER-3 (NCT04975308)?
How well does imlunestrant + abemaciclib work
compared with standard hormone therapy?
HR+, HER2- locally
ABC or MBC.
+ Iffemale,
postmenopausal
+ ECOG PS 0or1
+ Measurable disease
(per RECIST v1.1)
+ Adequate organ
function
Imlunestrant +
abemaciclib
Exemestane or
fulvestrant
Imlunestrant
PeerView.com
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postMONARCH: Abemaciclib + Fulvestrant
Following Progression on P
Primary Analysi
PFS, %
g
ior CDK4/6i + ET
bemaciclib Improved Investigator-Assessed PFS
Abemaciellb bo
+ Fulvestrant — + Fulvestrant
(n= 18;
117 141
Median (95% Cl),mo 60(5686) 5387.58)
HR (95% CI) 0.73(0.57-0.5)
Pp 02
Abemaciclib + fulvestrant
L,
Placebo + fulvestrant
o 3
No at Rsk
Abe hiv 182 m
PRO +R 186 m
15 18
2
Abemaciclib led to 27% reduction in the risk of developing PFS event.
1. Kaïnsk K et al ASCO 2024. Abstract LBA1001
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Following Progression on P
Primary Analysi
PFS, %
g
ior CDK4/6i + ET
bemaciclib Improved Investigator-Assessed PFS
Abemaciellb bo
+ Fulvestrant — + Fulvestrant
(n= 18;
117 141
Median (95% Cl),mo 60(5686) 5387.58)
HR (95% CI) 0.73(0.57-0.5)
Pp 02
Abemaciclib + fulvestrant
L,
Placebo + fulvestrant
o 3
No at Rsk
Abe hiv 182 m
PRO +R 186 m
15 18
2
Abemaciclib led to 27% reduction in the risk of developing PFS event.
1. Kaïnsk K et al ASCO 2024. Abstract LBA1001
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postMONARCH: Abemaciclib + Fulvestrant
Following Progression on Prior CDK4/6i + ET!
Investigator-Assessed PFS by Subgroup: Consistent Effect Across Subgroups
ona
Esto eo. Ban
te oe no
vo z m oran
e mw omauanı
me nao
ae on nate a
e ee osas
a o 3 omar
aca or et mm umasamı
ARE me ona co 5 © ono
1. Kaïnaky K etal ASCO 2024. Abstract LBA1001 PeerView.com
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Following Progression on Prior CDK4/6i + ET!
Investigator-Assessed PFS by Subgroup: Consistent Effect Across Subgroups
ona
Esto eo. Ban
te oe no
vo z m oran
e mw omauanı
me nao
ae on nate a
e ee osas
a o 3 omar
aca or et mm umasamı
ARE me ona co 5 © ono
1. Kaïnaky K etal ASCO 2024. Abstract LBA1001 PeerView.com
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postMONARCH: Abemaciclib + Fulvestrant
Following Progres
n on Prior CDK4/6i + ET!
Secondary Analysis: BICR-Assessed PFS
5 mo PFS ate
» Ss Sm 506977
o hi HR CD 2:07)
Pr H pa Fr
Sipe Abemacicll + fuvestrant
be 1 7 Estimates impacted
= H pro «a ne sta à ORR by 7
5 H (ascordance vi mentos Investigator, %
H ‘Sten: 1% sbemacei am,
Sr er ee o pacto em)
Time, mo
ee wees 1 0 ORRby BICR% = 23
‘Abemaciclib led to 45% reduction in the risk of developing PFS
event per BICR
1. Kalinshy K etal. ASCO 2024, Abstract BA1001
PeerView.com/BEX827
Nominal P
Value
7 ous
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Following Progres
n on Prior CDK4/6i + ET!
Secondary Analysis: BICR-Assessed PFS
5 mo PFS ate
» Ss Sm 506977
o hi HR CD 2:07)
Pr H pa Fr
Sipe Abemacicll + fuvestrant
be 1 7 Estimates impacted
= H pro «a ne sta à ORR by 7
5 H (ascordance vi mentos Investigator, %
H ‘Sten: 1% sbemacei am,
Sr er ee o pacto em)
Time, mo
ee wees 1 0 ORRby BICR% = 23
‘Abemaciclib led to 45% reduction in the risk of developing PFS
event per BICR
1. Kalinshy K etal. ASCO 2024, Abstract BA1001
PeerView.com/BEX827
Nominal P
Value
7 ous
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postMONARCH: Abemaciclib + Fulvestrant
Following Progression on Prior CDK4/6i + ET
Safety Consistent With Known Abemaciclib Profile
Abemaciclib + Fulvestrant (n = 181) Placebo + Fulvestrant (
‘Grade 5 TRAE”, n (%) 108) o
Dose reduction due to AE, n (%) 55 (20.0) 6@0)
Discontinuation due to AE, n (% 41 (60) 0
TEAES, % Any Grade Any Grade Grade 23
Any 97 82 20
Diarhea 75 7 2
Neutropenia? 41 3 o
‘Anemia? 35 15 4
Fatigue” 3 3 23 1
Nausea 3 3 18 o
Abdominal pain? 24 2 16 o
Vomiting 20 2 6 o
‘Thrombocytopenia? 18 4 6 2
Decreased appetite 18 1 7 o
Leukopenia® 18 8 3 o
AST increased 15 6 " 2
ALT increased 13 4 10 2
Arthralgia 12 1 12 1
Greatiine increased 1 o 2 o
Cough “ 0 7 o
vr 2 3 1
3 3 1 2
One grade 5 TRAE of pneumonia
* Consolidated term Includes: wo febrie nevropenia (one grade 3, one grade 4). one grade 5 pulmonary embolism, * one grade 3, on grade 4 LD. 7
1. KalnakyK et al ASCO 2024. Abstract LBATOO1 PeerView.com
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Following Progression on Prior CDK4/6i + ET
Safety Consistent With Known Abemaciclib Profile
Abemaciclib + Fulvestrant (n = 181) Placebo + Fulvestrant (
‘Grade 5 TRAE”, n (%) 108) o
Dose reduction due to AE, n (%) 55 (20.0) 6@0)
Discontinuation due to AE, n (% 41 (60) 0
TEAES, % Any Grade Any Grade Grade 23
Any 97 82 20
Diarhea 75 7 2
Neutropenia? 41 3 o
‘Anemia? 35 15 4
Fatigue” 3 3 23 1
Nausea 3 3 18 o
Abdominal pain? 24 2 16 o
Vomiting 20 2 6 o
‘Thrombocytopenia? 18 4 6 2
Decreased appetite 18 1 7 o
Leukopenia® 18 8 3 o
AST increased 15 6 " 2
ALT increased 13 4 10 2
Arthralgia 12 1 12 1
Greatiine increased 1 o 2 o
Cough “ 0 7 o
vr 2 3 1
3 3 1 2
One grade 5 TRAE of pneumonia
* Consolidated term Includes: wo febrie nevropenia (one grade 3, one grade 4). one grade 5 pulmonary embolism, * one grade 3, on grade 4 LD. 7
1. KalnakyK et al ASCO 2024. Abstract LBATOO1 PeerView.com
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Coming Back to Our Case
pS
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 18 months develops asymptomatic
progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals no ESR1 mutations, gBRCA1/2 mutations, or PIK3CA/AKT/PTEN
pathway alterations
Let’s discuss:
> What treatment would you recommend to this patient and why?
> What are the implications of the postMONARCH trial results presented at ASCO 2024?
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
pS
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 18 months develops asymptomatic
progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals no ESR1 mutations, gBRCA1/2 mutations, or PIK3CA/AKT/PTEN
pathway alterations
Let’s discuss:
> What treatment would you recommend to this patient and why?
> What are the implications of the postMONARCH trial results presented at ASCO 2024?
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
Case Variation
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 10 months develops asymptomatic
progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals an ESR1 mutation and PIK3CA mutation
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
+ A67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
+ Receives first-line CDK4/6i (palbociclib) + ET, but after 10 months develops asymptomatic
progression in bone and 1.5-cm new liver lesions
+ ctDNA testing reveals an ESR1 mutation and PIK3CA mutation
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Acquired ESR1 Mutations‘?
Clonal Selection Scenarios
Preexisting rare mutation De novo acquired mutation
Primary ER+
breast ESR1 mutations: ~1%
cancer
Endocrine therapy
(Als, Tam)
Recurrent
disease
H
z
iy a V7 ESR1 mutations: 10%-50%
4. Jeselsohn R et al. Nat Rev Cn Oncol 015:12:573-583. 2. Zundelavich À et al Broast Cancer Res. 2020:22:16. PeerView.com
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Clonal Selection Scenarios
Preexisting rare mutation De novo acquired mutation
Primary ER+
breast ESR1 mutations: ~1%
cancer
Endocrine therapy
(Als, Tam)
Recurrent
disease
H
z
iy a V7 ESR1 mutations: 10%-50%
4. Jeselsohn R et al. Nat Rev Cn Oncol 015:12:573-583. 2. Zundelavich À et al Broast Cancer Res. 2020:22:16. PeerView.com
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ESR1 Mutations: Liquid Biopsy Testing Is the Standard!
ctDNA testing identified more ESR1 mutations Different
metastases may develop different
than contemporaneous biopsy
resistance mutations
‘Contemporaneous Paired Samples
ms
92 10 Ez) 987
15%
|
|
|
25%
ou
oe bot antl
0. On
TACT (v=) VER 558) ERE PRGA = 5) NDA —
ae en ce MOON
pa
A. Tumer NC et al, Lancet Oncol. 202021:1296-1308, PeerView.com
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ctDNA testing identified more ESR1 mutations Different
metastases may develop different
than contemporaneous biopsy
resistance mutations
‘Contemporaneous Paired Samples
ms
92 10 Ez) 987
15%
|
|
|
25%
ou
oe bot antl
0. On
TACT (v=) VER 558) ERE PRGA = 5) NDA —
ae en ce MOON
pa
A. Tumer NC et al, Lancet Oncol. 202021:1296-1308, PeerView.com
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Overview of ER-Targeted Therapies’
E
El
3
ee
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A. Cott C et al, Cancer Treat Rev 2023:117:102569,
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E
El
3
ee
PeerView.com
A. Cott C et al, Cancer Treat Rev 2023:117:102569,
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EMERALD Phase 3 Trial of Elacestrant vs SOC
in ER+/HER2- MBC: Study Design and Patients’?
Key Eligibility Criteria Elacestrant
ER#HER2- MBC Patient Characteristics.¢n(%) |All ESRAmut
+ 1-2 prior lines of ET, one of which in combination (n=239) (n= 115)
with CDK4/6i
+ 1 line of chemotherapy for advanced disease Median age (range), years 63 (24-89) 64 (28-89)
+ ECOG PS 0-1 Female 233(97.5) 115 (100)
0 143(598) 67 (58.3)
ECOGPS
96(402) 48 (41.7)
MARTE, Visceral metastasis, % 163682) 81(70.4)
(soc Prior CDK4/6i 239(100) 115 (100)
A 73(63:
eee 29(540) 73 (635)
110(460) 42(36.5)
Fulvestrant 70(293) 27 (23.5)
TipeofpiorET Al 193(808) 101 (7.
PD or withdrawal eriterion® ARME ee)
Tamoxten 1979) 978)
89774)
26 (22.6)
63 (32-83)
238 (99.6)
135 (56.5)
103 (43.1)
170 (71.1)
239 (100)
142 (59.4)
97 (40.6)
75 (31.4)
194 (81.2)
15 (6.3)
180 753)
59 (24.7)
63 (32-83)
113 (100)
61 (54.9)
51 (45.1)
84 (743)
113 (100)
69 (61.1)
44 (889)
28 (246)
96 (85.0)
90)
8117)
32 (28.3)
Primary endpoints: PES in al, PFS in ESRimut | nes CT 0 191 (799)
ondary endpoints: OS, safety ot es! 1 48 (20.1)
* Protocol defined dose reductions permitted. > Restagng CT scans every 8 weeks. © By BICR. “Patient characteristics are update trom 2022 SGO presentation.
1. Bidad Fetal. J Cin Oncol. 2022:40'3248-3256, 2 Bardia A et al SABCS 2022. Abstract GS3.01
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in ER+/HER2- MBC: Study Design and Patients’?
Key Eligibility Criteria Elacestrant
ER#HER2- MBC Patient Characteristics.¢n(%) |All ESRAmut
+ 1-2 prior lines of ET, one of which in combination (n=239) (n= 115)
with CDK4/6i
+ 1 line of chemotherapy for advanced disease Median age (range), years 63 (24-89) 64 (28-89)
+ ECOG PS 0-1 Female 233(97.5) 115 (100)
0 143(598) 67 (58.3)
ECOGPS
96(402) 48 (41.7)
MARTE, Visceral metastasis, % 163682) 81(70.4)
(soc Prior CDK4/6i 239(100) 115 (100)
A 73(63:
eee 29(540) 73 (635)
110(460) 42(36.5)
Fulvestrant 70(293) 27 (23.5)
TipeofpiorET Al 193(808) 101 (7.
PD or withdrawal eriterion® ARME ee)
Tamoxten 1979) 978)
89774)
26 (22.6)
63 (32-83)
238 (99.6)
135 (56.5)
103 (43.1)
170 (71.1)
239 (100)
142 (59.4)
97 (40.6)
75 (31.4)
194 (81.2)
15 (6.3)
180 753)
59 (24.7)
63 (32-83)
113 (100)
61 (54.9)
51 (45.1)
84 (743)
113 (100)
69 (61.1)
44 (889)
28 (246)
96 (85.0)
90)
8117)
32 (28.3)
Primary endpoints: PES in al, PFS in ESRimut | nes CT 0 191 (799)
ondary endpoints: OS, safety ot es! 1 48 (20.1)
* Protocol defined dose reductions permitted. > Restagng CT scans every 8 weeks. © By BICR. “Patient characteristics are update trom 2022 SGO presentation.
1. Bidad Fetal. J Cin Oncol. 2022:40'3248-3256, 2 Bardia A et al SABCS 2022. Abstract GS3.01
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=
ra
E
# ©
2 s
a 4
E
e pu
2 >
TERN eo ee
POS Time, mo
(n= 239) (02250)
Event, n (%) 144 (60.3) 156 (65.5)
HR (95% Cl) 0.70 (0.55-0.88)
P 0018
6-mo OS, % (95% CI) 34.3 (27.2-41.5) 20.4 (14.1-26.7)
12-mo OS, % (95% CI) 223(15.2-29.4) 9.4 (4.0-14.8)
EMERALD: PFS With Elacestrant vs SOC
in ITT and ESR1mut Populations’
PFS in All Patients
1. Bidar Feta. J Cin Oncol. 2022:40:3246-3256,
PeerView.com/BEX827
PFS in Patients With ESR1mut Tumors
so
E
>
o
Los
Lo A
2 soc
E
:
ue
Event, n (%) 62 (53.9) 78 (69.0)
HR (95% Cl) 0.55 (0.39-0.77)
iR 0005
6-mo OS, % (95% Cl) 40.8 (30.1-51.4) 19.1 (10.5-27.8)
12-mo OS, % (95% Cl) 26.8 (16.2-37.4) 8.2 (1.3-15.1)
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ra
E
# ©
2 s
a 4
E
e pu
2 >
TERN eo ee
POS Time, mo
(n= 239) (02250)
Event, n (%) 144 (60.3) 156 (65.5)
HR (95% Cl) 0.70 (0.55-0.88)
P 0018
6-mo OS, % (95% CI) 34.3 (27.2-41.5) 20.4 (14.1-26.7)
12-mo OS, % (95% CI) 223(15.2-29.4) 9.4 (4.0-14.8)
EMERALD: PFS With Elacestrant vs SOC
in ITT and ESR1mut Populations’
PFS in All Patients
1. Bidar Feta. J Cin Oncol. 2022:40:3246-3256,
PeerView.com/BEX827
PFS in Patients With ESR1mut Tumors
so
E
>
o
Los
Lo A
2 soc
E
:
ue
Event, n (%) 62 (53.9) 78 (69.0)
HR (95% Cl) 0.55 (0.39-0.77)
iR 0005
6-mo OS, % (95% Cl) 40.8 (30.1-51.4) 19.1 (10.5-27.8)
12-mo OS, % (95% Cl) 26.8 (16.2-37.4) 8.2 (1.3-15.1)
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EMERALD: PFS in ESR1mut by Duration
of Prior CDK4/6i'
PFS by Duration of CDK4/6i in Patients With ESR1mut Tumors.
26 Months CDKAI6i 212 Months CDKAI6i 218 Months CDK4/6i
* x. *
¢ ¢ E
É £ £
3 o 3.”
E 2. cea 2. Brent
3 »
i i ES
A att Timm
PFS by
Duration Elacestrant Elacestrant Elacestrant
of CDK4/ (n=103) { 8) (n= 55)
mPFS,
mo (95% CI) 4.14 (220-779) 1.87 (1.87-3.29) 8.61 (4.14-10.84) 1.91 (1.87-3.68) 8.61 (5.45-16.89) 2.10 (1.87-3.75)
ROC) 260215123692) 645 (0.001365) 35.81 (21.84.4978) 830(000-17.66) —23570(19545205) — 773(0.002020)
HR (95% Cl 0.517 (0.361-0.738) 0.410 (0.262-0.634) 466 (0.270-0.791
1. Kaklamani VO et al. ASCO 2023 Abstract 1070. PeerView.com
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of Prior CDK4/6i'
PFS by Duration of CDK4/6i in Patients With ESR1mut Tumors.
26 Months CDKAI6i 212 Months CDKAI6i 218 Months CDK4/6i
* x. *
¢ ¢ E
É £ £
3 o 3.”
E 2. cea 2. Brent
3 »
i i ES
A att Timm
PFS by
Duration Elacestrant Elacestrant Elacestrant
of CDK4/ (n=103) { 8) (n= 55)
mPFS,
mo (95% CI) 4.14 (220-779) 1.87 (1.87-3.29) 8.61 (4.14-10.84) 1.91 (1.87-3.68) 8.61 (5.45-16.89) 2.10 (1.87-3.75)
ROC) 260215123692) 645 (0.001365) 35.81 (21.84.4978) 830(000-17.66) —23570(19545205) — 773(0.002020)
HR (95% Cl 0.517 (0.361-0.738) 0.410 (0.262-0.634) 466 (0.270-0.791
1. Kaklamani VO et al. ASCO 2023 Abstract 1070. PeerView.com
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EMERALD: Improvement in PFS Across All Subgroups’
PIK3CA-mut PIK3CA-wt
212 mo Prior CDK4/6i 212 mo Prior CDK4/6i
as With ESR1mut and PIK3CAmut ar With ESR1mut and PIK3CAwt
mPFS mo CI) — S45(2141084) 194180390)
A A PFS, mo (95% CI) 909(640-1689) 187187370)
60 0) 60
= HR (95% CH) 0423 0.176-041) = nena cant AS
2 2
Eso * 0
lacestran
20 Elacestrant 2 E
o
3 70 15 20 2 20 o 5 10 15 2 2 30
Time, mo Time, mo
No, at Risk
Elacestant 27 13 7 6 5 5 2 2 2 2 2 2 2 0 70a 1
sc 38 10 8 5 4 3 1 0 ado
1. Bardia A etal. SABCS 2023 Abstract PS16-01 PeerView.com
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PIK3CA-mut PIK3CA-wt
212 mo Prior CDK4/6i 212 mo Prior CDK4/6i
as With ESR1mut and PIK3CAmut ar With ESR1mut and PIK3CAwt
mPFS mo CI) — S45(2141084) 194180390)
A A PFS, mo (95% CI) 909(640-1689) 187187370)
60 0) 60
= HR (95% CH) 0423 0.176-041) = nena cant AS
2 2
Eso * 0
lacestran
20 Elacestrant 2 E
o
3 70 15 20 2 20 o 5 10 15 2 2 30
Time, mo Time, mo
No, at Risk
Elacestant 27 13 7 6 5 5 2 2 2 2 2 2 2 0 70a 1
sc 38 10 8 5 4 3 1 0 ado
1. Bardia A etal. SABCS 2023 Abstract PS16-01 PeerView.com
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EMERALD: Consistent Improvement in PFS
Across All Relevant ESR1mut Subgroups vs SOC
PFS Summary in ESR1-mut Patients With 12 Months of Prior CDK4/6 Inhibitor
Median PFS, mo (95% Cl)
Patients HR (95% Cl)
Elacestrant
All ESR1mut patients 159 (100) | 8.61 (4.14-10.84) | 1.91 (1.87-3.68) 0.41 (0.26-0.63)
1.91 (1.87-3.71) 0.38 (0.23-0.62)
1.87 (1.84-1.94) 0.35 (0.21-0.59)
ESR tmut and bone mets? 136 (86) | 9.13 (5.49-16.89)
ESR mut and liver and/or lungmets® 113(71) | 7.26 (2.20-10.84)
ESR1mut and PIK3CAmut® 62 (39)
5.45 (2.14-10.84) | 1.94 (1.84-3.94) 0.42 (0.18-0.94)
ESRimut and HER2-low expression? 48 (77) | 9.03 (5.49-16.89)
1.87 (1.84-3.75) 0.30 (0.14-0.60)
ESRimut and TP53mut 38 (61) 8.61 (3.65-24.25) | 1.87 (1.84-3.52) 0.30 (0.13-0.64)
85% of pis had bone and other tes ol mets (30% ofthese pis had no Ive or lung involvement) 55% of patients had Iver and other sites of mets (10% ofthese
had no lung or bone involvement) 25% of pts had ung and other sites of mets (2% ofthese pts had no liver or bone involvement) Includes ES4SK, H1047R, ES2K
“amongst ers *MERZ IHC 1+, and 2+ wih no ISH ampiifieaon. Data not availabe fr al patents =;
Y Bardia À et a. SABCS 2023, Abstract 51601 PeerView.com
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Across All Relevant ESR1mut Subgroups vs SOC
PFS Summary in ESR1-mut Patients With 12 Months of Prior CDK4/6 Inhibitor
Median PFS, mo (95% Cl)
Patients HR (95% Cl)
Elacestrant
All ESR1mut patients 159 (100) | 8.61 (4.14-10.84) | 1.91 (1.87-3.68) 0.41 (0.26-0.63)
1.91 (1.87-3.71) 0.38 (0.23-0.62)
1.87 (1.84-1.94) 0.35 (0.21-0.59)
ESR tmut and bone mets? 136 (86) | 9.13 (5.49-16.89)
ESR mut and liver and/or lungmets® 113(71) | 7.26 (2.20-10.84)
ESR1mut and PIK3CAmut® 62 (39)
5.45 (2.14-10.84) | 1.94 (1.84-3.94) 0.42 (0.18-0.94)
ESRimut and HER2-low expression? 48 (77) | 9.03 (5.49-16.89)
1.87 (1.84-3.75) 0.30 (0.14-0.60)
ESRimut and TP53mut 38 (61) 8.61 (3.65-24.25) | 1.87 (1.84-3.52) 0.30 (0.13-0.64)
85% of pis had bone and other tes ol mets (30% ofthese pis had no Ive or lung involvement) 55% of patients had Iver and other sites of mets (10% ofthese
had no lung or bone involvement) 25% of pts had ung and other sites of mets (2% ofthese pts had no liver or bone involvement) Includes ES4SK, H1047R, ES2K
“amongst ers *MERZ IHC 1+, and 2+ wih no ISH ampiifieaon. Data not availabe fr al patents =;
Y Bardia À et a. SABCS 2023, Abstract 51601 PeerView.com
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Select Clinical Trials With ER-Targeting Therapies
PROTAC
Giredestrant Camizestrant Imlunestrant Vepedegestrant Palezestrant
METASTATIC SETTING
1L: Combination PersevERA: NCTO4546009 | seRena-4: NCTO4711252 | EMBER 1: NCTO4188548 VERITAC-3.
O rd AI) Prose) | crasosse (Phase 3)
A: Combination Same
with CDK4/6i NCTO4964934
(switch) (Phase 3-ESR1m)
Post COK as A e | _venmea _Jorenaoı novosorerse
itor crore ‘ena (Phased) | morose erase) | nase)
EARLY-STAGE SETTING
Preoperative | comena moroeseras [seras nome] enserz worusner]| GIVEN,
Sting ‘trae ‘one ere’) coset
HER CARIN
Adjuvant seting | cris ES
Das ‘nase
fajwvant ting CHER nomeması | EMBER NOTOREOSE
swe (ne ene’
Results available
Trial completed accrual
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PROTAC
Giredestrant Camizestrant Imlunestrant Vepedegestrant Palezestrant
METASTATIC SETTING
1L: Combination PersevERA: NCTO4546009 | seRena-4: NCTO4711252 | EMBER 1: NCTO4188548 VERITAC-3.
O rd AI) Prose) | crasosse (Phase 3)
A: Combination Same
with CDK4/6i NCTO4964934
(switch) (Phase 3-ESR1m)
Post COK as A e | _venmea _Jorenaoı novosorerse
itor crore ‘ena (Phased) | morose erase) | nase)
EARLY-STAGE SETTING
Preoperative | comena moroeseras [seras nome] enserz worusner]| GIVEN,
Sting ‘trae ‘one ere’) coset
HER CARIN
Adjuvant seting | cris ES
Das ‘nase
fajwvant ting CHER nomeması | EMBER NOTOREOSE
swe (ne ene’
Results available
Trial completed accrual
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SERENA-2: PFS With Camizestrant vs Fulvestrant!
PFS in Overall Patient Population
esto ade
2
3
2
2
&
2
E
a
Camisesrant 75 m9
th detectable ESR1 mutations
PeerView.com
Camizestrant improved PFS over fulvestrant in all patient
1. Olvera Metal. SABCS 2022. Abstract 6S3-02.
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PFS in Overall Patient Population
esto ade
2
3
2
2
&
2
E
a
Camisesrant 75 m9
th detectable ESR1 mutations
PeerView.com
Camizestrant improved PFS over fulvestrant in all patient
1. Olvera Metal. SABCS 2022. Abstract 6S3-02.
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Imlunestrant EMBER (Phase 1a/b): Updated Efficacy’
Imlunestrant Imlunestrant * | Imlunestrant +
Imlunestrant + "P20 400 mg
abemaciclib
ER+HER2- ET Ex] Ex
ABC Rn) sun 205 om #00
imlunestrant+ Me nel 5607282 36(18.54) San) 370785
abemaciclib + Al ETC] 456879 726789 MAMA) MAR)
mont PFS, % (95% CD) DIM RUNAS) __742(662.087) resume)
Tumor Response in Patients With Measurable Disease
muestra
Imtunesrant RPZD Imunesrant + abemacicib |) Imiunestant+abemacied + Al
Change in Tumor So, %
4 I tt Haag dat may 5
1. Shaver K etal SABCS 2023, Abstract PS15-00 PeerView.com
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Imlunestrant Imlunestrant * | Imlunestrant +
Imlunestrant + "P20 400 mg
abemaciclib
ER+HER2- ET Ex] Ex
ABC Rn) sun 205 om #00
imlunestrant+ Me nel 5607282 36(18.54) San) 370785
abemaciclib + Al ETC] 456879 726789 MAMA) MAR)
mont PFS, % (95% CD) DIM RUNAS) __742(662.087) resume)
Tumor Response in Patients With Measurable Disease
muestra
Imtunesrant RPZD Imunesrant + abemacicib |) Imiunestant+abemacied + Al
Change in Tumor So, %
4 I tt Haag dat may 5
1. Shaver K etal SABCS 2023, Abstract PS15-00 PeerView.com
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EMBER (Phase 1a/b): Efficacy
Tumor Response in Patients With Measurable Disease!
z
E
id
i
A
E
E
‘Objective response rate, n/N (%)
Clinical benef rate, n (%)
4. Shaver Ket al. ESMO 2022, Abstract 38310.
PeerView.com/BEX827
Imlunestrant Imiunestrant Imlunestrant
monotherapy e s + alpelisio
(n=73) (n= 25) (n= 12)
6/28 (21) 7/12 (68)
26 (62) 13 (62)
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Tumor Response in Patients With Measurable Disease!
z
E
id
i
A
E
E
‘Objective response rate, n/N (%)
Clinical benef rate, n (%)
4. Shaver Ket al. ESMO 2022, Abstract 38310.
PeerView.com/BEX827
Imlunestrant Imiunestrant Imlunestrant
monotherapy e s + alpelisio
(n=73) (n= 25) (n= 12)
6/28 (21) 7/12 (68)
26 (62) 13 (62)
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Selection of Phase 3 SERD Trials in ER+/HER2- MBC
persevERA (NCT04546009)
Giredestrant 30 mg QD
Letrozole 25 mg
Palbociel 125 mg
Giradestrant-mstched PLA
Anastrozole 1 mg
fell 125 mg.
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persevERA (NCT04546009)
Giredestrant 30 mg QD
Letrozole 25 mg
Palbociel 125 mg
Giradestrant-mstched PLA
Anastrozole 1 mg
fell 125 mg.
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Selection of Adjuvant SERD Trials in ER+/HER2- BC
Study Name | SERD Study Design Status _ | NCT Number
Phase 3 adjuvant giredestrant vs physician choice ET
ER em in medium/high risk ER+/HER2- BC
‘Ongoing NCTO4961996
Phase 3 adjuvant imlunestrant vs standard ET after 2-5 years
EMBER Imlunestrant of agjuvant ET for ER+/HER2- BC with an increased risk of recurrence
Ongoing NCTO5514054
Phase 3 adjuvant camizestrant vs standard ET after 2-5 years of adjuvant
CAMBRIA-1 Camizestrant "ET for ER+/HER2- BC with an intermediate/high risk of recurrence
Ongoing NCTOS774951
Phase 2 trial with ctDNA surveillance and treatment with palbociclib +
TRAGER Fitvestrant fulvestrant vs standard ET in pts with ER+HER2- BC
Ongoing NCTO4985266
Phase 2 ctDNA guided trial of adjuvant palbociclib + fulvestrant vs
DARE Fulvestrant standard ET in clinically high risk, stage II-lll, ER+/HER2- BC after Ongoing NCTO4567420
6 months to 7 years of adjuvant Al or tamoxifen.
Phase 2 trial with ctDNA surveillance in HR+/HER2- early stage BC at
MiRaDoR Giredestrant higher risk of relapse evaluating treatment efficacy of standard ET vs Planned NCTOS708235
giredestrant vs giredestrant + abemaciclib vs giredestrant + inavolisib
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Study Name | SERD Study Design Status _ | NCT Number
Phase 3 adjuvant giredestrant vs physician choice ET
ER em in medium/high risk ER+/HER2- BC
‘Ongoing NCTO4961996
Phase 3 adjuvant imlunestrant vs standard ET after 2-5 years
EMBER Imlunestrant of agjuvant ET for ER+/HER2- BC with an increased risk of recurrence
Ongoing NCTO5514054
Phase 3 adjuvant camizestrant vs standard ET after 2-5 years of adjuvant
CAMBRIA-1 Camizestrant "ET for ER+/HER2- BC with an intermediate/high risk of recurrence
Ongoing NCTOS774951
Phase 2 trial with ctDNA surveillance and treatment with palbociclib +
TRAGER Fitvestrant fulvestrant vs standard ET in pts with ER+HER2- BC
Ongoing NCTO4985266
Phase 2 ctDNA guided trial of adjuvant palbociclib + fulvestrant vs
DARE Fulvestrant standard ET in clinically high risk, stage II-lll, ER+/HER2- BC after Ongoing NCTO4567420
6 months to 7 years of adjuvant Al or tamoxifen.
Phase 2 trial with ctDNA surveillance in HR+/HER2- early stage BC at
MiRaDoR Giredestrant higher risk of relapse evaluating treatment efficacy of standard ET vs Planned NCTOS708235
giredestrant vs giredestrant + abemaciclib vs giredestrant + inavolisib
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Therapeutic Advances in Targeting
the PIK3CA/AKT/mTOR Pathway
in HR+ Breast Cancer
Cynthia X. Ma, MD, PhD
Professor iy
Division of Oncology
Department of Medicine M
Washington University
St. Louis, Missouri
the PIK3CA/AKT/mTOR Pathway
in HR+ Breast Cancer
Cynthia X. Ma, MD, PhD
Professor iy
Division of Oncology
Department of Medicine M
Washington University
St. Louis, Missouri
PIK3 and AKT as Therapeutic Targets’
PIK3CA/AKT/mTOR Pathway
ue ie
pe de À Ze EIN
Mechanisms of PIK3CA/AKT Activation Lido as po ag
+ Loss of function of negative regulators By e
= PTEN, INPP4B, PHLPP, PP2A ou ARTO
Gain of function of positive regulators en SR
= PI3K, AKT, RTKs (eg, HER2) y
Therapy-induced survival response
— Chemotherapy, endocrine therapy
mTORC4/2
1. Dent R et al. SABCS 2020. Presentation GS3-04 PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
PIK3CA/AKT/mTOR Pathway
ue ie
pe de À Ze EIN
Mechanisms of PIK3CA/AKT Activation Lido as po ag
+ Loss of function of negative regulators By e
= PTEN, INPP4B, PHLPP, PP2A ou ARTO
Gain of function of positive regulators en SR
= PI3K, AKT, RTKs (eg, HER2) y
Therapy-induced survival response
— Chemotherapy, endocrine therapy
mTORC4/2
1. Dent R et al. SABCS 2020. Presentation GS3-04 PeerView.com
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Post-Progression on CDK4/6 Inhibition:
BYLieve: Alpelisib!
PFS (Whole Cohort)
postmenopausal women
Mi HR MERZ- ABE patents ave
Win PICA mutation A | 10
Fate open SST 2 E,
Bene 5 “4
oo TT Sens ri)
Secondary 07 D
PRE reason”
reset) E
E
Rooms | 403
oz
Las
o
IE TE TE em mm
stint Time, mo
zu
2116)
Primary endpoint for the prior CDKi + Al cohort
was met (lower bound of 95% Cl was >30%),
Primary endpoint: patents alive 50.4% with 50.4% of patients alive without
without disease progression at 6 mo (n= 61; 95% Cl, 41.2806) disease progression at 6 months
73 m0
‘Secondary endpoint: median PFS
Lin = 72 (69.5%) wth event 95% CI, 56-8.)
4. Rugo HS et al ASCO 2020. Abstract 1006, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
BYLieve: Alpelisib!
PFS (Whole Cohort)
postmenopausal women
Mi HR MERZ- ABE patents ave
Win PICA mutation A | 10
Fate open SST 2 E,
Bene 5 “4
oo TT Sens ri)
Secondary 07 D
PRE reason”
reset) E
E
Rooms | 403
oz
Las
o
IE TE TE em mm
stint Time, mo
zu
2116)
Primary endpoint for the prior CDKi + Al cohort
was met (lower bound of 95% Cl was >30%),
Primary endpoint: patents alive 50.4% with 50.4% of patients alive without
without disease progression at 6 mo (n= 61; 95% Cl, 41.2806) disease progression at 6 months
73 m0
‘Secondary endpoint: median PFS
Lin = 72 (69.5%) wth event 95% CI, 56-8.)
4. Rugo HS et al ASCO 2020. Abstract 1006, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
CAPItello-291: Capivasertib + FULV vs Placebo + FULV
in Al-Resistant, HR+/HER2- Advanced Breast Cancer!
+ Capivasertib: Investigational oral inhibitor of AKT1/2/3; in combination with fulvestrant, significantly
prolonged PFS and OS in postmenopausal women with Al-resistant HR+/HER2- ABC
and no prior CDK4/6i in phase 2 FAKTION trial!
CAPItello-291: International, randomized, double-blind phase 3 trial24
Capivasertib 400 mg PO BID
Men and pre/postmenopausal women a ale
with HR+/HER2- ABC Mane ea ARE Dual primary endpoints:
Recurred on or <12 mo from end of PORE Investigator assessed PFS in overall
adjuvant Al, or PD on prior Al for ABC € nen population and in those with AKT
2 lines of ET and $1 line of CT for ABC (Dee pathway-altered tumors (21 qualifying
No prior SERD, mTOR, PISKi, or AKT 4.1 _ Stratified by liver mets (yes vs no), PIK3CA, AKT1, or PTEN alteration)
AIC <8.0% and diabetes not requiring prior CDK4/6i (yes vs no), and region
insulin permitted F Key secondary endpoints: OS and
Prior CDK4/6i permitted? ORR in overall and AKT pathway
FFPE sample available from EEES altered tumor populations
primary/recurrent tumor à
(N =708)
‘Required 251%.
4 Howell J ta. Lance! Oncol 202223851. 2. Tumer NC etal. SABCS 2022 Abstract GS3-04 3. Tumer NC et a. N Engl Med. 2023:388:2058-2070, A
4 pa etncavialsgovet2/show NCTOA3054S6. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
in Al-Resistant, HR+/HER2- Advanced Breast Cancer!
+ Capivasertib: Investigational oral inhibitor of AKT1/2/3; in combination with fulvestrant, significantly
prolonged PFS and OS in postmenopausal women with Al-resistant HR+/HER2- ABC
and no prior CDK4/6i in phase 2 FAKTION trial!
CAPItello-291: International, randomized, double-blind phase 3 trial24
Capivasertib 400 mg PO BID
Men and pre/postmenopausal women a ale
with HR+/HER2- ABC Mane ea ARE Dual primary endpoints:
Recurred on or <12 mo from end of PORE Investigator assessed PFS in overall
adjuvant Al, or PD on prior Al for ABC € nen population and in those with AKT
2 lines of ET and $1 line of CT for ABC (Dee pathway-altered tumors (21 qualifying
No prior SERD, mTOR, PISKi, or AKT 4.1 _ Stratified by liver mets (yes vs no), PIK3CA, AKT1, or PTEN alteration)
AIC <8.0% and diabetes not requiring prior CDK4/6i (yes vs no), and region
insulin permitted F Key secondary endpoints: OS and
Prior CDK4/6i permitted? ORR in overall and AKT pathway
FFPE sample available from EEES altered tumor populations
primary/recurrent tumor à
(N =708)
‘Required 251%.
4 Howell J ta. Lance! Oncol 202223851. 2. Tumer NC etal. SABCS 2022 Abstract GS3-04 3. Tumer NC et a. N Engl Med. 2023:388:2058-2070, A
4 pa etncavialsgovet2/show NCTOA3054S6. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
CAPItello-291: Investigator-Assessed PFS
in Overall Population’?
Capivasertib + FULV MP
(n= 365)
PFS events 258
100
Median PFS, mo 72 36
(95% cl) (657.4) (2837)
80
7 Adjusted HR 0.60(95% CI, 0.51-0.71; 2-sided P <.001)
= 60
©
&
40: Capivasertib + FULV
20
Placebo + FULV
OT TO E taht hi i ie N
0 123 45 67 8 9 1011121314 15 16 17 18 19 20 21 22 2324 25 26
hd, Time From Randomization, mo
Caphaset + FULV 235 200 266252 207 199 172 166 138 139 115 98 78 04 55 44 43 25 25 21 8 8 5 2 2 1 0
Placebo + FULV 259 329 207 182 142136 106 100 86 81 66 59 51 41 23 24 23 12 11 10 4 4 3 1 1 0 0
41, Tumer NC et al. SABCS 2022. Abstract GS3-06, 2, Tumer NC et a. N Engl J Med. 2023,388 2058-2070. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
in Overall Population’?
Capivasertib + FULV MP
(n= 365)
PFS events 258
100
Median PFS, mo 72 36
(95% cl) (657.4) (2837)
80
7 Adjusted HR 0.60(95% CI, 0.51-0.71; 2-sided P <.001)
= 60
©
&
40: Capivasertib + FULV
20
Placebo + FULV
OT TO E taht hi i ie N
0 123 45 67 8 9 1011121314 15 16 17 18 19 20 21 22 2324 25 26
hd, Time From Randomization, mo
Caphaset + FULV 235 200 266252 207 199 172 166 138 139 115 98 78 04 55 44 43 25 25 21 8 8 5 2 2 1 0
Placebo + FULV 259 329 207 182 142136 106 100 86 81 66 59 51 41 23 24 23 12 11 10 4 4 3 1 1 0 0
41, Tumer NC et al. SABCS 2022. Abstract GS3-06, 2, Tumer NC et a. N Engl J Med. 2023,388 2058-2070. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
CAPItello-291: Investigator-Assessed PFS in
AKT-Pathway Altered Population’?
Capivasertib + FULV | Placebo + FULV
(n= 134)
100:
PFS events 115
80 Median PFS, mo 73 31
. - (95% CI) (6.59.0) (2.03.7)
= 60 Capivasertib + FULV
ao Adjusted HR 0.50 (95% Cl, 0.38-0.65; 2-sided P < .001)
ra
E 40
20
+ Censored Placebo + FULV
aS SSS aa RSR
01234567 8 9 1011121314 15 1617 18 192021 22 2324 2526
No, at Risk Time From Randomization, mo
Capivasertib + FULV 155150127212 99 97 80 76 65 62 54 49 38 31 29 22 21 42 12 9 3 3 2 1 1 0 0
Placebo + FULV 134124 77 64 48 47 37 35 28 27 24 20 17 18 1 6 6 2 2 2 1 4 1 0 0 0 0
+ Study met dual primary endpoints, showing significantly prolonged PFS with capivasertib + FULV vs placebo + FULV in
overall and AKT pathway-altered populations
+ Exploratory analysis observed improved PFS in nonaltered subpopulation (HR = 0.70; 95% CI, 0.56-0.88)
1. Tumer NC et al SABCS 2022. Abstract 653-04, 2. Tumer NC et al. N Engl J Med. 2023:388-2088-2070, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
AKT-Pathway Altered Population’?
Capivasertib + FULV | Placebo + FULV
(n= 134)
100:
PFS events 115
80 Median PFS, mo 73 31
. - (95% CI) (6.59.0) (2.03.7)
= 60 Capivasertib + FULV
ao Adjusted HR 0.50 (95% Cl, 0.38-0.65; 2-sided P < .001)
ra
E 40
20
+ Censored Placebo + FULV
aS SSS aa RSR
01234567 8 9 1011121314 15 1617 18 192021 22 2324 2526
No, at Risk Time From Randomization, mo
Capivasertib + FULV 155150127212 99 97 80 76 65 62 54 49 38 31 29 22 21 42 12 9 3 3 2 1 1 0 0
Placebo + FULV 134124 77 64 48 47 37 35 28 27 24 20 17 18 1 6 6 2 2 2 1 4 1 0 0 0 0
+ Study met dual primary endpoints, showing significantly prolonged PFS with capivasertib + FULV vs placebo + FULV in
overall and AKT pathway-altered populations
+ Exploratory analysis observed improved PFS in nonaltered subpopulation (HR = 0.70; 95% CI, 0.56-0.88)
1. Tumer NC et al SABCS 2022. Abstract 653-04, 2. Tumer NC et al. N Engl J Med. 2023:388-2088-2070, PeerView.com
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CAPItello-291: PFS by Prior CDK4/6 Inhibitor
(Overall Population)!
Prior CDK4/6 Inhibitor Exposure
100
Events
Median, mo (95% C1)
Placebo + fuvestant
02468
20 ms 129 102001 a
2 moss. 25
»
550888)
Placebo
26.2035)
Capivasertb + tuvestrant
1
1
o
10 12 14 16 18 20 22 24 26
Time From Randomization, mo
No Prior CDK4/6 Inhibitor Exposure
100
90
80
70
60
50
40 Ccapwasert + fuvestrant
30
20
10
o
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time From Randomization, mo
10701 78 70 9 8 38 2% 2
105 78 62 52 41 32 2% 16016 7
In the overall population, consistent clinically meaningful benefit with capivasertib + fulvestrant
was observed in patients with and without prior CDK4/6 inhibitor exposure
+. Tumer NC et al, ESMO Breast 2023. Abstract 1870.
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Copyright O 2000-2024, Peerview
(Overall Population)!
Prior CDK4/6 Inhibitor Exposure
100
Events
Median, mo (95% C1)
Placebo + fuvestant
02468
20 ms 129 102001 a
2 moss. 25
»
550888)
Placebo
26.2035)
Capivasertb + tuvestrant
1
1
o
10 12 14 16 18 20 22 24 26
Time From Randomization, mo
No Prior CDK4/6 Inhibitor Exposure
100
90
80
70
60
50
40 Ccapwasert + fuvestrant
30
20
10
o
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time From Randomization, mo
10701 78 70 9 8 38 2% 2
105 78 62 52 41 32 2% 16016 7
In the overall population, consistent clinically meaningful benefit with capivasertib + fulvestrant
was observed in patients with and without prior CDK4/6 inhibitor exposure
+. Tumer NC et al, ESMO Breast 2023. Abstract 1870.
PeerView.com/BEX827
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CAPItello-291 Exploratory Analysis: Capivasertib
and Fulvestrant for Al-Resistant HR+, HER2- MBC’
+ Objective: Explore PFS by tumor PIK3CA/AKT1/PTEN-mutated status among patients from the CAPItell-291 study
(including pooled analysis with inclusion of data from the Chinese extension cohort)
+ CAPItell-291 population: Patients with HR+/HER2- advanced breast cancer after progression during Al treatment
with/without prior CDK4/6i therapy
PIK3CA Alteration Only
AKT1 Alteration Only
(n= 110) (n 92)
PES mo on y
GS%C) @2NC) (1795)
HR (05% ch 0.51 (22-112)
PTEN Alteration Only
onto (neo |
ene ota
esi asen
100
BC) (4274) (1836)
HR 95% cn) _ 051 (037-070)
PFS, %
”
so
70
©
so
“o cap su
bak caP + FUL
20 caps FUL
10 Po Pu
o
0 24 6 8 101214 16 18 20 2 4
Time From Randomization, mo
0 24 6 8 10 12 14 16 10 20 2 4
Time From Randomization, mo
D 246 6 104214 16 18 222%
Time From Randomization, mo
1. Howel Su etal. SABCS 2023, Abstract PS17-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
and Fulvestrant for Al-Resistant HR+, HER2- MBC’
+ Objective: Explore PFS by tumor PIK3CA/AKT1/PTEN-mutated status among patients from the CAPItell-291 study
(including pooled analysis with inclusion of data from the Chinese extension cohort)
+ CAPItell-291 population: Patients with HR+/HER2- advanced breast cancer after progression during Al treatment
with/without prior CDK4/6i therapy
PIK3CA Alteration Only
AKT1 Alteration Only
(n= 110) (n 92)
PES mo on y
GS%C) @2NC) (1795)
HR (05% ch 0.51 (22-112)
PTEN Alteration Only
onto (neo |
ene ota
esi asen
100
BC) (4274) (1836)
HR 95% cn) _ 051 (037-070)
PFS, %
”
so
70
©
so
“o cap su
bak caP + FUL
20 caps FUL
10 Po Pu
o
0 24 6 8 101214 16 18 20 2 4
Time From Randomization, mo
0 24 6 8 10 12 14 16 10 20 2 4
Time From Randomization, mo
D 246 6 104214 16 18 222%
Time From Randomization, mo
1. Howel Su etal. SABCS 2023, Abstract PS17-03, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
FDA Regulatory Approval of Capivasertib*
November 16, 2023: FDA approved capivasertib with fulvestrant for adult
patients with HR+, HER2- locally advanced or metastatic breast cancer
with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an
FDA-approved test, following progression on at least one endocrine-based
regimen in the metastatic setting or recurrence on or within 12 months of
completing adjuvant therapy
FDA also approved the FoundationOne CDx assay as a companion diagnostic
device to identify patients with breast cancer for treatment with capivasertib
with fulvestrant
1. pee da. govidrugeresources-infrmaton-approved:-drugiida-approves-capivasertbulvestrant breast-cancer PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
November 16, 2023: FDA approved capivasertib with fulvestrant for adult
patients with HR+, HER2- locally advanced or metastatic breast cancer
with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an
FDA-approved test, following progression on at least one endocrine-based
regimen in the metastatic setting or recurrence on or within 12 months of
completing adjuvant therapy
FDA also approved the FoundationOne CDx assay as a companion diagnostic
device to identify patients with breast cancer for treatment with capivasertib
with fulvestrant
1. pee da. govidrugeresources-infrmaton-approved:-drugiida-approves-capivasertbulvestrant breast-cancer PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, Peerview
INAVO120: 1L Therapy for Early Relapse
and PIK3CA-Mutated HR+, HER2- ABC!
Enroliment period: December 2019-September 2023
ia Key eligibility criteria
| Enrichment of patients with poor prognosis Inavolisib (9 mg QD PO)
1*. PIK3CA-mutated, HR+, HER2- ABC by central + palbocicib (125 mg PO QD D1-D21) nu
| ciDNA" or local tissue/CIDNA test + fulvestrant (500 mg C1D1/15 and QW) 37
Until PD 223
I* Measurable disease or toxicity E 3
1* Progression during/within 12 months of adjuvant acebo ir}
\ _ET completion + palbociclb (125 mg PO QD 01-021 op
«No prior therapy for ABE "77777777 | (ea) (UN 300 mg C1D4/15 and Q4W)
* Fasting glucose <126 mg/dL and HbA;c <6.0%
Stratification factors: Endpoints.
* Visceral Disease (yes vs no) * Primary: PFS by Investigator
* Endocrine Resistance (primary vs secondary) * Secondary: OS*, ORR, BOR, CBR, DOR, PROs
Asia, and Other)
‘Central testing for PIKSCA mutations was done on cIDNA using FoundationOnetiqud (Foundation Medicine) In China, the central DNA test was the PredicineCARE NGS assay (Hui)
® Defined per Ah European School of Oncology (ESO)-European Sony for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer. Primary relapse
le onthe fst 2 years of adjuvant ET: secondary elapse wie on adjuvant ET a a least 2 years or relapse within 12 months of completing aduvant ET. « Pre-menopausa women
received ovarian suppression * OS testing only it PFS is postive: interim OS analysis at primary PFS analysis. 7
Y Jhaven K et al SABCS 2023. Abstract 6503-13, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
and PIK3CA-Mutated HR+, HER2- ABC!
Enroliment period: December 2019-September 2023
ia Key eligibility criteria
| Enrichment of patients with poor prognosis Inavolisib (9 mg QD PO)
1*. PIK3CA-mutated, HR+, HER2- ABC by central + palbocicib (125 mg PO QD D1-D21) nu
| ciDNA" or local tissue/CIDNA test + fulvestrant (500 mg C1D1/15 and QW) 37
Until PD 223
I* Measurable disease or toxicity E 3
1* Progression during/within 12 months of adjuvant acebo ir}
\ _ET completion + palbociclb (125 mg PO QD 01-021 op
«No prior therapy for ABE "77777777 | (ea) (UN 300 mg C1D4/15 and Q4W)
* Fasting glucose <126 mg/dL and HbA;c <6.0%
Stratification factors: Endpoints.
* Visceral Disease (yes vs no) * Primary: PFS by Investigator
* Endocrine Resistance (primary vs secondary) * Secondary: OS*, ORR, BOR, CBR, DOR, PROs
Asia, and Other)
‘Central testing for PIKSCA mutations was done on cIDNA using FoundationOnetiqud (Foundation Medicine) In China, the central DNA test was the PredicineCARE NGS assay (Hui)
® Defined per Ah European School of Oncology (ESO)-European Sony for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer. Primary relapse
le onthe fst 2 years of adjuvant ET: secondary elapse wie on adjuvant ET a a least 2 years or relapse within 12 months of completing aduvant ET. « Pre-menopausa women
received ovarian suppression * OS testing only it PFS is postive: interim OS analysis at primary PFS analysis. 7
Y Jhaven K et al SABCS 2023. Abstract 6503-13, PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
INAVO120 Primary Endpoint: PFS (Investigator Assessed)!
6-month 12month 18-month + Palbo + Fulv + Fulv
ken H i (n= 461) 64)
No, of events, (%) 82 (50.9) 113 (68.9)
A Median PFS, mo (95% Cl) 15.0 (11.3, 20.5) 73 (66,93)
Stratified HR (95% Cl) 0.43 (0.32, 0.59); P <.0004
x
g 50
Es
Inavo + Palbo + Fulv
25 H Median follow-up:
H 21.3 months
5 sil H E Pbo + Palbo + Fulv
DI 1200 A A cscs
Time, mo
No at Risk
asa
A mm m m men
0000: 200 September 2023
PeerView.com
4. Shaver K et al. SABCS 2023, Abstract 6503-13.
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
6-month 12month 18-month + Palbo + Fulv + Fulv
ken H i (n= 461) 64)
No, of events, (%) 82 (50.9) 113 (68.9)
A Median PFS, mo (95% Cl) 15.0 (11.3, 20.5) 73 (66,93)
Stratified HR (95% Cl) 0.43 (0.32, 0.59); P <.0004
x
g 50
Es
Inavo + Palbo + Fulv
25 H Median follow-up:
H 21.3 months
5 sil H E Pbo + Palbo + Fulv
DI 1200 A A cscs
Time, mo
No at Risk
asa
A mm m m men
0000: 200 September 2023
PeerView.com
4. Shaver K et al. SABCS 2023, Abstract 6503-13.
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
INAVO120 Key Secondary Endpoint:
OS (Interim Analysis)!
Palbo + Fu
61)
12:month 12:month 18-month | No/orevents,n(%) 42 (26.1) 55 (33.5)
oa 197.9% = | H Median PFS, mo (95% CI) NE(27.3,NE) 31.1 (223, NE)
je59% =}
y H Stratified HR (95% Cl) 0.64 (0.43, 0.97); P=.0338
173.7%
75
e ' Inavo + Palbo + Fulv
o H
oi H
H Pbo + Palbo + Fulv
25 H Median follow-up:
En ! 21.3 months
is ; H i
Y fy RATE O a ee a a Ss ee
Time, mo
No. at Risk
tnavo+Pabo+Fuv 161 19127 10 0 wS Go Ht
Poo+Pabo+Fuv 166 130 E O
+ The pre-specified boundary for OS (P of .0098 or HR of 0.592) was not crossed at this interim analysis
A. haven K et al SABCS 2023, Abstract 6503-13 PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
OS (Interim Analysis)!
Palbo + Fu
61)
12:month 12:month 18-month | No/orevents,n(%) 42 (26.1) 55 (33.5)
oa 197.9% = | H Median PFS, mo (95% CI) NE(27.3,NE) 31.1 (223, NE)
je59% =}
y H Stratified HR (95% Cl) 0.64 (0.43, 0.97); P=.0338
173.7%
75
e ' Inavo + Palbo + Fulv
o H
oi H
H Pbo + Palbo + Fulv
25 H Median follow-up:
En ! 21.3 months
is ; H i
Y fy RATE O a ee a a Ss ee
Time, mo
No. at Risk
tnavo+Pabo+Fuv 161 19127 10 0 wS Go Ht
Poo+Pabo+Fuv 166 130 E O
+ The pre-specified boundary for OS (P of .0098 or HR of 0.592) was not crossed at this interim analysis
A. haven K et al SABCS 2023, Abstract 6503-13 PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
INAVO120 Safety: AEs With Any Grade AEs 220%
in Either Treatment Group!
Inavo + Palbo + Fulv Pbo + Palbo + Fulv
Adverse Events" (n=162) (n=162)
AI Grades Grade 34 ‚All Grades Grade 34
Neutropenia 144 (88.9%) 130 (80.2%) 147 (90.7%) 127 (78.4%)
Thrombocytopenia 78 (48.1%) 23 (14.2%) 73 (45.1%) 7 (4.3%)
Stomatitis/Mucosal inflammation 83 (51.2%) 9 (5.6%) 43 (26.5%) o
Anemia 60 (37.0%) 10 (6.2%) 59 (36.4%) 3 (1.9%)
Hyperglycemia 95 (58.6%) 9 (54 14 (8. o
Diarrhea 78 (48.1%) 26 (16.0%) o
Nausea 27 (16.7%) o
Rash 41 (25.3%) 28 (17.3%) o
Decreased Appetite 38 (23.5%) 14 (8.6%) <2%
Fatigue 38 (23.5%) <2% 21 (13.0%) 2%
COVID-19 37 (22.8%) <2% 17 (10.5%) <2%
Headache 34 (21.0%) 2% 22(13.6%) 2%
Leukopenia 28 (17.3%) 11 (6.8%) 40 (24.7%) 17 (10.5%)
Ocular Toxicities 36 (22.2%) o 21 (13.0%) o
6.8% stopped inavolisib due to toxicity; 70% had dose interruption and/or reduction
Key AES are shown in bold, AES were assessed per CTCAE VS; neutropenia, thrombocytopenia, stomattisimucosalinfammation, anemia, hyperglycemia, darrhea,
nausea, rash assessed as medial concepts using grouped terms.
1. naveriK etal SABCS 2023. Abstract 6609-13.
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in Either Treatment Group!
Inavo + Palbo + Fulv Pbo + Palbo + Fulv
Adverse Events" (n=162) (n=162)
AI Grades Grade 34 ‚All Grades Grade 34
Neutropenia 144 (88.9%) 130 (80.2%) 147 (90.7%) 127 (78.4%)
Thrombocytopenia 78 (48.1%) 23 (14.2%) 73 (45.1%) 7 (4.3%)
Stomatitis/Mucosal inflammation 83 (51.2%) 9 (5.6%) 43 (26.5%) o
Anemia 60 (37.0%) 10 (6.2%) 59 (36.4%) 3 (1.9%)
Hyperglycemia 95 (58.6%) 9 (54 14 (8. o
Diarrhea 78 (48.1%) 26 (16.0%) o
Nausea 27 (16.7%) o
Rash 41 (25.3%) 28 (17.3%) o
Decreased Appetite 38 (23.5%) 14 (8.6%) <2%
Fatigue 38 (23.5%) <2% 21 (13.0%) 2%
COVID-19 37 (22.8%) <2% 17 (10.5%) <2%
Headache 34 (21.0%) 2% 22(13.6%) 2%
Leukopenia 28 (17.3%) 11 (6.8%) 40 (24.7%) 17 (10.5%)
Ocular Toxicities 36 (22.2%) o 21 (13.0%) o
6.8% stopped inavolisib due to toxicity; 70% had dose interruption and/or reduction
Key AES are shown in bold, AES were assessed per CTCAE VS; neutropenia, thrombocytopenia, stomattisimucosalinfammation, anemia, hyperglycemia, darrhea,
nausea, rash assessed as medial concepts using grouped terms.
1. naveriK etal SABCS 2023. Abstract 6609-13.
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Copyright © 2000-2024, PeerView
INAVO120: Summary and Further Analyses‘?
+ INAVO120 met its primary endpoint, with a statistically significant and clinically meaningful improvement
in PFS (15.0 months vs 7.3 months; HR, 0.43 [95% Cl = 0.32, 0.59]; P< .0001)
Inavolisib with palbociclib and fulvestrant was associated with sustained benefit beyond disease
progression, demonstrating a delayed need for subsequent therapy (A 8.9 months), including
chemotherapy (NE versus 15.0 months), and supporting the clinical benefit of the inavolisib-based
therapy
Inavolisib discontinuations for hyperglycemia, diarrhea, rash, and stomatitis/mucosal inflammation were
low, confirming inavolisib's manageable safety and tolerability profile
Patient-reported outcomes suggest patients receiving inavolisib in addition to fulvestrant and palbociclib
experienced a longer median time to deterioration in pain severity (A 12.8 months), and maintained day-
to-day functioning and HRQOL while on treatment with little increased treatment burden
Inavolisib with palbociclib and fulvestrant is a promising new treatment option for patients with PIK3CA-
mutated, HR+, HER2- locally advanced or metastatic breast cancer
4. dhaver K et a. SABCS 2023, Abstract 6503-13. 2, Jure D et al ASCO 2024. Abstract 1003. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
+ INAVO120 met its primary endpoint, with a statistically significant and clinically meaningful improvement
in PFS (15.0 months vs 7.3 months; HR, 0.43 [95% Cl = 0.32, 0.59]; P< .0001)
Inavolisib with palbociclib and fulvestrant was associated with sustained benefit beyond disease
progression, demonstrating a delayed need for subsequent therapy (A 8.9 months), including
chemotherapy (NE versus 15.0 months), and supporting the clinical benefit of the inavolisib-based
therapy
Inavolisib discontinuations for hyperglycemia, diarrhea, rash, and stomatitis/mucosal inflammation were
low, confirming inavolisib's manageable safety and tolerability profile
Patient-reported outcomes suggest patients receiving inavolisib in addition to fulvestrant and palbociclib
experienced a longer median time to deterioration in pain severity (A 12.8 months), and maintained day-
to-day functioning and HRQOL while on treatment with little increased treatment burden
Inavolisib with palbociclib and fulvestrant is a promising new treatment option for patients with PIK3CA-
mutated, HR+, HER2- locally advanced or metastatic breast cancer
4. dhaver K et a. SABCS 2023, Abstract 6503-13. 2, Jure D et al ASCO 2024. Abstract 1003. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
INAVO121: Inavolisib + Fulvestrant vs Alpelisib + Fulvestrant
in HR+, HER2-, PIK3CA-mut LA/mBC"
Patients with HR+, HER2- PIK3CA-
mutated LA/ÍMBC
Prior CDK4/6i + ET therapy
+ <2 prior lines of systemic therapy
Inavolisib 9 mg PO QD
+ fulvestrant IM 500 mg*
Until disease progression,
unacceptable toxicity, patient|
withdrawal of consent,
death, or study termination
for LA/MBC (St line of chemotherapy R E]
for mBC)
+ Measurable or evaluable disease
+ ECOG PS 0-2
N = 400 (planned)
Alpelisib 300 mg PO QD
+ fulvestrant IM 500 mg"
Stratification factors Primary endpoint
+ Visceral disease (yes vs no) + Progression-free survival (time from randomization until disease
+ Prior CDK4/6i therapy (adjuvant vs progression or death due to any cause) by BICR
metastatic setting) ‘Secondary endpoint
+ Overall survival + Safety and tolerability
+ Objective response rate by BICR + Patient-reported outcomes
+ Best overall response by BICR + Pharmacokinetics
+ Duration of response by BICR.
* ondays 1 and 15 yt 1, hen on day 1 of subsequent oyes. Clinical benefit rate by BICR
Survival
follow-up
1. dure D et al ASCO 2024. Abstract TPS1136. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
in HR+, HER2-, PIK3CA-mut LA/mBC"
Patients with HR+, HER2- PIK3CA-
mutated LA/ÍMBC
Prior CDK4/6i + ET therapy
+ <2 prior lines of systemic therapy
Inavolisib 9 mg PO QD
+ fulvestrant IM 500 mg*
Until disease progression,
unacceptable toxicity, patient|
withdrawal of consent,
death, or study termination
for LA/MBC (St line of chemotherapy R E]
for mBC)
+ Measurable or evaluable disease
+ ECOG PS 0-2
N = 400 (planned)
Alpelisib 300 mg PO QD
+ fulvestrant IM 500 mg"
Stratification factors Primary endpoint
+ Visceral disease (yes vs no) + Progression-free survival (time from randomization until disease
+ Prior CDK4/6i therapy (adjuvant vs progression or death due to any cause) by BICR
metastatic setting) ‘Secondary endpoint
+ Overall survival + Safety and tolerability
+ Objective response rate by BICR + Patient-reported outcomes
+ Best overall response by BICR + Pharmacokinetics
+ Duration of response by BICR.
* ondays 1 and 15 yt 1, hen on day 1 of subsequent oyes. Clinical benefit rate by BICR
Survival
follow-up
1. dure D et al ASCO 2024. Abstract TPS1136. PeerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
BOLERO-2: mTOR Inhibitor Everolimus‘?2
PFS by Local Investigator
HR = 045 (95% CI, 038-054) HR = 0.89 (95% CI, 0.73-1.10)
> Vegan P< 6001 Lan made
8 Kaplan Maier means, mo ze Keplareier means, mo
3 Everolimus + exemestane: 7.8 3 Everolimus + exemestane: 31.0
3 Paco » remain 32 Bo Pace » eremestano: 26
3 2
e Eos
g Late r
E Os
7 2 ww 1 me me 5
Te ÉEREESTITTET TE EF ESE PIPE
(No. at Risk : No. at Risk Time; mo,
Esa nam TN
parc) 1 1 7 + 4 ers 200232220211201 194 142170 162 153145 130120113 100102 98 77 56 41 28 18 8 5 1 0
h mews a7 7 + 6 2 ooo |»
‘Adding everolimus to exemestane did not confer a statistically significant improvement in the
secondary endpoint OS despite producing a clinically meaningful and statistically significant
improvement in the primary endpoint, PFS (4.6-months prolongation in median PFS; P < .0001)
1. Yardley DA et al, Adv Ther. 2013:30:870-884, 2. Piecar M etal. Ann Oncol. 2014:25:2387-2362 'eerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
PFS by Local Investigator
HR = 045 (95% CI, 038-054) HR = 0.89 (95% CI, 0.73-1.10)
> Vegan P< 6001 Lan made
8 Kaplan Maier means, mo ze Keplareier means, mo
3 Everolimus + exemestane: 7.8 3 Everolimus + exemestane: 31.0
3 Paco » remain 32 Bo Pace » eremestano: 26
3 2
e Eos
g Late r
E Os
7 2 ww 1 me me 5
Te ÉEREESTITTET TE EF ESE PIPE
(No. at Risk : No. at Risk Time; mo,
Esa nam TN
parc) 1 1 7 + 4 ers 200232220211201 194 142170 162 153145 130120113 100102 98 77 56 41 28 18 8 5 1 0
h mews a7 7 + 6 2 ooo |»
‘Adding everolimus to exemestane did not confer a statistically significant improvement in the
secondary endpoint OS despite producing a clinically meaningful and statistically significant
improvement in the primary endpoint, PFS (4.6-months prolongation in median PFS; P < .0001)
1. Yardley DA et al, Adv Ther. 2013:30:870-884, 2. Piecar M etal. Ann Oncol. 2014:25:2387-2362 'eerView.com
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Everolimus in the Post-CDK4/6i Setting
(mPFS: 4-5 Months)!
EVERMET Cook et al.
Phase 1/2, single-arm, 22L, — Retrospective multicenter study, — Retrospective single center
Design all had prior CDK4/6i some with prior CDK4/6i study, some prior CDK4/6i
ET partner Exemestane + ribociclib Exemestane Exemestane
N 104 273 43
mPFS, mo 5.7 49 3.6
(Cin Cancer Res. 2021,27:4177-4185. 2. NichetF et al Ann Oncol, 2020.31:5382. 3. Cook Metal. Oncologist 2021,28:101-108 PeerView.com
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Copyright © 2000-2024, PeerView
(mPFS: 4-5 Months)!
EVERMET Cook et al.
Phase 1/2, single-arm, 22L, — Retrospective multicenter study, — Retrospective single center
Design all had prior CDK4/6i some with prior CDK4/6i study, some prior CDK4/6i
ET partner Exemestane + ribociclib Exemestane Exemestane
N 104 273 43
mPFS, mo 5.7 49 3.6
(Cin Cancer Res. 2021,27:4177-4185. 2. NichetF et al Ann Oncol, 2020.31:5382. 3. Cook Metal. Oncologist 2021,28:101-108 PeerView.com
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Coming Back to Our Case
pe
A 67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
Receives first-line CDK4/6i (palbociclib) + ET, but after 10 months develops asymptomatic progression in
bone and 1.5-cm new liver lesions
ctDNA testing reveals an ESR1 mutation and PIK3CA mutation
Let’s discuss:
What would you recommend to this patient?
What if the patient had a long PFS on 1L CDK4/6i therapy?
When and how to conduct biomarker testing, and how to interpret the results?
How to determine the optimal, individualized therapy choice and sequence for each patient
based on the biomarker testing results and other factors?
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
pe
A 67-year-old postmenopausal woman is diagnosed with HR+, HER2- MBC
Receives first-line CDK4/6i (palbociclib) + ET, but after 10 months develops asymptomatic progression in
bone and 1.5-cm new liver lesions
ctDNA testing reveals an ESR1 mutation and PIK3CA mutation
Let’s discuss:
What would you recommend to this patient?
What if the patient had a long PFS on 1L CDK4/6i therapy?
When and how to conduct biomarker testing, and how to interpret the results?
How to determine the optimal, individualized therapy choice and sequence for each patient
based on the biomarker testing results and other factors?
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
Discussion @
& Conclusion
PeerView.com/BEX827 Copyright © 2000-2024, PeerView
& Conclusion
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