Malattia ormonodipendente

Carcinoma mammario ormonodipendente

Novità

Lucia Del Mastro

SS Sviluppo Terapie Innovative Pisa 14 novembre 2015

IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro

COI Del Mastro

• Honoraria from:

– Pfeizer – Novartis – Ipsen – Takeda

– Astrazeneca

Agenda

• Adjuvant treatment of premenopausal women

• ER+ metastatic disease

• Emerging role of androgen receptor pathway

Benefits of 5 years of Tamoxifen:

entry age < 45 years and ER+ disease only

EBCTCG, Lancet 2011

SOFT

• Primary endpoint: DFS

• Secondary endpoints: BCFI, DRFI, OS

Francis P, et al. SABCS 2014. Abstract S3-08. Francis PA, et al. N Engl J Med. 2014;

Premenopausal pts ER+/PgR+ BC

(N = 3047)

5 Yrs

*Triptorelin, oophorectomy, or irradiation

OFS* + Tamoxifen (n = 1015)

OFS* + Exemestane 25 mg/day (n = 1014)

Tamoxifen 20 mg/day (n = 1018)

Stratified by prior chemotherapy

(yes vs no) and nodal status (+ vs -)

SOFT

“No chemotherapy” pts had low risk features

• 90% ≥ 40 yrs,

• 91% node negative,

• 85% tumor ≤ 2 cm,

• 41% grade 1

Francis P, et al. SABCS 2014. Abstract S3-08. Francis PA, et al. N Engl J Med. 2014.

Premenopausal No Chemotherapy

Cohort selected for low risk clinicopathologic features

Francis P, et al. SABCS 2014. Abstract S3-08. Francis PA, et al. N Engl J Med. 2014.

Premenopausal after Prior Chemotherapy

T+OFS v T: Absolute improvement in 5-yr BCFI: 4.5%

E+OFS v T: Absolute improvement in 5-yr BCFI: 7.7%

E+OFS v T: Absolute improvement in 5-yr DRFI: 4.2%

Francis P, et al. SABCS 2014. Abstract S3-08. Francis PA, et al. N Engl J Med. 2014.

• 350 patients (11.5%) < age 35

• 94% received chemotherapy in this age group

All women < 35 years of age

Francis P, et al. SABCS 2014. Abstract S3-08. Francis PA, et al. N Engl J Med. 2014.

2015: Strategy for Pre-menopausal ER+

Breast Cancer Management

Pre-menopausal HR+ early stage breast

cancer

Low risk Smaller tumors

Node negative Grade 1

Older

High risk Larger tumors

Node positive Grade 3 Younger

No chemotherapy Chemotherapy

Intermediate risk

Low grade but larger tumor Low grade but node positive

Tam x at least 5 yrs Duration?

Chemo + OS + T or AI

(particularly in < 35 y/o) (OS + AI > OS + T) Chemo + OS/T or AI?

or

OS + endocrine treatment?

Quesiti GRADE 2015

QUESITO 1: Nelle donne in premenopausa con carcinoma mammario operato, recettori ormonali positivi, non sottoposte a chemioterapia adiuvante, è

raccomandabile l’aggiunta dell’LHRH analogo al tamoxifene?

QUALITA’ DELLE EVIDENZE

GRADE

RACCOMANDAZIONE FORZA DELLA RACCOMDAZIONE

CLINICA

BASSA

Nelle donne in premenopausa con ca

mammario operato, recettori ormonali positivi, non sottoposte a chemioterapia adiuvante, l’aggiunta dell’LHRH analogo al tamoxifene

può essere presa in considerazione

POSITIVA DEBOLE

1. Studio ZIPP; Baum M et al, EJC 2006;

Hackshaw A et al, JNCI 2009;

1. Studio SOFT; Francis PA et al, NEJM 2015

2. Studio INT-0142; Tevaarwerk AJ et al , JCO 2014

Bilancio beneficio/danno

Incerto

Quesiti GRADE 2015

QUESITO 2: Nelle donne in premenopausa con carcinoma mammario operato, recettori ormonali positivi, sottoposte a chemioterapia adiuvante, è

raccomandabile l’aggiunta dell’LHRH analogo al tamoxifene?

QUALITA’ DELLE EVIDENZE

GRADE

RACCOMANDAZIONE FORZA DELLA RACCOMDAZIONE

CLINICA

BASSA

Nelle donne in premenopausa con carcinoma mammario operato, recettori ormonali positivi,

sottoposte a chemioterapia adiuvante, l’aggiunta dell’LHRH analogo al tamoxifene

dovrebbe essere presa in considerazione in prima intenzione

POSITIVA FORTE

1. Studio ZIPP; Baum M et al, EJC 2006;

Hackshaw A et al, JNCI 2009;

2. Studio SOFT; Francis PA et al, NEJM 2015

Bilancio beneficio/danno

Favorevole

Quesiti GRADE 2015

QUESITO 3: Nelle donne in premenopausa con carcinoma mammario operato, recettori ormonali positivi, il trattamento con LHRHa + inibitore dell’aromatasi è

raccomandabile rispetto a LHRHa + tamoxifene?

QUALITA’ DELLE EVIDENZE

GRADE

RACCOMANDAZIONE FORZA DELLA RACCOMDAZIONE

CLINICA

BASSA

Nelle donne in premenopausa con carcinoma mammario operato, recettori ormonali positivi,

il trattamento con LHRHa + inibitore dell’aromatasi può essere preso in

considerazione

POSITIVA DEBOLE

Bilancio beneficio/danno Incerto

Studi TEXT e SOFT; Pagani O et al. NEJM 2014 Studio ABCSG-B12; Gnant MF et al., JCO 2007;

Gnant M et al, Lancet Oncol 2008;

Gnant M et al, Ann Oncol 2015.

Figure 2015

Agenda

• Adjuvant treatment of premenopausal women

• Metastatic disease

• Emerging role of androgen receptor pathway

Finn RS et al Breast Can Res in press 2015

Landscape: CDK Inhibitors

Agent Targets Phase of Development

Alvocidib (flavopiridol) CDK 1/2/4/6/7/9 Phase I/II Seliciclib (R-

roscovitine) CDK 2/7/9 Phase I

Dinaciclib (SCH

727965) CDK 1/2/5/9 Phase III

BAY 1000394 CDK 1/2/4/9 Phase I

Palbociclib (PD

0332991) CDK 4/6 Phase III- FDA

Approved Abemaciclib(LY283521

9) CDK 4/6 Phase III

Ribaciclib (LEE 011) CDK 4/6 Phase III

prostate cancer^79–81, pointing to a potential role as a tumour suppressor rather than as an oncogene.

Mutations have also been implicated in aberrant cyclin D1 expression (TABLE 1), although they have rarely been investigated, and thus the importance of their role is not yet clear. Mutations in the 3′ untranslated region that result in the stabilization of the CCND1 mRNA have been repor ted in M CL⁸², and muta- tions and deletions clustering around T286 have been reported in oesophageal and endometrial cancers^83,84. Phosphorylation at this site governs the turnover and nuclear export of the cyclin D1 protein, and mutations in F-box 4 (FBXO4), an SCF E3 ubiquitin ligase that targets T286-phosphor ylated cyclin D1 protein for degradation, have also been detected in endometrial cancers⁸⁵: up to 20% of endometrial cancers may dis- play nuclear overexpression of stable cyclin D1 through mutations in CCND1 or FBXO4. An initial study has also indicated that cyclin D1 stabilization might be important in breast cancer⁸⁶.

Many polymorphisms have been identified within the CCND1 locus, but the G/A870 polymorphism is the only one that has been investigated in any detail⁶⁹. The A870 allele is present in a large proportion of the population (AA, 25.0%; AG, 50.0% in Caucasians) and is associated with a significant, but small, increase in cancer risk⁸⁷. It favours the production of cyclin D1b. In some cancers, such as lung cancer, cyclin D1b is coordinately overex- pressed with full-length cyclin D1, although the absolute expression level of cyclin D1b is much lower⁸⁸. In other cancers, cyclin D1b is independently overexpressed^89–91. The G/A870 polymorphism is not the only determinant of increased cyclin D1b expression, and although factors that affect cyclin D1 splicing have been identified⁹², the mechanisms for the cancer-specific overexpression of cyclin D1b are not known (reviewed in REF. 69).

Overexpression of cyclin D1 is much more common than can be accounted for by copy number or muta- tional events that affect CCND1 (TABLE  1 ). Another route to cyclin D1 overexpression is as a consequence Table 1 | Cyclin D1 deregulat ion in cancer

Mechanism of deregulation Tumour type Frequency Refs

Amplification and overexpression

CCND1 amplification Head and neck squamous cell carcinoma 26–39% 112,178

Cyclin D1 overexpression Head and neck squamous cell carcinoma 20–68% 112,178

CCND1 amplification Non-small-cell lung cancer 5–30% 65,74

Cyclin D1 overexpression Non-small-cell lung cancer 18–76% 65,74,88

CCND1 amplification Endometrial cancer 26% 179,180

Cyclin D1 overexpression Endometrial cancer 40–56% 179,180

CCND1 amplification Melanoma 0–25% 181

Cyclin D1 overexpression Melanoma 30–65% 181

CCND1 amplification Pancreatic cancer 25% 182

Cyclin D1 overexpression Pancreatic cancer 42–82% 182

CCND1 amplification Breast cancer 15–20% 74,102

Cyclin D1 overexpression Breast cancer 50–70% 74,102

CCND1 amplification Colorectal cancer 2.5% 183

Cyclin D1 overexpression Colorectal cancer 55% 184

Chromosomal rearrangement and overexpression

CCND1: IGH translocation t(11;14)(q13;q32) Mantle cell lymphoma >90% 76

Cyclin D1 overexpression Mantle cell lymphoma >90% 76

CCND1: IGH translocation t(11;14)(q13;q32) Multiple myeloma 16% 185

Cyclin D1 overexpression Multiple myeloma 30–50% 185

Splice variants and transcript aberrations

3′ UTR rearrangements, microdeletions or point mutations Mantle cell lymphoma 4–10% 82,104

Cyclin D1b overexpression Breast cancer 22%* 89,91

Cyclin D1b overexpression Prostate cancer 27%* 90

Mutations affecting nuclear export and proteolysis

Oesophageal cancer 4% 83

Endometrial cancer 4% 84

FBXO4 S8R, S12L, P13S, L23Q, G30N and P76T Oesophageal cancer 14% 85

FBXO4, F-box 4; IGH, immunoglobulin heavy chain locus; UTR, untranslated region.*Cyclin D1b overexpression without overexpression of full-length cyclin D1.

REV I EW S

NATURE REVI EWS | CANCER VOLUM E 11 | AU GU ST 2011 | 563

© 2011 Macmillan Publishers Limited. All rights reserved

Musgrove EA et al. Nat Rev Cancer 2011; 11:558-72

27

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

H

O

N O N

CDK (partner) IC

(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

LINEE GUIDA AIOM 2015

Finn RS et al. Lancet Oncol 2015; 16:25-35

PALOMA-1 / TRIO-18 Study (N= 165 pts)

- Post-menopausal MBC;

- Hormone-receptor positive;

- HER2 negative;

- No prior therapy for MBC;

- No AI in the prior 12 months.

Letrozole + palbociclib (125 mg/die 3 w on 1 w

off)

Letrozole

84 pts

81 pts

PALOMA-1/TRIO-18 Study Design (NCT00721409)

• Randomized phase II open-label trial involving 50 centers in 12 countries

• Key eligibility criteria: inoperable ER+/HER2– locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG

performance status ≤1, adequate bone marrow and renal function Palbociclib

125 mg/d

+ Letrozole

2.5 mg/d

Letrozole 2.5 mg/d ER+/HER2−

advanced breast cancer

*Randomization stratified by disease site and disease-free interval.

† Palbociclib schedule 3/1 (28-day cycles).

Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

1:1

R A N D O M I Z A T I O N

*

Palbociclib 125 mg/d

+

Letrozole 2.5 mg/d

Letrozole 2.5 mg/d ER+/HER2−

advanced breast cancer with

CCND1 amplification and/or loss of

p16

1:1

n=66 n=99

R A N D O M I Z A T I O N

*

Cohort 1 Cohort 2

Paloma 1

Finn RS et al. Lancet Oncol 2015; 16:25-35 20.2 months

10.2 months

Progression-free survival

Best overall response

PALOMA-1/TRIO-18: PFS (Cohorts)

Cohort 1 Cohort 2

0 10 20 30 40 50 60 70 80 90 100

P rog re ssi on -fr ee surviva l, %

Number at risk Palbociclib plus letrozole Letrozole

5 1 8 3 13

4 11

4 18

8 15

5 34

32

8 3 26

15 23 10

1 HR 0.299 (95% CI 0.156–0.572; one-sided P = .0001)

Time, months Time, months

0 10 20 30 40 50 60 70 80 90 100

HR 0.508 (95% CI 0.303–0.853; one-sided P = .0046)

15 10

10 2 29

20 21 14 50

49

5 41

33 37 26

Palbociclib plus letrozole Letrozole

0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40

Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

February 3 ^rd 2015

• U.S. Food and Drug Administration (FDA) granted accelerated approval of palbociclib (IBRANCE ^® )

• Indicated in combination with letrozole, for the treatment of postmenopausal women with ER+/ HER2- advanced breast cancer as initial endocrine-based therapy

• This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and

description of clinical benefit in a confirmatory trial

(PALOMA-2)

PALOMA-2 (1008)/ TRIO 22 – Study Design

Detect PFS improvement from 9 mos (SOC) to 14 mos (HR=0.64) with 90%

power, 1-sided =0.025; 1-IA Efficacy/Futility

• P ^OST - ^{MENOPAUSAL WOMEN}

• ER(+) / HER2 (-) ^BREAST

CANCER

• N ^{O PRIOR SYSTEMIC}

ANTICANCER TREATMENT FOR ADVANCED DISEASE .

Letrozole 2.5mg QD +

Placebo 3/1 weeks Letrozole 2.5mg QD

+

PD 0332991 125 QD 3/1 weeks

2:1 R ANDOMI ZA TI ON

• N=450. Double-blind, Multicenter, Placebo-Controlled

• Primary Endpoint: PFS (239 events needed) by local assessment

• Secondary Endpoints: OS, OR, DR, DC, safety, PRO, Biomarkers, Trough PK, QTc

• Stratification Factors: DFI, Previous therapy, Disease Site

Note: 9 Month benchmark based on: Mouridsen H. et al.; J Clin Oncol 19:2596-2606, 2001

Letrozole 2.5mg daily +

Placebo

21 Days on / 7 days off Letrozole 2.5mg daily

+

Palbociclib125mg daily 21

Days on / 7 days off

LINEE GUIDA AIOM 2015

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19

PALOMA3 Study (N= 521 pts)

- HR+ and HER2-

- Pre- and post-menopausal status - Relapsed or progressed during

prior ET*

- 0-1 prior line of CT

- No prior exposure to everolimus - No symptomatic visceral spread

Fulvestrant + Palbociclib

(125 mg/die 3 w on 1 w off)

Fulvestrant + Placebo

347 pts

174 pts

Primary end-point: investigator-assessed progression-free survival

Secondary end-points: overall survival, survival probability at 1, 2 and 3 years, objective response, duration of response, rate of clinical benefit,

patient-reported outcomes, pharmacokinetics, safety

* Post-menopausal patients: PD on AI for metastatic disease or ≤ 12 months from adjuvant therapy Pre-menopausal patients: PD on ET for metastatic disease or ≤ 12 months from adjuvant tamoxifen

2:1 + goserelin in pre-menopausal patients

Stratified for:

-visceral metastatsis

-menopausal status

-sensitivity to prior ET

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19

Progression-Free Survival (assessed by investigator)

HR = 0.42 (95% CI 0.32-0.56); P < 0.001

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19

Progression-Free Survival: subgroup analyses

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19

Adverse events

The PALOMA3 Study

Turner NC et al. N Engl J Med 2015; 373:209-19. Baselga J et al. N Engl J Med 2012; 366:520-9. Piccart M et al. Ann Oncol 2014; 25:2357-62

The PALOMA3 study The BOLERO2 study

No. patients 521 724

Premenopausal patiens (%) 20.7% 0.0%

Patients with visceral disease 59.7% 56.0%

≥ 3 lines of therapy (%) 10.9% 54%

Progression-free survival, months (ET + targeted agent vs ET alone)

9.2 vs 3.8 HR = 0.42, P < .001

6.9 vs 2.8

HR = 0.43, P < .001 Overall survival, months

(ET + targeted agent vs ET alone)

- 31.0 vs 26.6

HR = 0.89, P = .14

GEICAM/2013-02: Phase III study of Palbociclib (PD-0332991) in combination with Exemestane versus chemotherapy (capecitabine) in Hormonal Receptor (HR) positive/HER2 negative Metastatic Breast Cancer (MBC) patients with Resistance to

non-steroidal Aromatase inhibitors (PEARL)

• Phase 3 study Postmenopausal women with ER

HER2- advanced breast cancer

• Resistant to NSAIs

• Measurable disease

• No more than 1 prior line of therapy for M1

Primary endpoint PFS

Secondary endpoints ORR, CBR, DoCR, OS,

TTD, QoL, safety, PK, biomarkers Capecitabine 1250

mg/m2/12hr x 14 days q3w

Exemestane 25 mg/d + palbociclib 125mg/d x 21 days

q4w

PEARL trial, ClinTrials.gov NCT02028507, EudraCT Number: 2013-003170-27.

N=348

40 sites in six countries (Austria, Bosnia, Hungary, Israel, Romania and Spain); recruitment period of approximately 24 months.

80% power to detect a difference between the control arm (median PFS of 6 months) and the experimental arm (median PFS of 8.75 months, HR of 0.686, with a 5% two sided significance level.

PI: M.Martin

PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)-

Negative Early Breast Cancer (PALLAS)

N=4600

Diagnosis

• HR+ and HER2-

• Stage II or III

R A N D OM IZ A TION

Sponsor: Alliance for Clinical Trials in Oncology Foundation, ABCSG

Phase 3, PALLAS

Arm B**

Endocrine Treatment (5+ years)

Arm A*

Palbociclib (2 Years)

+ Endocrine Treatment

(5+ years)

*ARM A: palbociclib at a dose of 125 mg once daily, Day 1-21 in a 28-day cycle

**ARM B: standard adjuvant endocrine therapy (AI; tamoxifen)

Surgery 1:1

Survival/Disease Follow-up

Neo/Adjuvant Systemic Therapy

FFPE Tissue Sample received at central

biorepository

QOL & Adherence Monitoring

Stratification Factors:

•Pathologic stage (IIA vs IIB/III) or clinical stage if pre-operative therapy was given with the higher stage determining eligibility

•Neo/adjuvant chemotherapy (yes vs. no)

•Age (< 50 vs ≥ 50 years)

•Geographic region (North America vs. Europe vs. Asia)

Single-agent Palbociclib for Patients with Refractory Tumors

Back

49

A5481006 Breast Cancer Cohort: Study Endpoints

Primary Endpoints Disease

response

• CR, PR, SD, or PD, defined by RECIST version 1.0

‒ Clinical benefit rate defined as sum of CR + PR + SD

≥6 months

• Evaluated after every 2 cycles (reduced to every 3 cycles for patients treated >18 months)

Tolerability • Adverse events based on NCI CTCAE version 3.0

• Assessed in cycle 1 on days 1, 8, 15, and 21 and then on day 1 of subsequent cycles

Secondary Endpoints Progression-

free survival

• Time from initial palbociclib treatment to progression or death (whichever occurred first)

Biomarker assessments

• RB localization, Ki-67 index, and p16 loss, assessed by immunohistochemistry (primary tumor or metastatic lesion)

• CCND1 amplification assessed by fluorescence in situ

hybridization DeMichele A, et al. Clin Cancer Res 2015;21:995-1001

50

A5481006 Breast Cancer Cohort: Baseline Characteristics

Characteristic Total (N=37)

Median age (range), years 59 (39–88)

Hormone receptor status, n (%)

Any HR 33 (89)

ER+, PR– 7 (19)

PR+, ER– 4 (11)

Both ER+ and PR+ (HR+) 22 (60)

Receptor group, n (%)

HR+/HER2– 31 (84)

HR+/HER2+ 2 (5)

HR–/HER2- 4 (11)

Prior hormonal therapy

Adjuvant, n (%) 22 (59)

Advanced, n (%) 31 (84)

Median no. of advanced lines (range) 2 (0–5)

0 or 1 line of therapy, n (%) 13 (35)

≥2 lines of therapy, n (%) 24 (65)

Prior chemotherapy

Adjuvant, n (%) 26 (70)

Advanced, n (%) 34 (92)

Median no. of advanced lines (range) 2 (0-13)

0 or 1 line of therapy, n (%) 9 (24)

≥2 lines of therapy, n (%) 28 (76)

DeMichele A, et al. Clin Cancer Res 2015;21:995-1001

51

Total (N=37) HR+ (n=33) Disease response, n (%)

CR 0 0

PR 2 (5) 2 (6)

SD <6 months 14 (38) 13 (39)

SD ≥6 months 5 (14) 5 (16)

PD 16 (43) 13 (39)

CBR (PR + SD ≥6 months), n (%) 7 (19) 7 (21)

CBR by prior metastatic hormonal therapy, n/n (%)

Patients with 0 or 1 prior lines N/A 0/9 (0)

Patients with ≥2 prior lines N/A 7/24 (29)

CBR by prior metastatic chemotherapy, n/n (%)

Patients with 0 or 1 prior lines 4/9 (44) 4/9 (44) Patients with ≥2 prior lines 3/28 (11) 3/24 (13) Median duration of response (range),

months

4 (2–5) 5 (2–6)*

A5481006 Breast Cancer Cohort: Response Rates

P=0.081

P values from Fisher’s exact test

*High end of range reported as 5 for total cohort but as 6 for HR+ subgroup

P=0.045 P=0.068

DeMichele A, et al. Clin Cancer Res 2015;21:995-1001

52

A5481006 Breast Cancer Cohort: Progression-Free Survival

DeMichele A, et al. Clin Cancer Res 2015;21:995-1001

Median PFS:

3.7 mo. (95% CI: 1.9–5.1)

Median PFS:

4.5 (HR+) vs 1.5 (HR–) mo.

Median PFS:

5 (≥2 lines) vs 2 (<2 lines) mo.

Median PFS:

5 (≥2 lines) vs 5 (<2 lines) mo.

Overall HR+ vs HR–

Prior hormone therapy Prior chemotherapy

Log-rank P=0.030

Log-rank P=0.114 Log-rank P=0.023

Progression-free survivalProgression-free survival

1.0

0.8

0.6

0.4

0.2

0.0

0 10 20 30 40 0 10 20 30 40

0 10 20 30 40 0 10 20 30 40

Time (months) Time (months)

HR- HR+

<2 advanced lines

≥2 advanced lines

<2 advanced lines

≥2 advanced lines

1.0 0.8 0.6 0.4

0.2 0.0

1.0 0.8 0.6 0.4

0.2 0.0 1.0

0.8

0.6

0.4

0.2

0.0

Targeting the PI3K-MTOR pathway

Rationale

The PI3K/AKT/mTOR Pathway in Breast Cancer:

Common Molecular Alterations

The PI3K/AKT/mTOR pathway is frequently activated in breast cancers due to: ^1,2

- Increased HER2-mediated signaling

- Mutational inactivation or loss of PTEN

- Activating mutation or amplification of PIK3CA - Inhibitors of the

PI3K/AKT/mTOR pathway are currently in clinical trials

1. Liu P, et al. Nat Rev Drug Discov 2009;8:627–644; 2. Baselga J. Oncologist 2011;16:Suppl 1:12–19;

3. Stemke-Hale K, et al. Cancer Res 2008;68:6084–6091.

Incidence of PI3K and PTEN mutations in 547 human breast cancer samples

23%

35%

8%

0%

3%

0% 0%

5%

10%

15%

20%

25%

30%

35%

40%

HER2+ tumors HR+ tumors Triple-negative tumors

Inc ide nce (% of s a mple s )

All PI3K mutations

PTEN mutations

Drug Source Target(s)

GDC-0032 Genentech PI3Kα

MLN-1117 Millenium PI3Kα

BYL719 Novartis PI3Kα

GS-1101 Gilead PI3Kd

XL-147/SA245408 Exelixis/Sanofi Pan-PI3K

BKM120 Novartis Pan-PI3K

GDC-0941 Genentech Pan-PI3K PF-05212384/PKI-587 Pfizer Pan-PI3K GDC-0941 Genentech Pan-PI3K XL-765/SAR245409 Exelixis/Sanofi PI3K/mTOR

BEZ235 Novartis PI3K/mTOR

GDC-0980 Genentech PI3K/mTOR MLN-128/MLN0128 Millenium TORC1/2

OSI-027 OSI Pharma TORC1/2

AZD2014 AstraZeneca TORC1/2

AZD5363 AstraZeneca AKT (catalytic)

MK2206 Merck AKT (allosteric)

GDC-0068 Genentech AKT (catalytic)

PI3K Pathway Inhibitors in Clinical Development in Breast Cancer

ClinicalTrials.gov. From: www.clinicaltrials.gov. Accessed August 2013.

AR expression in breast cancer

BC type AR expression

ER+ 70-90% (1,2)

TNBC 10-20% (3,4)

1. HU, Clin Cancr Res 2011 2. Park Ann Oncol 2011

3. Niemeier Mod Pathol 2010

4. Tung, ASCO 2015; A1005

ER -

ER+

AR agonists may

be of benefit AR antagonists may

be of benefit AR antagonists may

be of benefit

Lim et al

.

Slide 7

Presented By Myles Brown at 2015 ASCO Annual Meeting

Abiraterone acetate, exemestane or the combination in post- menopausal patients with ER+ metastatic breast cancer

• Phase II randomized study

• ER+ MBC sensitive to NSAI prior to disease progression

• <= 2 prior regimens for metastatic disease

• Primary end-poni: PFS

• 297 patients; 1:1:1 randomization

– Abiraterone acetate 1000 mg + prednisone 5 mg – AA plus exemestane

– Exemestane alone

O’Shaughnessy, Ann Oncol 2015 in press

Slide 7

Presented By Myles Brown at 2015 ASCO Annual Meeting

O’Shaughnessy, Ann Oncol 2015 in press

Abiraterone acetate, exemestane or the combination in post-menopausal

patients with ER+ metastatic breast cancer

ER -

AR antagonist may

be of benefit