Optimising the Treatment of ER+ Metastatic Breast Cancer

Stephen RD Johnston

Professor of Breast Cancer Medicine

The Royal Marsden Hospital,

Chelsea, London, UK.

UK Breast Cancer Meeting,

London,

21st November 2014

Hormone Receptor Positive

Metastatic Breast Cancer

• Most common subset of Breast Cancer

– HR+ disease comprises 65-70% of pts with MBC

• International Guidelines for Treatment:

– In patients with HR+ advanced breast cancer, hormone therapy

should be the treatmnet of choice in the first-lien setting,

except in tehs etting of rapidly progressing visceral disease

• Prognosis variable and dependent on hormone

responsiveness:

– Influenced by disease-free interval, prior treatment given in

the adjuvant setting, tumor biology

Goals & Challenges in the Treatment of

HR+ Metastatic Breast Cancer

• Maintain QOL:

– Improve outcome without adverse impact on Quality of Life

– Provide effective anti-cancer Rx

• Improve Response to Hormonal Therapy:

– Improve Tumour Response Rates of current Endocrine Rx

– Prolong PFS, and delay start of chemotherapy

– Delay development of acquired (secondary) resistance to Endo Rx

– Overcome upfront (primary) resistance to Endo Rx

Question 1: What is the median PFS for First-

line Endocrine Rx in HR+ MBC (either no prior Endocrine Rx, or relapse >few yrs since

completion of adjuvant endocrine Rx)

1. 6 months

2. 9 months

3. 12 months

4. 15 months

5. 20 months

Question 2: What is your treatment of choice

as First Line Endocrine Rx in

Postmenopausal HR+ MBC

(either no prior Endocrine Rx, or relapse >few yrs

since completion of adjuvant endocrine Rx)

1. Anastrozole

2. Letrozole

3. Exemestane

4. Fulvestrant 500 mg monthly

5. Fulvestrant 500 mg + AI

6. Tamoxifen (if not given adjuvantly)

Question 3: What is the median PFS for

Second-line Endocrine Rx in HR+ MBC (ie. progression after response to letrozole as first-line

endocrine Rx for HR+ MBC)

1. 2-3 months

2. 4-5 months

3. 9 months

4. 12 months

Question 4: What is your treatment of choice

as Second Line Endocrine Rx in

Postmenopausal HR+ MBC

(ie. progression after response to letrozole as first-line

endocrine Rx for HR+ MBC)

1. Exemestane

2. Fulvestrant 500 mg monthly

3. Fulvestrant 500mg + AI

4. Exemestane + Everolimus

5. Tamoxifen (if not given adjuvantly)

1st line hormonal therapy 1st line chemotherapy

Determine sites and extent of disease & symptoms; ER status; HER2 status; disease free & treatment-free intervals; performance status

No Response

No life-threatening disease Hormone-responsive

Hormone-unresponsive, or Life-threatening disease

Response No

Response

2nd-line hormonal therapy

2nd-line chemotherapy

Progression

Progression

Progression

Progression

3rd-line hormonal therapy

Response

No Response

3rd-line chemotherapy

Supportive care

Algorithm for Management of Post-menopausal ER+ MBC

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2012

Median PFS 3-4 mo

Median PFS 12-15 mo

Therapy for HR+ MBC in 2014

• Is combination hormonal therapy any better than appropriate

sequential use ?

– Should untreated HR+ MBC be treated differently to relapsed

disease (sensitive vs acquired resistance) ?

• What are the best strategies for combining Molecular Targeted

Therapies with Endocrine Rx ?

– Can this approach prevent / reverse Endocrine Resistance, and

when should we use mTOR Rx (1L or 2L) ?

– What strategies look to be the most promising ?

10

Efficacy of AIs in 1st-line MBC

Trial Treatment # Patients TTP/PFS,

months

ORR, % CBR, %

Ai

vs

Ta

mo

xif

en

Bonneterre et al1

Anastrozole vs

Tamoxifen

340

328

8.2

8.3

32.9

32.6

56.2

55.5

Nabholtz et al1

Anastrozole vs

Tamoxifen

171

182

11.1

5.6

21.1

17.0

59.1

45.6

Mouridsen et al1

Letrozole vs

Tamoxifen

453

454

9.4

6.0

32

21

50

38

Paridaens et al1

Exemestane vs

Tamoxifen

182

189

9.9

5.8

46

31

NR

NR

Chernozemsky et al1

Exemestane vs

Tamoxifen

83

84

12

8.3

37.4

29.8

79.5

78.6

AI

vs

AI

+ f

ulv

es

tran

t Mehta et al2

Anastrozole vs

Anastrozole + Fulvestrant

345

349

13.5

15.0

P=0.007

NR

NR

70

73

P=0.26

Bergh et al3 Anastrozole vs

Anastrozole + Fulvestrant

256

258

10.2

10.8

P=0.91

33.6

31.8

P=0.76

55.1

55.0

P=0.99

1. Cardoso F, et al. Cancer Treat Rev. 2013;39:457-65

2. Bergh J, et al. J Clin Oncol. 2012;30:1919-25

3. Mehta RS, et al. N Engl J Med. 2012;367:435-44

AI=aromatase inhibitor; CBR=clinical benefit rate;

NR=not reported; ORR=objective response rate;

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

Bergh J et al. JCO 2012;30:1919-1925

FACT: PFS SWOG 0226: PFS

Mehta RS et al. N Engl J Med 2012;367:435-444.

Optimal First-Line Endocrine Therapy for ER+ MBC

SWOG 0226: PFS according to Subgroups

Mehta RS et al. N Engl J Med 2012;367:435-444.

Johnston et al., Lancet Oncol Sept 2013 14(10): 989-998

Fulvestrant LD +

placebo

(n=250)

2nd-line following progression on non-steroidal AI

Exemestane 25 mg

orally daily

(n=250)

Fulvestrant LD + anastrozole

1 mg orally daily

(n=250)

Patients continue treatment until disease progression

Follow-up for survival

Endpoints: PFS, ORR, CB, DoCB, TTP, OS, tolerability, biomarkers

Prior Hormone Sensitive

500 mg Day 1,

250 mg Days 14

& 28, and

monthly

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

Wo

me

n s

urviv

ing

pro

gre

ssio

n f

re

e (

%)

Time from randomisation (months)

SoFEA: Progression free survival

Median PFS: F+A = 4.4 months, 95%CI (3.4, 5.4) F = 4.8 months, 95%CI (3.6, 5.5)

HR = 1.00, 95%CI (0.83, 1.21) Log rank p=0.98

F=221/231

F+A=235/243

Johnston SRD et al, Lancet Oncology 2013 14(10); 989-98

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

Wo

me

n s

urviv

ing

pro

gre

ssio

n f

re

e (

%)

Time from randomisation (months)

Median PFS: F = 4.8 months, 95%CI (3.6, 5.5) E = 3.4 months, 95%CI (3.0, 4.6)

HR = 0.95, 95%CI (0.79, 1.14) Log rank p=0.56

F=221/231

E=233/249

F+A vs F F vs E

15

FIRST study: follow-up TTP analysis

(all randomized patients, N=205)1†

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d

pro

gre

ss

ion

-fre

e

†After the primary data cut-off, progression was determined by investigator opinion

0

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

6 12 18 24 30 36 48

Anastrozole 1 mg

Fulvestrant 500 mg

42

No. of patients at risk:

Fulvestrant 500 mg 102 74 65 52 45 34 20 6 0

Anastrozole 1 mg 103 69 55 39 30 21 8 2 0

1. Robertson JFR et al. Cancer Res. 2010;70(Suppl 2):abstract S1-3

TTP results are consistent with the primary analysis

Median TTP, months: Fulvestrant 500 mg 22.1

Anastrozole 1 mg 12.5

Hazard ratio 0.63; 95% CI: 0.39–1.00; p=0.0496

Progression

Fulvestrant + placebo to Anastrozole

Fulvestrant (500 mg/day i.m.) days 0, 14

& 28 then every 28 days

+ placebo to Anastrozole (1 mg/day p.o.)

Survival

Postmenopausal women with ER+ve and/or PgR+ve locally

advanced or metastatic breast cancer not previously treated

with any hormonal therapy

Progression

Survival

Anastrozole + placebo to Fulvestrant

Anastrozole (1 mg/day p.o.)

+ placebo to Fulvestrant (500 mg/day i.m.)

days 0, 14 & 28 then every 28 days

FALCON Study Design

PFS analysis at 306

progression events

OS analysis at 50%

Therapy for HR+ MBC in 2014

• Is combination hormonal therapy better than appropriate

sequential use ?

– Not as second line post NSAI

– Possible benefit seen in endocrine naïve 1st line setting

– Role of Fulvestrant HD as first-line therapy

• What are the best strategies for combining Molecular Targeted

Therapies with Endocrine Rx ?

– Can this approach prevent / reverse Endocrine Resistance, and

when should we use mTOR Rx (1L or 2L) ?

– What strategies look to be the most promising ?

• Growth Factor Receptor inhibitors (EGFR / HER2; FGFR: IGFR)

• Src inhibitors, PI3K inhibitors

• HCAC inhibitors, CDK 4/6 inhibitors

SOS RAS

RAF

Basal transcription

machinery p160

ERE ER target gene transcription

ER CBP P

P P P

ER

P

Akt P

MAPK P

Cytoplasm

Nucleus

ER

PI3-K P

P

P

P P

P

MEK P

Plasma membrane

EGFR / HER2

IGFR-1

Estrogen

mTOR

2

Endo Rx

3

5

1

6

Current Strategies to Overcome Endocrine

Resistance in Breast Cancer

Adapted from: Johnston SRD Clin. Cancer Res. 2005; 11:889S-899S.

c-Src

7

4

P

FGFR-1

Endo Rx

c-Src

7

Combinations of mTOR inhibitors and AIs as

2nd line or 1st line therapy for ER+ HER2- MBC

Median PFS (central)

EXE + EVEROL: 11.0 mo

EXE + placebo: 4.1 mo

HR = 0.38 (95% CI: 0.31–0.48)

Log-rank P value: < 0.0001

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

0

20

40

60

80

100

Pro

ba

bil

ity o

f E

ve

nt,

%

Time, weeks

BOLERO-2

Baselga J et al, N Engl J Med 2011 366; 520-529

Piccart M, et al. ASCO 2012; # 559.

19

56% no prior Endocrine Rx

Median PFS

LET + TEMSIROL: 9.2 mo

LET + placebo: 9.2 mo

HR = 0.92 (95% CI: 0.75–1.13)

0.7

0.6

0.5

0.2

0.1

0

0.4

0.3

0.8

0.9

1.0

Pro

gre

ss

ion

-fre

e s

urv

iva

l

Time (months)

HORIZON

Wolff AC, et al. J Clin Oncol 2013; 31; 195-202.

84% prior endocrine response

Which Novel Agents offer most Promise to enhance Endocrine Responsiveness in ER+ MBC

Target Therapeutic Pre-clinical Evidence for

Role in Endocrine Resistance Strength of Clinical Data * * * * *

EGFR / HER2 inhibitors Significant amount of data from

several groups 1 negative Phase II RCT in 1st Line *

IGF-1R inhibitors Significant amount of data from

several groups 1 negative Phase II in 2nd Line *

FGFR inhibitors Some evidence N/A ?

mTOR inhibitors Significant amount of data from

several groups 1 positive Phase III RCT in 2nd Line 1 negative Phase III RCT in 1st Line ****

PI3K / Akt inhibitors Significant amount of data from

several groups N/A ?

Src inhibitors Some evidence 2 negative Phase II RCTs in 2nd Line 1 positive Phase II RCT in 1st Line **

HDAC inhibitors

Restores sensitivity in-vivo

1 positive phase II RCT in 2nd Line **

Angiogenesis inhibitors Some evidence 1 negative Phase II RCT *

CDK 4/6 inhibitors

Synergy with tamoxifen 1 positive Phase II RCT in 1st Line ***

Adapter and

structural proteins

Src

GF

MEK2

ERK

Raf

PI3K

Akt

Migration/morphogenesis Survival Cellular

transformation Mitogenesis

Growth factors

(EGF, PDGF, HGF)

Ras

Rac Rho

Grb2

Gab1

SOS

GF

Integrins

FAK

Cas Src

Actin cytoskeleton

p190RhoGAP

Translocation to

cytoskeleton

Extracellular matrix

MEK1

PLCg

RTKs (EGFR,

PDGFR, c-Met) PY

PY

PY

PY

PY

PY

P

Shc

Shp2

P

P

P

STAT3

C-Myc

Src

SRC-family kinases in signal transduction

RCTs in ER+ MBC of Endocrine Rx +/-

Src kinase inhibitors

Agent / Comparator

Setting ClinicalTrials.gov

Identifier

Estimated

Enrollment (n

pts)

Src kinase inhibitors

Dasatinib + fulvestrant

vs fulvestrant alone

MBC refractory to AI

Phase II

randomized, open label

NCT00754325 1

100

Dasatinib + exemestane

vs exemestane alone

MBC refractory to a NSAI

Phase II

randomized, double-

blind

NCT00767520 2

157

Dasatinib + letrozole

vs letrozole alone

1st line ER+ MBC

(De-Novo Stg IV or relapse after

prior adjuvant endo Rx)

Phase II

randomized, open label

NCT00767520 3

120

CDK 4/6 Inhibitors

PD-0332991 + letrozole

versus letrozole alone

1st line MBC

Phase I/II

randomized, open label

NCT00721409 3

177

PD-0332991 + letrozole

versus placebo +

letrozole

1st line MBC

Phase III

randomized, double-

blind

NCT01740427

450

1. Wright GL et al. Cancer Res 2011;71(24 Suppl):Abstract nr PD01-01. 2. Llombart A et al. Cancer Res 2011;71(24 Suppl):Abstract nr PD01-02.

3. Paul D et al. SABCS 2013 Abstract S3-07.

Phase II RCTs of Dasatinib plus Endocrine Rx in ER+ MBC

following progression on NSAI

ORR

n (%)

CBR

n (%)

Fulvestrant +Dasatinib (n=50) 1 (2%) 19 (38%)

Fulvestrant (n=49) 3 (6%) 21 (43%)

Evaluable for Respone ORR

n (%)

CBR

n (%)

Exemestane +Dasatinib (n=50) 6 (12%) 18 (36%)

Exemestane (n=49) 1 (2%) 11 (22%)

Wright GL et al. Cancer Res 2011;71(24 Suppl): #PD01-01.

GROUP # PROGRESSION/DEATH / # RANDOMIZED MEDIAN (95% CI)

DASA+EXEM 68/79 22.0 (15.3 - 24.4)PBO+EXEM 67/78 15.9 (12.1 - 18.1)

SUBJ ECTS AT RISK

DASA+EXEM 79 74 66 52 42 39 35 25 19 18 13 12 11 10 7 3 3 2 1 1 1 1 1 1 1 0

PBO+EXEM 78 75 59 46 37 27 26 22 20 13 10 7 7 6 5 4 3 1 1 1 1 0 0 0 0 0

DASA+EXEMCENSORED

PBO+EXEMCENSORED

PR

OP

OR

TIO

N N

O P

RO

GR

ES

SIO

N/D

EA

TH

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

WEEKS

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

Llombart A et al. Cancer Res 2011;71(24 Suppl):# PD01-02.

Median PFS E+D: 5.5 mo E: 4.0 mo

HR (95% CI) 0.85 (0.6, 1.19)

Study CA180261 Study USON #06-030

This presentation is the intellectual property of the presenter. Contact: stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

Efficacy for Letrozole / Dasatinib vs Letrozole –

Clinical Benefit Rate & Progression-Free Survival:

24

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

Paul D et al. SABCS 2013 Abstract S3-07

L+D 57 39 29 21 12 8 4

L 63 39 20 16 8 5 3

HR = 0.69 (exploratory)

Pts at risk

0 6 12 18 24 30 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Pro

gres

sion

-fre

e P

roba

bilit

y

L+D (n=57), median PFS=20.1 mosL (n=63), median PFS=9.9 mos

Pts at risk

Clinical Benefit Rate (CR+PR+SD>6mo) L+D 71% (95% CI 58%-83%) L 66% (95% CI 52%-77%)

Drug Pharma Source Target(s)

BYL719 Novartis PI3Kα

GDC-0032 Genentech PI3Kα

MLN-1117 Millenium PI3Kα

CAL-101 Calistoga PI3Kd

XL-147 Exelixis/Sanofi Pan-PI3K

BKM120 Novartis Pan-PI3K

GDC-0941 Genentech Pan-PI3K

PKI-587 Pfizer Pan-PI3K

XL-765 Exelixis/Sanofi PI3K/mTOR

BEZ235 Novartis PI3K/mTOR

GDC-0980 Genentech PI3K/mTOR

PF-4691502 Pfizer PI3K/mTOR

MLN-128 Millenium TORC1/2

OSI-027 OSI Pharma TORC1/2

AZD2014 AstraZeneca TORC1/2

AZD5363 AstraZeneca AKT (catalytic)

MK-2206 Merck AKT (allosteric)

GDC-0068 Genentech AKT (catalytic)

PI3K/mTOR inhibitors in clinical development

26

Drug Company Indication

Entinostat ER+ MBC

Ofatumumab / CLL

Ibrutinib / CLL, MCL, Waldenstrom’s macroglobulinemia

Obinutuzumab CLL

Palbociclib ER+ MBC

Volasertib AML

LDK378 ALK+ NSCLC

Alectinib ALK+ NSCLC

Lambrolizumab Melanoma

Daratumumab / MM

2013 - FDA designates Oncology “Breakthrough” Drugs

According to the FDA a breakthrough therapy is a drug that is:

- Intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition

and

- That may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,

such as substantial treatment effects observed early in clinical development, as indicated by preliminary clinical evidence.

27

Exemestane + Placebo (PLA)

5 mg po weekly

N ~ 57

Exemestane + Entinostat (ENT)

5 mg po weekly

N ~ 57

R

A

N

D

O

M

I

Z

E

Post-menopausal

women with metastatic or

locally advanced ER+

breast cancer

progressing

on a non-steroidal AI

(anastrozole or letrozole)

Hypothesis: Entinostat re-sensitizes tumors to aromatase inhibitors (AI)

Randomized, double-blind, placebo-controlled

Endpoints include: 1⁰ PFS, 2⁰ ORR and CBR; Exploratory Endpoint - OS

Yardley D, et al. J Clin. Oncol. 2013 31; (epub May 6th)

ENCORE 301 - Phase II RCT of Exemestane +/-

Entinostat in ER+ MBC progressing after NSAI

EE: median PFS 4.3 months

EP: median PFS 2.3 months

Hazard ratio 0.73 (95% CI: 0.50, 1.07) P=0.055 (1-sided)

PFS - ITT population

EE: median OS 28.1 months

EP: median OS 19.8 months

Hazard Ratio 0.59 (95% CI: 0.36, 0.97) P=0.04 (2-sided) ; P=0.02 (1-sided)

OS - ITTpopulation

Yardley D, et al. J Clin. Oncol. 2013 31; (epub May 6th)

ENCORE 301 - Phase II RCT of Exemestane +/-

Entinostat in ER+ MBC progressing after NSAI

Eligible:

Advanced breast cancer

ER/PR+, HER2-

Progression on prior

non-steroidal AI

Exemestane plus

Entinostat

Exemestane plus

Placebo

Blood sampling: baseline, 2 wks

Treatment until Progression/Intolerance: Exemestane 25mg daily po

AND Entinostat/Placebo 5mg po weekly.

R

A

N

D

O

M

I

Z

E

N=600

Stratification by 1) Setting in which AI resistance developed; 2) Prior everolimus therapy; 3) Visceral disease

E2112 STUDY SCHEMA

PIs

Roisin Connelly

Joseph Sparano

Kathy Miller

Targeting CDKs in ER+ Breast Cancer

• Cyclin dependent kinases (CDK), a group of serine/threonine kinases, play a key role in regulating cell cycle progression by interacting with specific regulatory subunits (cyclin proteins) 1

• PD 0332991 (palbociclib) is an oral, highly selective inhibitor of CDK4/6 kinase

– prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase

– Synergistic activity also observed in vitro when combined with tamoxifen 2

1. Musgrove EA, et al. Nat Rev Can. 2011;11(8):558-572; 2. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77;

31

Rb as Master-Regulator of the R-point

31

palbociclib

32

Palbociclib: an Oral Selective

CDK 4/6 Kinase Inhibitor

• Inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression from G1 to S phase

• In vitro activity in retinoblastoma-positive tumor cell lines and primary

tumors

• Low nanomolar concentrations block Rb phosphorylation, inducing G1

arrest in sensitive cell lines

• Specific cell cycle arrest in G1 phase

Fry DW, et al. Mol Cancer Ther 2004;3:1427-38

Menu E, et al. Cancer Res 2008;68:5519-23

Sutherland RL, Musgrove EA. Breast Cancer Res 2009;11:112 Palbociclib (PD-0332991)

N

N

N

HN

N+

H2

O

O N

N

CDK (partner) IC50 (mM)

CDK4 (cyclin D1) 0.011

CDK4 (cyclin D3) 0.009

CDK6 (cyclin D2) 0.015

CDK2 (cyclin A) >10

CDK1 (cyclin B) >10

CDK5 (p25) >10

33

Abstract CT101

Final Results of a Randomized Phase 2 Study of

Palbociclib (PD 0332991) a Cyclin-Dependent Kinase

(CDK) 4/6 Inhibitor, in Combination with Letrozole vs

Letrozole Alone for First-Line Treatment of

ER+, HER2– Advanced Breast Cancer

(PALOMA-1/TRIO-18)

RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8 T Pinter,9 M Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voytko,13 X Huang,14

ST Kim,14 S Randolph,14 DJ Slamon1

1University of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin,

Ireland; 3Orszagos Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; 5Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-and-

Prophylactic Institution, Donetsk, Ukraine; 7Technical University of Munich, Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital

Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology Center, Ukraine;

14Pfizer Oncology, San Diego, CA, USA

Presented at AACR 2014; April 6, 2014; San Diego, CA USA

34

Phase 2 Study Design

ER+, HER2– Locally Recurrent or Metastatic Breast Cancer

N=66

1:1

Part 1

• Post-

menopausal

• ER+, HER2–

BC status

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Part 2

N=99

1:1

• Post-

menopausal

• ER+, HER2–

BC with

CCND1

amplification

and/or loss

of p16

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Stratification Factors

• Disease Site (Visceral vs Bone only vs Other)

• Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

aSchedule 3/1

Key Eligibility Criteria

• Measurable disease (RECIST 1.0) or bone-only disease

• ECOG PS of 0 or 1

• Adequate blood counts and organ function

• No prior/current brain metastases

35

Study Endpoints and Analyses

• Primary Endpoint

– Progression-free survival (PFS) by investigator assessment

– Designed to detect 50% improvement in median PFS from 9 to 13.5 months (80% power, 1-sided =10%)

• IMPAKT 2012 – Interim Analysis 1 (Part 1)

– Significant improvement in PFS (HR=0.35; P=0.006)1

– Exploratory biomarkers for CCND1 gains or p16 loss did not add to ER+ alone as a selection marker

• SABCS 2012 – Interim Analysis 2 (combined Part 1 + Part 2)

– 61 PFS events, data cutoff July 2012

– Continued significant improvement in PFS (HR=0.37; P<0.001)2

• AACR 2014 - Final Analysis (combined Part 1 + Part 2)

– 100 PFS events, data cutoff Nov 2013

– Confirmed signifciant improvement in PFS (HR=0.49; p<0.0004) 3

1. Finn RS, et al. IMPAKT 2012, Abstract 100O

2. Finn RS, et al SABCS 2012, Abstract S1-6

3. Finn RS, et al AACR 2014, Abstract CT101

36

PALOMA-1: Baseline Characteristics (ITT)

PAL + LET

(N=84)

LET

(N=81)

Median Age, years (range) 63 (41–89) 64 (38–84)

ECOG PS, n (%)

0

1

46 (55)

38 (45)

45 (56)

36 (44)

Disease Stage, n (%)

Stage IIIB

Stage IV

2 (2)

82 (98)

1 (1)

80 (99)

Disease Site, n (%)

Visceral

Bone only

Other (Non-Visceral)

37 (44)

17 (20)

30 (36)

43 (53)

12 (15)

26 (32)

Disease-Free Interval, n (%)

>12 mos from adjuvant to recurrence

≤12 mos from adjuvant to recurrence or de novo advanced disease

[de novo advanced disease]

25 (30)

59 (70)

[44 (52)

30 (37)

51 (63)

37 (46)]

Prior Systemic Treatment, n (%)

None

Chemotherapy

Hormonal

Tamoxifen

Anastrozole

Letrozole

Exemestane

44 (52)

34 (40)

27 (32)

24 (29)

8 (10)

2 (2)

4 (5)

37 (46)

37 (46)

28 (35)

24 (30)

11 (14)

1 (1)

2 (2)

37

0 4 8 12 16 20 24 28 32 36 40Time (Month)

0

10

20

30

40

50

60

70

80

90

100P

rog

res

sio

n F

ree

Su

rviv

al

Pro

ba

bil

ity (

%)

84 67 60 47 36 28 21 13 8 5 1PAL+LET81 48 36 28 19 14 6 3 3 1LET

Number of patients at risk

PALOMA-1: Progression-Free Survival (ITT)

PAL + LET

(N=84)

LET

(N=81)

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

Median PFS, months

(95% CI)

20.2

(13.8, 27.5)

10.2

(5.7, 12.6)

Hazard Ratio

(95% CI)

0.488

(0.319, 0.748)

p-value 0.0004

Finn RS, et al AACR 2014, Abstract CT101

38

PALOMA-1: PFS Subgroup Analysis

0 . 062 0 . 125 0 . 25 0 . 50 1 . 0 2 . 0 4 . 0

Hazard Ratio ( log scale )

Time from End of Adju . Trt to Dis . Recur . Ms

Time from End of Adju . Trt to Dis . Recur . > 12 Ms

Time from End of Adju . Trt to Dis . Recur . Ms or De Novo

Prior Systemic Therapy : No

Prior Systemic Therapy : Yes

Previous Antihormonal Therapy : No

Previous Antihormonal Therapy : Yes

Previous Chemotherapy : No

Previous Chemotherapy : Yes

Disease Site : Other

Disease Site : Bone Only

Disease Site : Visceral

Baseline ECOG : 1

Baseline ECOG : 0

Age ≥ 65

Age < 65

Part 2

Part 1

All patients

15

25

59

44

40

57

27

71

13

30

17

37

38

46

37

47

50

34

84

14

30

51

37

44

53

28

65

16

26

12

43

36

45

39

42

49

32

81

Number of Patients

PAL + LET LET Population In favor of PAL + LET In favor of LET

≤12

≤12

Finn RS, et al AACR 2014, Abstract CT101

39

Most Common Treatment-Related AEs ≥10% (AT)

● Neutropenia was self-limited and not associated with infectious

complications

PAL + LET

(N=83)

LET

(N=77)

G1/2 (%) G3 (%) G4 (%) G1/2 (%) G3 (%) G4 (%)

Neutropenia 19 48 6 1 1 0

Leukopenia 23 18 0 0 0 0

Anemia 23 4 1 0 0 0

Fatigue 22 2 0 14 0 0

Alopecia 22 0 0 3 0 0

Hot flush 18 0 0 10 0 0

Arthralgia 17 0 0 9 1 0

Thrombocytopenia 14 2 0 0 0 0

Nausea 14 1 0 1 0 0

Decreased appetite 8 1 0 0 0 0

Stomatitis 10 0 0 0 0 0

AT=As Treated Population

Finn RS, et al AACR 2014, Abstract CT101

PALOMA-1: Conclusions

• Palbociclib, a first-in-class CDK 4/6 inhibitor, in combination with letrozole significantly improves median PFS in patients with advanced ER+/HER2– breast cancer in the first-line setting

─ PFS: 20.2 vs 10.2 months; HR=0.488; P=0.0004

• Beneficial effect is consistently observed in secondary measures of efficacy (ORR and CBR), and in all clinical subgroups

• The safety profile of the combination is acceptable and manageable with uncomplicated neutropenia as the most frequently reported AE

Confirmatory Studies in BC

• A randomized phase 3 study (PALOMA-2, NCT01740427) of letrozole +/- palbociclib to confirm these results in a similar 1st line population has completed recruitment

• A randomised phase 3 study (PALOMA-3, NCT01942135) of fulvestant +/- palbociclib in a 2nd line population has also just completed recruitment

• A randomised phase 3 study (PENELOPE-B, NCT01864746) of letrozole +/- palbociclib in ER+ high risk EBC post neo-adjuvant chemotherapy is underway (GBG & BIG)

in partnership with

In collaboration with

The PALLET Trial:

Phase 2 Randomised Study of Palbociclib with Letrozole as Neo-adjuvant Treatment

for ER+ Postmenopausal Early Breast Cancer

PALLET Launch Meeting

Friday 5th September 2014

43

PALLET Trial Design: Phase 2 Study of Palbociclib with Letrozole as Neoadjuvant Treatment for ER+ BC

• Primary Endpoints: Decrease in Ki67 at wk 14; Clinical response at wk 14

• Secondary Endpoints: Ki67 at 2 weeks & changes wks 2-14; pCR at wk 14; PEPI (pre-op endocrine prognostic index) score at wk 14; safety & tolerability

• N=301 Open label, Multicenter (UK & USA), Active controlled, Ph2

Patients

Characteristics

• Postmenopausal women with localized ER+HER2- invasive early breast cancer suitable for neoadjuvant therapy with letrozole

Letrozole (given for 14 weeks)

Su

rge

ry

Letrozole (given 2 wks)

Palbociclib (given 2 wks)

Letrozole + Palbociclib

(given 2 wks)

Letrozole + Palbociclib (given 12 weeks)

Phase 2 Study (ICR-CTSU & NSABP):

• Exploratory Endpoints: biomarker profiles that predict benefit; molecular effects of therapy

Study name Endocrine

therapy

Combination

agent

Clinical trial number Line of

therapy

Estimated

primary

completion date†

PALOMA-2 Letrozole Palbociclib NCT01740427 1st line October 2015

MONALEESA-2 Letrozole LEE011 NCT01958021 1st line January 2017

ECOG-E2112 Exemestane Entinostat NCT02115282 2nd line February 2017

PALOMA-3 Fulvestrant Palbociclib NCT01942135 1st / 2nd line July 2015

BELLE-2 Fulvestrant BKM120

(buparlisib) NCT01610284 2nd line September 2017

BELLE-3 Fulvestrant BKM120

(buparlisib) NCT01633060 2nd line October 2016

SWOG S1222 Fulvestrant Everolimus NCT02137837 1st line September 2017

MONARCH 2 Fulvestrant LY2835219

(abemaciclib) NCT02107703 1st line February 2017

MONARCH 3

Letrozole /

anastrozole

combination

LY2835219

(abemaciclib) Not available 1st line Not available

†final data collection date for primary outcome measure

Phase III studies combining novel targeted

agents with endocrine therapy

44

Optimising Treatment for ER+ Metastatic

Breast Cancer: Implications for Practice

• Improved Treatment Options for MBC:

– AIs remain Standard of Care in first-line Rx:

• Possible role for HD fulvestrant + AI in endocrine naive ER+ MBC

• HD fulvestrant as first-line Rx?

– Understanding Resistance in ER+ve MBC

• mTOR inhibition has set a new standard for second-line Rx

• CDK 4/6 inhibition looks a very promising new approach, possibly to

improve first-line treatment and delay secondary resistance