Endocrine therapy for advanced ER positive/HER2 negative ......“Endocrine therapy is the preferred option for hormone receptor positive disease, even in the presence of visceral

Endocrine therapy for advanced ER

positive/HER2 negative breast cancer

Giuseppe Curigliano MD PhDDepartment of Oncology and Hematology

University of Milano

Istituto Europeo di Oncologia

Milano, Italy

Grants: Associazione Italiana Ricerca sul Cancro, MSD, Italian Minister of Health

Personal fees: Astra Zeneca, Pfizer, Roche/Genentech, Novartis

Disclosures

• Endocrine therapy plus CDK 4-6 inhibitors as a new standard

of care for HR+/HER2- advanced breast cancer

• Endocrine sensitive and endocrine resistant disease

• The PALOMA, MONARCH and MONALEESA programs

• Positioning of CDK 4-6 inhibitors in standard clinical practice

Outline

Top line recommendations from ESO-ESMO ABC4 panel

•Cardoso F, et al. Annals of Oncology. 2018

“Endocrine therapy is the preferred option for

hormone receptor positive disease, even in the

presence of visceral disease, unless there is visceral

crisis or concern/proof of endocrine resistance”

How to select first line?

PRIMARY ENDOCRINE RESISTANCE

Relapse while on the first 2 years of

adjuvant ET, or PD within first 6 months

of 1st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE

Relapse while on adjuvant ET but after the first 2 years,

or relapse within 12 months of completing adjuvant ET,

or PD ≥ 6 months after initiating ET for MBC, while on ET

Endocrine sensitive disease: First line

FALCON: Phase III study design

• Randomised, double-blind, parallel-group, international, multicentre study

• Follow-up for disease progression and survival

• Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power

for statistical significance at the 5% two-sided level (log-rank test)

• Stratification factors: prior chemotherapy for advanced disease; measurable vs. non-measurable disease; locally advanced vs. metastatic

disease

• Subgroup analysis of PFS for pre-defined baseline covariates

• aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis

at the time of PFS analysis

• EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B,

Functional Assessment of Cancer Therapy – Breast; HRQoL, health related quality of life; OS,

overall survival; ORR, overall response rate; TOI, Trial Outcome Index. • Robertson JFR, et al. Lancet. 2016;388:2997–3005.

Fulvestrant 500 mg(500 mg IM on Days 0, 14 and 28,

then every 28 days)

+ placebo to anastrozole

• Postmenopausal women

• Locally advanced or metastatic

breast cancer

• ER+ and / or PgR+

• HER2-

• Endocrine therapy-naïve

Primary

endpoint: PFSa

Secondary endpoints:

OSb, ORR, CBR, DoR, EDoR,

DoCB, EDoCB, HRQoL (FACT-B

total and TOI), Safety

RA

ND

OM

ISA

TIO

N

1:1

Anastrozole 1 mg (daily PO)

+ placebo to fulvestrant

FALCON: Progression free survival

A circle represents a censored observation

ANA, anastrozole; FUL, fulvestrant.Robertson JFR, et al. Lancet. 2016;388:2997–3005.

Fulvestrant

Anastrozole

230

232

187

194

171

162

150

139

124

120

110

102

96

84

81

60

63

45

44

31

24

22

11

10

2

0

0

0

Pro

po

rtio

n o

f p

ati

en

ts

ali

ve

an

d p

rog

res

sio

n f

ree

3 6 9 12 15 18 21 24 27 30 3633 39

Time, months

FUL(n=230)

ANA(n=232)

Median PFS, months 16.6 13.8

HR (95% CI) 0.797 (0.637–0.999)

P value 0.0486

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

Number of patients at risk

Fulvestrant

Anastrozole

FALCON: PFS in patients with or without visceral disease

Post hoc interaction test p<0.01; A circle represents a censored observation

ANA, anastrozole; FUL, fulvestrant.

• Robertson JFR, et al. Lancet. 2016;388:2997–3005.

Without visceral disease

Pro

po

rtio

n o

f p

ati

en

ts

ali

ve

an

d p

rog

res

sio

n-f

ree

5 10 15 20 25 30 35 40

Time, months

0

FUL(n=95)

ANA(n=113)


HR (95% CI) 0.59 (0.42–0.84)

Pro

po

rtio

n o

f p

ati

en

ts

ali

ve

an

d p

rog

res

sio

n-f

ree

5 10 15 20 25 30 35 40

Time, months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

With visceral disease

FUL(n=135)

ANA(n=119)


HR (95% CI) 0.99 (0.74–1.33)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Fulvestrant

Anastrozole

Fulvestrant

Anastrozole

Fulvestrant plus Anastrozole in Metastatic Breast Cancer

• Metha R et al. N Engl J Med 2019; 380:1226-1234

Fulvestrant plus Anastrozole in Metastatic Breast Cancer

Metha R et al. N Engl J Med 2019; 380:1226-1234

2

1

Everolimus 10 mg/day +Exemestane 25 mg/day

(N = 485)

Placebo +Exemestane 25 mg/day

(N = 239)

▪ Stratification:

1. Sensitivity to prior hormonal therapy

2. Presence of visceral disease

▪ No cross-over

N = 724

Postmenopausal

ER+ HER2- ABC

refractory to

letrozole or

anastrozole

PFS

OS

ORR

Bone Markers

Safety

PK

Baselga J et al NEJM 2012;366(6):520

~50% prior tamoxifen

68% prior chemotherapy

Endocrine resistant disease: Everolimus and Exemestane

EVE+EXE

PBO+EXE

0

20

40

60

80

100

HR=0.45 (95% CI, 0.38-0.54)

Log-rank p<0.0001

Kaplan-Meier medians

EVE+EXE: 7.8 mo

PBO+EXE: 3.2 mo

Time, wk

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120

485436366 304257 221185158 124 91 66 50 35 24 22 13 10 8 2 1 0

239190132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0

EVE+EXE

PBO+EXE

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

485

239

427

179

359

114

292

76

239

56

211

39

166

31

140

27

108

16

77

13

62

9

48

6

32

4

21

1

18

0

11

0

10

0

5

0

0

0

Pro

babili

ty o

f E

vent,

%

0

20

40

60

80

100

Pro

babili

ty o

f E

vent,

%

HR=0.38 (95% CI, 0.31-0.48)

Log-rank p<0.0001

Kaplan-Meier medians

EVE+EXE: 11.0 mo

PBO+EXE: 4.1 mo

EVE+EXE (n/N=310/485)

PBO+EXE (n/N=200/239)

EVE+EXE (n/N=188/485)

PBO+EXE (n/N=132/239)

Patients at risk Patients at riskTime, wk

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.

Local Assessment Central Assessment

Everolimus and Exemestane

The PALOMA trials

• PFS, progression free survival Finn RS, et al. Lancet Oncol. 2015;16:25–35; Finn RS, et al. N Engl J Med. 2016;375:1925–1936;

Turner NC, et al. N Engl J Med. 2015;373:209–219; Cristofanilli M, et al. Lancet Oncol. 2016;17:425–439.

Trial Study design Study size

Target population

HR+/HER2– mBC Partner ET

Primary

endpoint

PALOMA-1Phase 2

Open label165 patients

AI sensitive

Treatment naïve for mBC

Postmenopausal

Letrozole PFS

PALOMA-2Phase 3

Placebo control666 patients

AI sensitive


Postmenopausal

Letrozole PFS

PALOMA-3Phase 3

Placebo control521 patients

Endocrine resistant

Pre/peri and

postmenopausal

Fulvestrant PFS

PALOMA-1: Phase II study design

• HER2, human epidermal growth factor receptor

2; QD, once daily Finn RS, et al. Lancet Oncol. 2015;16:25–35.

Letrozole

(2.5 mg QD)

Palbociclib

(125 mg QD, 3/1 schedule)

+ letrozole (2.5 mg QD)

Postmenopausal

ER+, HER2− MBC

CCND1 amplification and/or loss of p16

(part 2 only)

No prior treatment for advanced

disease

Primary endpoint:

progression-free survival

Secondary/exploratory

endpoints: response, overall

survival, safety, biomarkers,

patient-reported outcomes

Stratification factors: disease

site, disease-free intervalR

AN

DO

MIS

AT

ION

N=165

1:1


PAL+LET 84 67 60 47 36 28 21 13 8 5 1

LET 81 48 36 28 19 14 6 3 3 1

PALOMA-1: Progression free survival

• HR, hazard ratio; LET, letrozole; PAL, palbociclib; PFS, progression-free survival • Finn RS, et al. Lancet Oncol. 2015;16:25–35.

• FDA US Food and Drug Administration; www.FDA.gov.

PAL + LET

(n = 84)

LET

(n = 81)

Number of events (%) 41 (49) 59 (73)

Median PFS, months

(95% Cl)

20.2

(13.8–27.5)

10.2

(5.7–12.6)

HR

(95% Cl)

0.488

(0.319–0.748)

P value 0.0004

100

Palbociclib + letrozole (n=84)

Letrozole (n=81)

0 4 8 12 16 20 24 28 32 36 40

TIME (MONTHS)

90

80

70

60

50

40

30

20

10

0

PF

S P

RO

BA

BIL

ITY

(%

)

Accelerated

approval by

FDA

PALOMA-2: Phase III study design

• aActual.

• AI, aromatase inhibitor; OS, overall survival; PFS, progression-free survival;

QD, once daily

Finn RS, et al. N Engl J Med. 2016;375:1925–1936.

Placebo

(3/1 schedule)

+ letrozole

(2.5 mg QD)

Palbociclib

(125 mg QD, 3/1 schedule)

+ letrozole (2.5 mg QD)

Postmenopausal

ER+, HER2– advanced breast cancer

No prior treatment for advanced

disease

AI-resistant patients excluded

Primary endpoint

Investigator-assessed PFS

Secondary endpoints include:

Response, OS, safety,

biomarkers, patient-reported

outcomes

Stratification factors

– Disease site (visceral,

non-visceral)

– Disease-free interval

(de novo metastatic;

≤12 mo, >12 mo)

– Prior (neo)adjuvant

hormonal therapy (yes, no)

RA

ND

OM

ISA

TIO

N

N=666a

2:1

PALOMA-2: Progression free survival

HR, hazard ratio; LET, letrozole; NE, not estimable; PAL, palbociclib; PCB, placebo;

PFS, progression-free survival

Finn RS, et al. N Engl J Med. 2016;375:1925–1936.

444 395 360 328 295 263 238 154 69 29 10 2

222 171 148 131 116 98 81 54 22 12 4 2

PAL+LET

PCB+LET


PF

S p

rob

ab

ilit

y (

%)

Time from randomization (months)

0 3 6 9 12 15 18 21 24 27 30 33

HR 0.58 (95% CI 0.46, 0.72)

2-sided P<0.001

Median (95% CI) PFS

14.5 months (12.9–17.1)

Median (95% CI) PFS

24.8 months (22.1–NE)

0

10

20

30

40

50

60

70

80

90

100


Placebo + letrozole (n=222)

42.1

84.9

34.7

70.3

ORR (%) CBR (%)

PALOMA-2: Overall response rates

aConfirmed complete response + partial response (95% CI) bConfirmed complete response + partial response + stable disease ≥24 weeks (95% CI)

COne patient with bone-only disease at baseline was included; all other patients had measurable disease at baseline.

CBR, clinical benefit rate; ER+, estrogen receptor-positive;

HER2–, human epidermal growth factor receptor 2-negative; NR, not reported; OR, odds ratio; ORR, overall response rateFinn RS, et al. N Engl J Med. 2016;375:1925–1936.

As initial therapy for postmenopausal ER+/HER2– advanced breast cancer, palbociclib + letrozole improves ORR and CBR over letrozole alone

All randomized patients Patients with measurable disease Palbociclib + letrozole (n=444)


22.5months

16.8c

months22.5

months

16.8months

Median duration of response

OR NR

P = NR

Median duration of response

OR NR

P = NR

OR 1.40

P = 0.06OR 2.39

P = <0.001OR 1.55

P = 0.03

OR 2.23

P = <0.001

55.3

84.3

44.4

70.8

ORR (%) CBR (%)a ab b



PALOMA-1: All-causality AEs occurring in ≥25% of patients (safety population)

AE Arm Any grade Grade 3/4

Any AEPalbociclib + letrozole

Letrozole alone

NeutropeniaPalbociclib + letrozole

Letrozole alone

LeukopeniaPalbociclib + letrozole

Letrozole alone

FatiguePalbociclib + letrozole

Letrozole alone

AnaemiaPalbociclib + letrozole

Letrozole alone

NauseaPalbociclib + letrozole

Letrozole alone

99% 76%84% 21%

75% 54%5% 1%

43% 19%3% 0%

41% 5%23% 1%

35% 6%6% 1%

25% 2%13% 1%

PALOMA-2: All-causality haematological AEs occurring in ≥15% of patients in either arm (as-treated population)

AE Arm Any grade Grade 3 Grade 4

Any AEPalbociclib + letrozole

Letrozole alone

NeutropeniaaPalbociclib + letrozole

Letrozole alone

LeukopeniabPalbociclib + letrozole

Letrozole alone

AnaemiacPalbociclib + letrozole

Letrozole alone

ThrombocytopeniadPalbociclib + letrozole

Letrozole alone

99% 62%95% 22%

14%2%

80% 56%6% 1%

10%1%

39% 24%2% 0%

1%0%

24% 5%9% 2%

<1%0%

16% 1%1% 0%

<1%0%

PALOMA-3: Phase III study design

aAll received goserelin.

bMust have progressed on prior endocrine therapy (pre-/perimenopausal) or aromatase inhibitor therapy

(postmenopausal).

cPatients randomised. dAdministered on Days 1 and 15 of Cycle 1, then every 28 d.

HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; q4w, every 4

weeks; QD, once daily

Turner NC, et al. N Engl J Med. 2015;373:209–219;

Cristofanilli M, et al. Lancet Oncol. 2016;17:425–439.

Randomised Phase III double-blind trial at 144 centres in 17 countries

Placebo

(3 wks on/1 wk off)

+

Fulvestrantd

(500 mg IM q4w)

Palbociclib

(125 mg QD;

3 wks on/1 wk off)

+

Fulvestrantd

(500 mg IM q4w)

• Visceral metastases

• Sensitivity to prior

hormonal therapy

• Pre-/peri- vs.

postmenopausal

2:1 randomisation

N=521c

Stratification:

ER+ HER2– ABC

Pre-/peri-a or postmenopausal

Progressed on prior endocrine therapyb:

– On or within 12 mo of completion of

adjuvant treatment

– On or within 1 mo of treatment for ABC

≤1 prior chemotherapy regimen for

advanced cancer

n=347

n=174

PALOMA-3 final analysis: Investigator-assessed PFS

FUL, fulvestrant; HR, hazard ratio; NE, not estimable; PAL, palbociclib; PBO, placebo; PFS,

progression-free survival

174 109 42 16 6 1

347 279 132 59 16 6

Time, months

100

90

80

70

60

50

40

30

20

10

0

0 2 3 4 5 6 7 9 10 11 1281

PCB+FUL


PAL+FUL

PF

S p

rob

ab

ilit

y (

%)

PAL + FUL(n=347)

PBO + FUL(n=174)

Median PFS,months (95% CI)

9.2 (7.5–NE) 3.8 (3.5–5.5)

HR (95% CI) 0.42 (0.32–0.56)

P value <0.001

Placebo + fulvestrant (n=174)

Palbociclib + fulvestrant (n=347)



PALOMA-3 update: Investigator-assessed PFS

FUL, fulvestrant; NE, not estimable; PAL, palbociclib; PBO, placebo; PFS, progression-free

survival

347 333 281 273 247 244 202 197 91 85 32 023 7 7 1PAL + FUL

174 165 112 105 83 80 59 58 22 22 13 07 2 1 0PBO + FUL

1 2 3 4 5 6 7 8 9 10 1511 12 13 14

100

90

80

70

60

50

40

30

20

10

0

0

PF

S (

%)

Time, monthsNumber of patients at risk

PAL + FUL(n=347)

PBO + FUL(n=174)

Median PFS,months (95% CI)

9.5 (9.2–11.0) 4.6 (3.5–5.6)

HR (95% CI) 0.46 (0.36–0.59)

P value <0.0001

Placebo + fulvestrant (n=174)

Palbociclib + fulvestrant (n=347)



PALOMA-3 Final Analysis: Response Rates

Cristofanilli M, et al. Lancet Oncol 2016 [Published online 2 March 2016; http://dx.doi.org/10.1016/S1470-2045(15)00613-0]

Palbociclib + fulvestrant resulted in a

statistically significant improvement over

fulvestrant alone for:

• ORR in ITT (19% vs 9%, respectively) and

in patients with measurable disease (25%

vs 11%)

• CBR in ITT (67% vs 40%) and in patients

with measurable disease (64% vs 36%)

Palbociclib + fulvestrant

Placebo + fulvestrant

Population: Intent-to-treat Measurable disease Intent-to-treat Measurable disease

Odds ratio

(95% CI)

2.47

(1.36–4.91)

2.69

(1.43–5.26)

3.05

(2.07–4.61)

3.10

(1.99–4.92)

60

50

40

30

20

10

0Measurable

disease

Measurable

disease

Intent-to-treat

P<0.0001*

P=0.0019*

P=0.0012*

ORR

Intent-to-treat

CBR

P<0.0001*

Pa

tie

nts

(%

)

70PR CR SD

PR CR SD

* Two-sided exact tests stratified by the presence of visceral metastases and sensitivity

to previous hormonal therapy as per randomisation were used to calculate p values.

ORR, objective response rate; CBR, clinical benefit rate; PR, partial response;

CR, complete response; SD, stable disease; ITT; intent-to-treat

19%

9%

25%

11%

67%

40%

64%

36%

25

OVERALL SURVIVAL IN PALOMA-3 (ITT)

FUL=fulvestrant; HR=hazard ratio; ITT=intent-to-treat; PAL=palbociclib; PBO=placebo.

• Absolute improvement in median OS in the palbociclib arm versus the placebo arm was

6.9 months.

0 6 12 18 24 30 36 42 48 54

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Overa

ll S

urv

ival

Pro

bab

ilit

y (

%)

Palbociclib+Fulvestrant (N=347)

Median OS=34.9 months

95% CI (28.8–40.0)Placebo+Fulvestrant (N=174)


95% CI (23.6–34.6)

Stratified HR=0.81

95% CI (0.64–1.03)

1-sided P=0.043

Unstratified HR=0.79

95% CI (0.63–1.00)

1-sided P=0.025

347 321 286 247 209 165 148 126 17PAL+FUL

174 155 135 115 86 68 57 43 7PBO+FUL


• In patients with sensitivity to prior ET, absolute improvement in median OS in the

palbociclib arm versus the placebo arm was 10.0 months.

OVERALL SURVIVAL BY SENSITIVITY TO PRIOR ET

Patients With Sensitivity to Prior ET Patients Without Sensitivity to Prior ET

0 6 12 18 24 30 36 42 48 54Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Overa

ll S

urv

ival

Pro

bab

ilit

y (

%) Palbociclib+Fulvestrant (N=274)


95% CI (34.8–45.7)

Placebo+Fulvestrant (N=136)


95% CI (23.8–37.9)

HR=0.72

95% CI (0.55–0.94)

1-sided P=0.008

274 257 233 208 182 146 131 110 14PAL+FUL

136 122 107 93 70 57 48 35 5PBO+FUL


0 6 12 18 24 30 36 42 48 54Time (Months)

0

10

20

30

40

50

60

70

80

90

100Palbociclib+Fulvestrant (N=73)


95% CI (17.2–26.4)

Placebo+Fulvestrant (N=38)


95% CI (17.5–31.8)

HR=1.14

95% CI (0.71–1.84)

1-sided P=0.70

73 64 53 39 27 19 17 16 3PAL+FUL

38 33 28 22 16 11 9 8 2PBO+FUL


Overa

ll S

urv

ival

Pro

bab

ilit

y (

%)

TIME FROM RANDOMIZATION TO START OF

POSTPROGRESSION CHEMOTHERAPY

28

TCT=time to chemotherapy.

0 6 12 18 24 30 36 42 48 54

Time (Months)

0

10

20

30

40

50

60

70

80

90

100Palbociclib+Fulvestrant (N=347)

Median TCT=17.6 months

95% CI (15.2–19.7)Placebo+Fulvestrant (N=174)

Median TCT=8.8 months

95% CI (7.3–12.7)

HR=0.58

95% CI (0.47–0.73)

1-sided P<0.000001

347 254 182 133 99 78 56 41 6PAL+FUL

174 91 58 40 22 16 13 10 1PBO+FUL


Tim

e t

o C

hem

oth

era

py

Pro

bab

ilit

y (

%)

The MONARCH trials

• PFS, progression free survival

Trial Study design Study size

Target population


Primary

endpoint

MONARCH-1Phase 2

Open label

184

patients

AI resistant

CT treated mBC

Postmenopausal

Monotherapy RR

MONARCH-2

Phase 3

Placebo

control

669 patients

AI resistant

CT naïve for mBC

Pre-, peri and

Postmenopausal

Fulvestrant PFS

MONARCH-3

Phase 3

Placebo

control

493 patientsEndocrine sensitive

Postmenopausal

Anastrozole and

letrozolePFS

The MONALEESA trials

• PFS, progression free survival

Trial

Study

design Study size

Target population


Primary

endpoint

MONALEESA-2

Phase 3

Placebo

control

668 patients

Endocrine sensitive


Postmenopausal

Letrozole PFS

MONALEESA-

3*

Phase 3

Placebo

control

725 patients

Endocrine sensitive and

endocrine resistant

mBC

Postmenopausal

Fulvestrant PFS

MONALEESA-7

Phase 3

Placebo

control

493 patientsEndocrine sensitive

Pre-perimenopausal

Anastrozole and

letrozole plus

LH-RH analogue

PFS

The MONALEESA-7 trial












Are all CDK 4-6 created equal?

PALOMA

trials

MONALEESA

trialsMONARCH

trials

Abemaciclib Palbociclib Ribociclib

Are all CDK 4-6 created equal?

Chen P, et al Mol Cancer Ther. 2016;15(10):2273-2281.

Off-Target

Selectivity

1x

10x

100x

† Tested at 1 μm; considered inhibited if >65% reduction in binding.

Ribociclib Palbociclib Abemaciclib

Number of off-target

kinases inhibited†4 13 52

6% inhibition

(3 kinases)

16% inhibition

36% (CLK) and

11% (HIPK2) inhibition

25 off-target

kinases with

9-95% inhibition

CDK4/6

Selectivity

1x

7% inhibition

• HR+, HER2- ABC• Postmenopausal • Noprior systemic therapy in this setting• If neoadjuvant or adjuvant ET

administered, a disease free interval of >12 months since completion of ET

• ECOG PS ≤1

abemaciclib: 150 mg BID

Abemaciclib

plus

AI

Ra

nd

om

iza

tion

2 :1

placebo

plus

AI

N = 493


Palbociclib

plus

AI

Ra

nd

om

iza

tion

2 :1

placebo

plus

AI

N = 666


Ribociclib

plus

AI

Ra

nd

om

iza

tion

1 :1

placebo

plus

AI

N = 668

PALOMA-21

MONALEESA-22

MONARCH-33

Primary endpoint:


1Finn RS, et al. N Engl J Med 2016; 2Hortobagyi G, et al. N Engl J Med 2016; 3di Leo A, et al. J Clin Oncol 2017

Endocrine sensitive disease: 1st line

PALOMA 2 (2:1) MONALEESA 2 (1:1)

Median PFS

abemaciclib + NSAI: not reached

placebo + NSAI: 14.7 m

HR (95% CI): 0.543 (0.409, 0.723) p = 0.000021

MONARCH 3 (2:1)

Median PFS

Ribociclib + NSAI: 25.3 m

placebo + NSAI: 16 m

HR (95% CI): 0.568 (0.457, 0.704) p = 0.000000096


PCB + LET

222

171

148

131

116

98 81 54 22 12 4 2

PAL + LET

444

395

360

328

295

263

238

154

69 29 10 2

Prog

ress

ion-

Free

Sur

vival

, %

Time, months

100

90

80

70

60

50

40

30

20

10

0 0 3 6 9 12 15 18 24 27 30 33 21

Number of Events, n (%)

Median (95% CI) PFS

HR (95% CI); 1-sided P value

194 (44)

24.8 (22.1-NR)

0.58 (0.46-0.72); P<0.000001

137 (62)

14.5 (12.9-17.1)

PAL+LET (N=444)

PCB+LET(N=222)

Median PFS

Palbociclib + NSAI: 24.8 m

placebo + NSAI: 14.5 m

HR (95% CI): 0.58 (0.46, 0.72) p =<0.000001

Endocrine sensitive disease

• ER+, HER2- ABC

• Pre/peri & Postmenopausal*

• Progressed on prior endocrine therapy:

–On or within 12 mo adjuvant

–On therapy for ABC


Abemaciclib

plus

Fulvestrant

Ra

nd

om

iza

tion

2 :1

placebo

plus

Fulvestrant

N = 669

Palbociclib

plus

Fulvestrant

Ra

nd

om

iza

tion

2 :1

placebo

plus

Fulvestrant

N = 521


Ribociclib

plus

Fulvestrant

Ra

nd

om

iza

tion

1 :1

placebo

plus

Fulvestrant

PALOMA-31

MONALEESA-32

MONARCH-23Primary endpoint:


*Only postmenopausal

Endocrine resistant disease: 1st line

1Turner NC, et al. N Engl J Med 2015; 2Slamon D et al, J Clin Oncol 2018; 3Sledge G, et al. J Clin Oncol 2017

Endocrine resistant disease

PALOMA 31,2 MONARCH23

1Turner NC, et al. N Engl J Med 2015; 2Cristofanilli M, et al. Lancet Oncol 2016; 3Sledge G, et al. J Clin Oncol 2017, 4Slamon D et al, J Clin Oncol 2018

HR (95% CI): 0.46 (0.36, 0.59)

p =<0.0001HR (95% CI): 0.55 (0.45, 0.68)

p =<0.001

MONALEESA 34

HR (95% CI): 0.593 (0.480, 0.732)

p =<0.001

Selective toxicities across CDK 4-6 inhibitors

• Cross-trial comparisons need to be taken with

caution due to differences in trial design. • 1. Palbociclib SmPC, July 2018, accessed August 2018;

2. Ribociclib US PI, July 2018, accessed August 2018;

3. Abemaciclib US PI, February 2018, accessed August 2018.

Palbociclib1

• Neutropenia (81%)

• Diarrhoea (25%)

• Increased ALT (8%)

• Increased AST (9%)

Ribociclib2

• Neutropenia (69–78%)

• Diarrhoea (29–35%)

• Increased ALT (15–46%)

• Increased AST (13–44%)

• QTc prolongation (6%)

Abemaciclib3

• Neutropenia (41–46%)

• Diarrhoea (81–86%)

• Increased ALT (13–16%)

• Increased AST (12–15%)

• Thromboembolic events (5%)

Effect of toxicity in selecting CDK 4-6 Inhinitors

• AE, adverse event.

• 1. Riseberg D. Clin Med Insights Oncol. 2015;9:65–73;

2. Palbociclib SmPC, July 2018, accessed August 2018;

3. Ribociclib SmPC, April 2018, accessed August 2018;

4. Abemaciclib US PI, February 2018, accessed August 2018.

Elderly patients1–4

Patients with

cardiovascular

disease2–4

Patients with hepatic

impairment2–4

Patients with

comorbidities1

Neutropenia ✓ ✓

Diarrhoea ✓ ✓

Thromboembolic events ✓ ✓ ✓

Reversible transaminitis ✓ ✓ ✓

QTc prolongation ✓ ✓ ✓

ALT

AST

Alpelisib and PIK3CA mutation

– PI3K includes catalytic and regulatory subunits;

PIK3CA encodes the α-isoform of catalytic

subunit1,2

• Activation of this subunit can lead to pathway

hyperactivation

– Pan-PI3K inhibitors targeted multiple isoforms of

PI3K, which leads to excess toxicities and

marginal efficacy3–5

– Alpelisib (BYL719) is an oral inhibitor of the PI3K

α-isoform6,7

– Alpelisib has demonstrated antitumor activity in

preclinical models harboring PIK3CA alterations6,8

• 1. Engelman JA. Nat Rev Cancer 2009;9:550–562; 2. Janku F. Cancer Treat Rev 2017;59:93–101; 3. Baselga J, et al. J Clin Oncol 2018;36 (Suppl): LBA 1006;4. Di Leo A, et al. Lancet Oncol 2018 19(1):87–100; 5. Baselga J, et al. Lancet Oncol 2017;18(7):904–916; 6. Fritsch C et al. Mol Cancer Ther 2014;13:1117–1129;

7. Osborne CK, Schiff R. Annu Rev Med 2011; 62:233–247; 8. Huang A et al. AACR 2012;72; Abstract 3749

There is a strong rationale for targeting the α-isoform of PI3K in patients with a

PIK3CA mutation

Regulatory

subunit

Catalytic

subunit p110

p85

PI3K

PI3K

isoforms

α

β

γ

δ

Isoforms of the p110

catalytic subunit of PI3K1

Phase Ib: Preliminary clinical activity with alpelisib +

fulvestrant

– In a Phase Ib trial, alpelisib +

fulvestrant was administered in

heavily pretreated patients with

PIK3CA-altered ER+ ABC (median 5

lines of prior therapy)1

– In patients with PIK3CA-altered

disease, alpelisib plus fulvestrant led

to a median PFS of 9.1 months1

– In this trial, the potential clinical

activity of alpelisib in patients with

PIK3CA-wild-type disease was

unclear1

• 1. Juric D et al. JAMA Oncol 2018;In press.

Median PFS, months:

Pro

bab

ilit

y o

f P

FS

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

PIK3CA-altered (n=49) 9.1 (95% CI: 7–NE)

PIK3CA-WT (n=32) 4.7 (95% CI: 2–6)

There is a rationale to perform a Phase III trial to evaluate efficacy of alpelisib in

patients with PIK3CA-mutant ABC, while further exploring potential activity in

PIK3CA-non-mutant disease

Phase Ib: PFS with alpelisib + fulvestrant1

SOLAR-1: A Phase III randomized, controlled trial

(NCT02437318)

• *Fulvestrant given on Day 1 and Day 15 of the first 28-day cycle, then Day 1 of subsequent 28 day cycles. ABC, advanced breast caner; AI, aromatase inhibitor; ALP, alpelisib; CBR, clinical benefit rate; CT, chemotherapy;

ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; FUL, fulvestrant; IM, intramuscular; ORR, overall response rate; OS, overall survival; PBO, placebo; PFS, progression-free survival; PO, orally; QD, daily; R, randomization.

PIK3CA-non-

mutant cohort

(n=231)

ALP 300 mg QD PO

+ FUL 500 mg IM*

n=115

PBO

+ FUL 500 mg IM*

n=116

• Men or post-

menopausal women

with HR+, HER2– ABC

• Received prior AI

• Identified PIK3CA status

(in archival or fresh tumor

tissue)

• Measurable disease or

≥1 predominantly lytic

bone lesion

• ECOG performance

status ≤1

(N=572)

ALP 300 mg QD PO

+ FUL 500 mg IM*

n=169

PBO

+ FUL 500 mg IM*

n=172

PIK3CA-

mutant cohort

(n=341)

R

1:1, stratified by presence of

liver/lung metastases and prior

CDK4/6 inhibitor treatment

Primary endpoint

• PFS in PIK3CA-mutant cohort

(locally assessed)

Secondary endpoints include:

• OS (PIK3CA-mutant cohort)

• PFS (PIK3CA-non-mutant

cohort)

• PFS (PIK3CA-mutation in

ctDNA)

• OS (PIK3CA-non-mutant cohort)

• ORR/CBR

• Safety

R

Statistical analyses

The primary analysis population was all patients in the PIK3CA-mutant cohort*

• Two interim analyses for PFS (futility and efficacy) were performed†

• The primary endpoint would be met at the final PFS analysis if p<0.02

PFS was analyzed in the PIK3CA-non-mutant cohort as a proof of concept‡

Safety was analysed for all patients who received ≥1 dose of study treatment, in both cohorts

• *PFS was tested using a 3-look group-sequential design with 83.8% power to detect HR=0.60 using one-sided, 2.0% significance level for 243 PFS events.Median PFS was estimated using Kaplan–Meier method, HR for PFS was estimated using a stratified Cox regression model; the p-value was estimated using a stratified log-rank test. At the final

PFS analysis, superiority was declared if one-sided p-value was ≤0.0199 (Z=2.054). Audit-based BIRC PFS review was carried out in 50% of randomized patients in the PIK3CA-mutant cohort.

• †Superiority was declared at interim efficacy analysis if one-sided p-value was ≤0.0001 (Z≥3.719; Haybittle–Peto stopping boundary).

• ‡Proof of concept criteria: estimated hazard ratio ≤ 0.60 and posterior probability ≥ 90% that HR was < 1. Confidence level for the proof of concept analysis was 0.5%.

Inclusion criteria: Prior exposure to AI

Relapse

≤1 year

>1 year

Neo (Adjuvant) ET

Neo (Adjuvant) ET

D

i

a

g

n

o

s

i

s

Neo (Adjuvant) ET

ET for advanced

diseaseProgressi

on

ET for advanced

diseaseProgressi

on

Relapse

Relapse

>1 year

Excluded after a protocol amendment

– Patients who had received one prior line of endocrine therapy were enrolled

• Patients were considered endocrine resistant or sensitive according to the ESMO definitions1

• Patients who had not received ET for ABC were considered “first line”

1. Cardoso F, et al. Ann Oncol 2018;29:1634–57.

Baseline characteristics

Characteristic*

PIK3CA-mutant PIK3CA-non-mutant

Alpelisib + fulvestrant

(N=169)†


(N=172)‡

Alpelisib + fulvestrant(N=115)


(N=116)

Median age, years (range) 63 (25–87) 64 (38–92) 62 (39–82) 63 (32–88)

Race

Caucasian 117 (69.2) 109 (63.4) 82 (71.3) 69 (59.5)

Asian 34 (20.1) 40 (23.3) 25 (21.7) 26 (22.4)

Other 18 (10.7) 23 (13.3) 8 (7.0) 95 (18.1)

ECOG PS

0 112 (6.3) 113 (65.7) 84 (73.0) 79 (68.1)

1 56 (33.1) 58 (33.7) 30 (26.1) 37 (31.9)

Metastatic sites

Visceral disease 93 (55.0) 100 (58.1) 66 (57.4) 74 (63.8)

Lung/liver metastases 84 (49.7) 86 (50.0) 56 (48.7) 56 (48.3)

Bone-only disease 42 (24.9) 35 (20.3) 26 (22.6) 23 (19.8)

Line of advanced anti-cancer treatment

First line 88 (52.1) 89 (51.7) 71 (61.7) 62 (53.4)

Second line 79 (46.7) 82 (47.7) 42 (36.5) 53 (45.7)Endocrine status§

Primary resistance 23 (13.6) 22 (12.8) 31 (27.0) 26 (22.4)

Secondary resistance 120 (71.0) 127 (73.8) 66 (57.4) 65 (56.0)

Sensitive 20 (11.8) 19 (11.0) 16 (13.9) 20 (17.2)Prior chemotherapy

Neo-adjuvant 25 (14.8) 29 (16.9) 20 (17.4) 23 (19.8)

Adjuvant 78 (46.2) 86 (50.0) 64 (55.7) 58 (50.0)

Prior CDK 4/6 inhibitor treatment 9 (5.3) 11 (6.4) 7 (6.1) 8 (6.9)*Characteristics are given as n (%) unless otherwise stated; †One man was enrolled in the alpelisib group in the PIK3CA-mutant cohort.

All other study participants were postmenopausal women. ‡1 patient in the PIK3CA-mutant cohort randomized to placebo was not treated.§Primary and secondary resistance as per ESMO definition.1

1. Cardoso F, et al. Ann Oncol 2018;29:1634–57.

Patient disposition

•*Characteristics are n (%) unless otherwise stated. The data cut-off for both cohorts is June 12, 2018.

†1 patient in the PIK3CA-mutant cohort randomized to placebo was not treated.

Disposition*

PIK3CA-mutant PIK3CA-non-mutant


(N=169)

Placebo + fulvestrant(N=172)†


(N=115)


(N=116)

On Treatment 42 (24.9) 32 (18.6) 13 (11.3) 14 (12.1)

Discontinued 127 (75.1) 139 (80.8) 102 (88.7) 102 (87.9)

Reasons for discontinuation

Adverse Event 5 (3.0) 3 (1.7) 9 (7.8) 0

Death 3 (1.8) 4 (2.3) 1 (0.9) 0

Physician Decision 6 (3.6) 6 (3.5) 5 (4.3) 4 (3.4)

Progressive Disease 93 (55.0) 117 (68.0) 80 (69.6) 91 (78.4)

Protocol Deviation 4 (2.4) 3 (1.7) 1 (0.9) 3 (3.4)

Subject/Guardian Decision 16 (9.5) 6 (3.5) 6 (5.2) 4 (3.4)

Median follow-up (months) 20.2 19.9 7.3 7.4

Primary endpoint: Locally assessed PFS in the PIK3CA-

mutant cohort

Data cut-off:

Jun 12, 2018

Alpelisib +

fulvestrant

(N=169)

Placebo +

fulvestrant

(N=172)

Number of PFS

events, n (%)103 (60.9) 129 (75.0)

Progression 99 (58.6) 120 (69.8)

Death 4 (2.4) 9 (5.2)

Censored 66 (39.1) 43 (25.0)

Median PFS

(95% CI)

11.0

(7.5–14.5)

5.7

(3.7–7.4)

HR (95% CI) 0.65 (0.50–0.85)

p-value 0.00065

• The primary endpoint crossed the

pre-specified Haybittle-Peto

boundary (one-sided p≤0.0199)

BIRC audit: Centrally assessed PFS in the PIK3CA-mutant

cohort

BIRC, blinded independent review committee.

• Audit-based review of 50% of randomized patients in the PIK3CA-mutant cohort (n=173)

• Based on the prespecified thresholds to trigger a full BIRC review of all patient data in the PIK3CA-mutant

cohort, a full BIRC review was not required

Data cut-off:

Jun 12, 2018

Alpelisib +

fulvestrant

(N=85)

Placebo +

fulvestrant

(N=88)

Number of PFS

events, n (%)43 (50.6) 63 (71.6)

Median PFS

(95% CI)

11.1

(7.3–16.8)

3.7

(2.1–5.6)

HR (95% CI) 0.48 (0.32–0.71)

Proof of Concept: PFS in the PIK3CA-non-mutant cohortProof of concept criteria were not met in the PIK3CA-non-mutant cohort

Data cut-off:

Dec 23, 2016

Alpelisib +

fulvestrant

(N=115)

Placebo +

fulvestrant

(N=116)

Number of PFS

events, n (%)49 (42.6) 57 (49.1)

Progression 47 (40.9) 57 (49.1)

Death 2 (1.7) 0

Censored 66 (57.4) 59 (50.9)

Median PFS

(95% CI)

7.4

(5.4–9.3)

5.6

(3.9–9.1)

HR (95% CI) 0.85 (0.58–1.25)

Posterior probability

HR<1, %79.4

• Proof of concept criteria: estimated hazard ratio ≤ 0.60 and posterior probability ≥90% that HR was <1

• Statistical testing of OS was not carried out in the PIK3CA-non-mutant cohort, as proof of concept criteria

were not met

• Non-mutant patients were followed up for safety alongside the PIK3CA-mutant cohort

PFS by subgroup (PIK3CA-mutant cohort)

*Mutations detected in tissue. Patients may have had more than one PIK3CA mutation; †Includes multiple E545 subtypes; ‡Includes multiple

H1047 subtypes.

-1.5 -1 -0.5 0 0.5 1 1.5 2

Hazard Ratio (95% CI)Subgroup No. of Patients

All patients 341

Lung and/or liver metastases Yes 170

No 171

Bone-only disease Yes 264

No 77

Prior CDK4/6 inhibitor treatment Yes 20

No 321

Prior chemotherapy Neoadjuvant 46

Adjuvant 161

None 133

Line of advanced First-line 177

anti-cancer treatment Second-line 161

PIK3CA mutation exon* Exon 9 165

Exon 20 193

PIK3CA exon subtype* E542K 60

E545X† 105

H1047X‡ 193

0.65 (0.50–0.85)

0.62 (0.44–0.89)

0.69 (0.47–1.01)

0.62 (0.33–1.18)

0.66 (0.49–0.88)

0.48 (0.17–1.36)

0.67 (0.51–0.87)

0.63 (0.42–0.95)

0.87 (0.58–1.29)

0.71 (0.49–1.03)

0.61 (0.42–0.89)

0.61 (0.41–0.90)

0.68 (0.48–0.95)

0.60 (0.29–1.23)

0.61 (0.37–1.00)

0.68 (0.48–0.95)

0.37 (0.17–0.80)

Favors alpelisib Favors placebo


Overall response rate in the PIK3CA-mutant cohort

• ORR = complete response + partial response.


26.6

12.8

0

20

40

60

80

100

Overall response rate

All patients

Rat

e (%

)

35.7

16.2

0

20

40

60

80

100

Overall response rate

Patients with measurable disease

Ra

te (

%) p=0.0002p=0.0006

Adverse events in the total population*

• *Safety profiles were similar in the PIK3CA-mutant and PIK3CA-non-mutant cohorts

AEs ≥20% in either arm, %


N=284


N=287

All Grade 3 Grade 4 All Grade 3 Grade 4

Any adverse event 282 (99.3) 183 (64.4) 33 (11.6) 264 (92.0) 87 (30.3) 15 (5.2)

Hyperglycemia 181 (63.7) 93 (32.7) 11 (3.9) 28 (9.8) 1 (0.3) 1 (0.3)

Diarrhea 164 (57.7) 19 (6.7) 0 45 (15.7) 1 (0.3) 0

Nausea 127 (44.7) 7 (2.5) 0 64 (22.3) 1 (0.3) 0

Decreased appetite 101 (35.6) 2 (0.7) 0 30 (10.5) 1 (0.3) 0

Rash 101 (35.6) 28 (9.9) 0 17 (5.9) 1 (0.3) 0

Vomiting 77 (27.1) 2 (0.7) 0 28 (9.8) 1 (0.3) 0

Decreased weight 76 (26.8) 11 (3.9) 0 6 (2.1) 0 0

Stomatitis 70 (24.6) 7 (2.5) 0 18 (6.3) 0 0

Fatigue 69 (24.3) 10 (3.5) 0 49 (17.1) 3 (1.0) 0

Asthenia 58 (20.4) 5 (1.8) 0 37 (12.9) 0 0

• Eighteen patients (6.3%) discontinued alpelisib due to hyperglycemia and 9 patients (3.2%)

discontinued alpelisib due to rash; no patients discontinued placebo due to either

hyperglycemia or rash

Treatment exposure and dose adjustments

• *The data cut-off for both groups was June 12, 2018.

• †1 patient in the placebo arm of the PIK3CA-mutant cohort did not receive fulvestrant or placebo.

Treatment exposure

PIK3CA-mutant* PIK3CA-non-mutant*


(N=169)

Placebo + fulvestrant(N=171)†


(N=115)


(N=116)

Exposure to alpelisib/placebo

Median duration of exposure to alpelisib/placebo,

months (range) [n exposed]5.5 (0.0–29.0) [168] 4.6 (0.0–30.1) [170] 5.6 (0.3–30.8) [115] 6.2 (0.5–29.5) [116]

Median relative alpelisib/placebo dose intensity, % 82.7 100 84.5 100

Alpelisib/placebo dose adjustments, n (%)

Patients with dose interruptions 125 (74.0) 55 (32.2) 80 (69.6) 31 (26.7)

Dose interruptions due to AEs 116 (68.6) 27 (15.8) 73 (63.5) 13 (11.2)

Patients with dose reductions 108 (63.9) 15 (8.8) 60 (52.2) 6 (5.2)

Dose reductions due to AEs 105 (62.1) 8 (4.7) 59 (51.3) 5 (4.3)

Conclusions

– SOLAR-1 is the first Phase III trial of an α-specific PI3K inhibitor in HR+, HER2– advanced breast cancer,

and alpelisib is the first PI3K inhibitor to show clinically meaningful, statistically significant results in breast

cancer

– PFS was significantly prolonged with the addition of alpelisib to fulvestrant, vs placebo + fulvestrant, in

patients with PIK3CA-mutant disease

• Median PFS = 11.0 months vs 5.7 months; hazard ratio = 0.65; p = 0.00065

• The proof-of-concept criteria were not met in the PIK3CA-non-mutant cohort

– Treatment benefit was consistent across patient subgroups in the PIK3CA-mutant cohort

– The safety profile was as expected, and the majority of AEs were grade 1/2 in severity

• Hyperglycemia and rash were managed by dose modification and concomitant medical intervention as directed by

the study protocol

– Alpelisib + fulvestrant is a potential new treatment option for patients with PIK3CA-mutant HR+, HER2–

advanced breast cancer who have progressed on prior endocrine therapy (with/without a CDK 4/6

inhibitor)

0

Median TTP/PFS (months)

12 246 18

Evolution of therapy for endocrine sensitive metastatic breast cancer

PFS, progression-free survival; TTP, time-to-progression

1. Mouridsen H, et al. J Clin Oncol 2001;19:2596–606; 2. Mouridsen H, et al. J Clin Oncol

2003;21:2101–9; 3. Bonneterre J, et al. Cancer 2001;92:2247–58; 4. Nabholtz JM, et al. J Clin

Oncol 2000;18:3758–67; 5. Paridaens RJ, et al. J Clin Oncol 2008;26:4883–90; 6. Ellis M, et al.

ESMO 2016, LBA14_PR; 7. Finn RS, et al. N Engl J Med 2016;375:1925–36;

8. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48

Letrozole + CDK 4-6 inhibitors

24.8 months7

Fulvestrant 500 mg

16.6 months6

Aromatase inhibitors

10–14 months6–8

Tamoxifen

6 months1–5

0 6

Exemestane

3.2 months1

Fulvestrant 500 mg

4.6–6.5 months2–4

Exemestane + everolimus

7.8 months1

Fulvestrant + CDK 4-6 inhibitors

11.2 months2,3

123 9

Fulvestrant + alpelisib

11.1 months5

Evolution of therapy for endocrine resistant metastatic breast cancer

PFS, progression-free survival

1. Yardley DA, et al. Adv Ther 2013;30:870–84; 2. IBRANCE EU SmPC; 3. Turner NC, et al. SABCS 2016, Abstract

P4-22-06; 4. Di Leo A, et al. J Clin Oncol 2010;28:4594–600; 5. Baselga J, et al. Presented at SABCS 2015

Median PFS (months)

Optimal frontline therapy

•• Clinicaltrials.gov NCT02491983

Randomization (1:1) non-blinded. Stratified by:

• Visceral / non-visceral involvement

• De novo / non-de novo

480 patients• ER(+)/HER2(-)

• Advanced breast

cancer

Palbociclib

125 mg capsules

Daily for 3 weeks followed by a

week off over 28-day cycles

On days 1 and 14 of cycle 1;

then on day 1 of subsequent 28-day

cycles

Fulvestrant

500 mg/5mL i.m.

Palbociclib

125 mg capsules

Daily for 3 weeks followed by a

week off over 28-day cycles

Once daily continuously over

28-day cycles

Letrozole

2.5 mg tablet

End of study:

• Disease progression

• Symptomatic deterioration

• Unacceptable toxicity

• Death

• Withdrawal of consent

Arm B:

Arm A:

First line or second line?

Randomization (1:1) non-blinded. Stratified by:

• Visceral / non-visceral involvement

1050 patients• ER(+)/HER2(-)

• Advanced breast

cancer

• Endocrine

sensitive

• Pre and post

Any AI

+Fulvestrant

Any CDK 4-6

inhibitors

Primary endpoint

• Progression-free survival

after two lines of treatment

(PFS2)

Arm B:

Arm A:

PD

Fulvestrant + CDK 4-6 InhibitorsAny AIPD

NCT03425838. Available at: www.clinicaltrials.gov.

ABC 4 guidelines: Postmenopausal patients with ER+/HER2‒ ABC

aExcept for relapse <12 mths from finishing adjuvant AI

ABC, advanced breast cancer; AI, aromatase inhibitor; ER, oestrogen receptor; ET, endocrine therapy;

HER2, human epidermal growth factor receptor-2; NSAI, non-steroidal AI; PD, progressive disease

NO

(includes

visceral disease)

ER+/HER2‒ ABC

Postmenopausal

ET is the preferred option

Chemotherapy

AI OR tamoxifen OR fulvestrant (1A)

AI + CDK 4-6 inhibitora (1A)

AI + everolimus for some women with PD after NSAI (1B)

Tamoxifen ± everolimus (2B)

Is the patient in visceral crisis?

OR concern/proof of endocrine resistance?

YES

Different AI ± everolimus (1A)

Fulvestrant ± CDK 4-6 inhibitor (1A)

Tamoxifen ± everolimus (1A)

Megestrol acetate OR estradiol (1A)

1L

2L

Visceral crisis,

endocrine

resistance or PD

Thank you

Documents

Endocrine therapy for advanced ER positive/HER2 negative ......“Endocrine therapy is the preferred option for hormone receptor positive disease, even in the presence of visceral