Feb 2009

RAD001 – registrational program in Advanced HER2+ and ER+ Breast Cancer

Cristian Massacesi, M.D.

Sr Medical Director, CIL RAD001 BC

Feb 2009

mTOR Inhibition in HER2+ Breast Cancer

23

mTOR Is a Key Regulator of the PI3K/AKT Pathway Stimulated by HER2

AngiogenesisAngiogenesis

mTOR

AKT

AMPKTSC1 TSC2

PTENLKB1

Cell Growth &Cell Growth &ProliferationProliferation CellCell

MetabolismMetabolism

PI3K

RHEB

IGF-1R EGFR/HER2Nutrients mTOR is an intracellular serine/threonine kinase in the PI3K/Akt signaling pathway1

mTOR is a central regulator that senses changes in

• Growth factor signaling1,2

• Nutrients and energy1-3

mTOR activation promotes

• Cell growth and proliferation3

• Angiogenesis4

• Cancer cell metabolism through increased nutrient uptake and utilization3,5

1. Harris and Lawrence. Sci STKE. 2003;(212):re15. 2. Huang et al. Cancer Biol Ther. 2003;2:222-232. 3. Wullschleger et al. Cell. 2006;124:471-484. 4. Humar et al. FASEB J. 2002;16:771-780. 5. Edinger and Thompson. Mol Biol Cell. 2002;13:2276-2288.

Trastu

zum

ab

24

RAD001 Counters the Effects of Molecular Changes in Signaling Pathways Conferring Trastuzumab Resistance

AngiogenesisAngiogenesis

mTOR

AKT

AMPKTSC1 TSC2

PTENLKB1

Cell Growth &Cell Growth &ProliferationProliferation CellCell

MetabolismMetabolism

PI3K

RHEB

IGF-1R EGFR/HER2 Increased signaling throughIGF-1R

Constitutive PI3K/Akt activation

Elevated AKT or pAKT

Absent or low PTEN

Truncated HER2

Nutrients

Downstream inhibition withRAD001 counters these resistance mechanisms

RAD001

1. Widakowich et al. Anticancer Agents Med Chem. 2008,8:488-496.25

RAD001 Inhibits Growth and Proliferation of Breast Cancer Cells and Endothelial Cells

RAD001RAD001VEGF

VEGFR

RAD001RAD001Protein Synthesis

mTORmTOR

Hypoxic Stress Genes

HIF

Blood Vessel

Protein SynthesisProtein Synthesis

mTORmTOR

Hypoxic Stress Genes

HIF VHL

26

Feb 2009

RAD001 in Advanced HER2+ Breast Cancer

27

RAD001 Single Agent Phase II Study of Daily and Weekly Dosing in Advanced Breast Cancer

48 patients with ≤ 1 prior therapy for metastatic disease1 • 33 received RAD001 - 10 mg/day

- 1 CR, 3 PR, 15 SD (4 HER2+), 12% ORR

- Rash (67%), cough (56%), stomatitis, nausea, and diarrhea (44% each), pneumonitis (39%), neutropenia (61%)

• 16 received RAD001 70 mg weekly- 0 PR, 4 SD

- Rash (63%), cough (59%), diarrhea and nausea (53% each), stomatitis (38%), pneumonitis (41%), neutropenia (69%)

1. Ellard et al. Submitted to J Clin Oncol 20092. O’Donnell et al. J Clin Oncol. 2008;26:1588-1595.3. Tabernero et al. J Clin Oncol. 2008;26:1603-1610.4. Tanaka et al. J Clin Oncol. 2008:26:1596-1602.

Major implications RAD001 has single-agent antitumor activity in pretreated patients with metastatic breast cancer Daily dosing with 10 mg appeared superior to 70 mg weekly schedule in agreement with phase I pharmacodynamic2,3 and modeling studies4

28

Phase I RAD001 + Weekly Paclitaxel and Trastuzumab in HER2+ Patients With Prior Resistance to Trastuzumab

31 patients, 96% trastuzumab resistant; median 5 prior regimens1

• 6 RAD001 5 mg daily

- 1 CR, 4 PR (1 NE); RR = 83%, DCR = 83%

• 15 RAD001 10 mg daily

- 1 PR, 6 SD, 1 PD (7 too early); RR = 13%, DCR = 88%

• 10 RAD001 30 mg weekly

- 3 PR, 5 SD, 1 PD (1NE); RR = 30%, DCR = 80%

Relative to the 5mg cohort, pts in 10mg cohort had lower PS, younger age, longer duration of metastatic disease and a higher number of prior lines of therapy

Incidence of neutropenia (G3-4=73%) and stomatitis (G3=27%) is higher on the 10mg dose but manageable

Major implicationRAD001 is well tolerated in combination with weekly paclitaxel and trastuzumab and shows encouraging responses in patients with trastuzumab-resistant breast cancer. Phase II/III dose 10 mg/day

1. O’Regan et al. SABCS 2008. Abstract 3119. 29

Waterfall Plot - Strongest tumor regression on sum of target lesions

-120.0%

-100.0%

-80.0%

-60.0%

-40.0%

-20.0%

0.0%

10 mg 30 mg 30 mg 10 mg 30 mg 10 mg 30 mg 10 mg 30 mg 10 mg 30 mg 30 mg 30 mg 10 mg 30 mg 5 mg 5 mg 5 mg 5 mg 5 mgDose regimen

stro

ng

est

tum

or

reg

ress

ion

fro

m B

asel

ine

(su

m o

f ta

rget

le

sio

ns

- d

ecre

ase

in %

)

Resistant to trastuzumab and taxanes

Resistant to trastuzumab only

Phase I RAD001 + weekly Paclitaxel and Trastuzumab: Relevant activity observed in most of the patients

9 pts at 30 mg qw, 6 pts at 10 mg qd (one SD pt with no measurements yet), 5 pts at 5 mg qd

42+303936324121+27+11+54+ 7 27+ 39 21 15 29+ 33+ 40 2512

CRPRPRPRPR PR PRPRPRSDSDSDSDSDSD

SDSD

SD

PDDue to

New Lesion

PDDue to

New Lesion

Weeks on treatment

30

Regression of a Brain Metastasis in a patient with Taxane- / Trastuzumab-refractory tumor

Baseline Month 5Month 1

31

Phase I RAD001 + Vinorelbine and Trastuzumab in HER2+ Patients With Prior Resistance to Trastuzumab

41 patients, all trastuzumab resistant; median of 3 prior chemotherapy regimens1

• 21 RAD001 5 mg daily

– 1 CR, 2 PR, 9 SD; 3 PD (6 too early) RR = 20%, DCR = 80%

• 6 RAD001 20 mg weekly

– 1 PR, 3 SD, 2 PD; RR = 17%, DCR = 66%

• 14 RAD001 30 mg weekly

– 2 PR, 9 SD, 2 PD (1 NE); RR = 15%, DCR = 85%

High incidence of grade 3-4 neutropenia (86%) but manageable and no cases of febrile neutropenia

Major implications

RAD001 in combination with vinorelbine and trastuzumab is tolerablewith promising activity and clinical benefit in heavily pretreated pts with trastuzumab-resistant HER2+ metastatic breast cancer. Phase III dose 5 mg/day

1. Fasolo et al. SABCS 2008. Abstract 406. 32

4 pts at 20 mg qw, 9 pts at 30 mg qw 13 pts at 5 mg qd

CRPRPRPRPR SD SDPRSDSDSDSDSDSDSDSD SDSDSDPDSDSD

SDPDPDPDΩ

Ω

PR

patient ongoing

All patients had visceral disease except when Ω (identifying non visceral disease only)

Waterfall Plot - Strongest tumor regression on sum of target lesions

-13.0%

-21.9%

-100.0%

69.2%

23.5%

-6.3% -9.9%-17.6%-17.7%

-22.7% -26.2%

-37.7%

-46.4%

-56.3%

18.2%

0.0%

-14.1%

-22.7% -23.1%-26.1%-33.1%

-40.9%

-50.0%

-63.3%

-100.0%-100.0%

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

20mg

30mg 5 mg 5 mg

30mg

30mg

30mg 5 mg 5 mg

30mg 5 mg5 mg

20mg 5 mg

30mg 5 mg

30mg 5 mg

20mg

20mg 5 mg 5 mg

30mg

30mg 5 mg 5 mg

Dose regimen

str

on

ge

st

tum

or

reg

res

sio

n f

rom

Ba

se

lin

e

(su

m o

f ta

rge

t le

sio

ns

- d

ec

rea

se

in

%)

Resistant to Taxanes and to LapatinibResistant to taxanes only (& not treated with prior lapatinib)Not resistant to taxanes (& not treated with prior lapatinib)

Phase I RAD001 + Vinorelbine and Trastuzumab: very good disease control in heavily pretreated patients

33

Feb 2009

A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination with Trastuzumab and Paclitaxel, as First Line Therapy in Women with HER2 Positive Locally Advanced or Metastatic Breast Cancer

34

†* After a loading dose of 4 mg/kg on day 1, cycle 1

< 14 days prior to day 1 1 cycle = 28 days

SCREEN

2:1RAD:Placebo

N = 717

Randomize

RAD001 10 mg po daily

Paclitaxel 80 mg/m2 days 1, 8, 15

Trastuzumab 2 mg/kg* days 1, 8, 15, 22

Placebo 10 mg po daily

Paclitaxel 80 mg/m2 days 1, 8, 15

Trastuzumab 2 mg/kg* days 1, 8, 15, 22

PFS

Survival ResponseClin. Ben.

Safety

2009 2010 20112008 20132012

99 pts 717 pts

2014

BOLERO-1 (J2301) First line: Paclitaxel + Trastuzumab RAD001

HER2-overexpressing, unresectable locally advancedor metastatic breast cancer, no prior therapy foradvanced disease

Stratification by prior adjuvant or neoadjuvant trastuzumab and by presence of visceral metastases

35

Feb 2009

\

A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Daily Everolimus in Combination With Trastuzumab and Vinorelbine, in Pretreated Women With HER2/neu Over-expressing Locally Advanced or Metastatic Breast Cancer

38

* Trastuzumab resistance defined as progression on adjuvant trastuzumab ≤ 12 months of last infusion, or progression while on or ≤ 4 weeks of receiving last dose of trastuzumab for metastatic disease† after a loading dose of 4 mg/kg on day 1, cycle 1

< 21 days prior to day 1

SCREEN

1:1

N = 572

Randomize

RAD001 5.0 mg po daily

Vinorelbine 25 mg/m2 days 1, 8, 15

Trastuzumab 2 mg/kg† days 1, 8, 15

Placebo 5.0 mg po daily

Vinorelbine 25 mg/m2 days 1, 8, 15Trastuzumab 2 mg/kg† days 1, 8, 15

1 cycle = 21 days

2009 2010 20112008 20132012 2014

572 ptsW2301

BOLERO-3: Vinorelbine + Trastuzumab RAD001 in Patients with Her2+ ABC Resistant to Trastuzumab

HER2-overexpressing, locally advanced or metastatic ABC, prior taxane therapy and resistant to trastuzumab*

Stratification by prior lapatinib (Yes vs No)

PFS

Survival ORR, CBR

Safety

PKBiomarkers

39

HER2+ Breast Cancer: Summary and Conclusions

15% to 25% of breast cancers overexpress HER2. Overexpression of HER2 is a marker for more aggressive disease

Trastuzumab induces responses in <50% of patients with metastatic HER2+ breast cancer. Trastuzumab in combination with chemotherapy induces response in 2/3 of pts, but a high proportion will develop resistance within 1 year

2nd-line therapy with HER2-targeted therapy, trastuzumab or lapatinib, combined with capecitabine, will generate a response in fewer than 50% with progression within 9 months and survival of less than 2 years

Signaling defects upstream of mTOR are common in breast cancer and are the principal causes of resistance to trastuzumab

RAD001 has shown activity in breast cancer as a single agent and in combination with trastuzumab and paclitaxel or vinorelbine in HER2+ patients with prior resistance to trastuzumab-containing chemotherapy

RAD001 combined with trastuzumab and chemotherapy is a rational approach to enhancing responses in patients with HER2+ metastatic breast cancer and in the treatment of patients after failure of other trastuzumab-containing chemotherapy regimens

41

Selection of Adjuvant Endocrine Therapy for HR+ Breast Cancer Is Based on Menopausal Status

PRE

POST

TAM x 2-3 y± OS or OA

AI = aromatase inhibitor; OA = ovarian ablation; OS = ovarian suppression; PRE = premenopausal;POST = postmenopausal; TAM = tamoxifen.NCCN Clinical Practice Guidelines in Oncology—v.1.2009.

POST

PRE

Complete5 y TAM

AI to complete5 y or longer

Complete5 y TAM

AI for 5 y

PRE

POST

AI for 5 y

No further endocrine therapy

AI x 5 y

TAM x 2-3 y

TAM x 4.5-6 y

TAM x 5 y (women with a contraindication to AIs, who decline AIs,or who are intolerant of AIs)

AI to complete5 y or longer

AI x 5y

42

Selection of the First-line Regimen for Postmenopausal ER+ Advanced Breast Cancer

Agent Study Design Pivotal Trial Findings

Nonsteroidal Aromatase Inhibitor

Letrozole letrozole 2.5 mg/d vs tamoxifen 20 mg/d in 916 postmenopausal women—80% had not received adjuvant antiestrogen therapy

TTP: Letrozole (9.4 mo) vs tamoxifen (6.4 mo), P < 0.0001 ORR: Letrozole (32%) vs tamoxifen (21%), P = 0.0002Survival: Letrozole (35 mo) vs tamoxifen (32 mo), P = 0.5136

Anastrozole anastrozole 1.0 mg/d vs tamoxifen 20 mg/d in 353 postmenopausal women

TTP: Anastrozole (11.1 mo) vs tamoxifen (5.6 mo), P < 0.005 ORR: Anastrozole (21%) vs tamoxifen (17%), P = NS

Steroidal Aromatase Inactivator

Exemestane Not specifically approved for first-line treatment upfront of metastatic disease. Approval is after failure of tamoxifen

NCCN Clinical Practice Guidelines in Oncology: Breast Cancer—v.1.2009.

43

What after progression on AIs?

Currently no treatments approved for postmenopausal women with ER+ ABC after recurrence or progression on a NSAI (letrozole or anastrozole)

Double-blind phase III trial (N=693) Fulvestrant Vs Exemestane in postmenopausal ER+ BC after progression to NSAI (Chia 2008)

- PFS 3.7 month on both arms

- ORR 7.4% vs. 6.7%, respectively

- Disease control rate 32.2% vs. 31.5%

This modest level of activity emphasizes the need for new treatment options that are not solely targeting the estrogen receptor pathway

44

GfK Research Matters AG Breast Cancer Treatment Tracker 2008 – Global Report February 2009

21

Hormonal therapy in pre/peri-menopausal women (2nd line)

5‘090 patients in 2008

Hormonal therapy in post- menopausal women (2nd

line)

8‘770 patients in 2008

Mean % of pre/peri-menopausal

patients receiving …

Mean % of pre/peri-menopausal patients also

receiving LHRHa

Mean % of post-menopausal patients receiving …

Tamoxifen 19% 38% 12%

Arimidex 16% 46% 16%

Femara 20% 55% 16%

Aromasin 10% 39% 23%

Faslodex 24% 46% 32%

LHRHa alone 8% 0%

Other hormone 3% 42% 1%

Total of all patients receiving AIs 46% 55%

Total of all patients receiving a LHRHa

45%

Second Line Hormonal Therapy in Metastatic Breast Cancer Patients - USA

Base: All Part II physicians giving hormonal therapy as 2nd line (US pre/peri-menopausal n=129, post-menopausal n=134)

Q122a1,Q122bQ122a2

Thinking about all your pre/peri-menopausal and post-menopausal patients who received a second line metastatic hormonal therapy (either alone or in combination with chemotherapy) in the last 12 months, what different hormonal agents did these patients get? What proportion additionally received an LHRHa?

45

GfK Research Matters AG Breast Cancer Treatment Tracker 2008 – Global Report February 2009

22

Hormonal therapy in pre/peri-menopausal women (2nd line)

5‘790 patients in 2008

Hormonal therapy in post- menopausal women (2nd

line)

9‘870 patients in 2008

Mean % of pre/peri-menopausal

patients receiving …

Mean % of pre/peri-menopausal patients also

receiving LHRHa

Mean % of post-menopausal patients receiving …

Tamoxifen 20% 33% 14%

Arimidex 22% 50% 20%

Femara 18% 46% 19%

Aromasin 17% 44% 27%

Faslodex 17% 25% 18%

LHRHa alone 5% 0%

Other hormone 1% 100% 0%

Total of all patients receiving AIs 58% 54%

Total of all patients receiving a LHRHa

49%

Second Line Hormonal Therapy in Metastatic Breast Cancer Patients - Europe (t5)

Base: All Part II physicians giving hormonal therapy as 2nd line (US pre/peri-menopausal n=129, post-menopausal n=134)

Q122a1,Q122bQ122a2

Thinking about all your pre/peri-menopausal and post-menopausal patients who received a second line metastatic hormonal therapy (either alone or in combination with chemotherapy) in the last 12 months, what different hormonal agents did these patients get? What proportion additionally received an LHRHa?

46

Feb 2009

mTOR Inhibition in ER+ Breast Cancer

47

mTOR Inhibition Combines Effectively With Hormonal Therapy in Breast Cancer

Objective responses and stable disease in patients with BC treated with mTOR inhibitors alone1-3

Combination mTOR inhibition and hormonal therapy reduced cell proliferation and induced apoptosis in BC cells to a greater extent than either agent alone4

mTOR inhibition reverses resistance to hormonal therapy in BC5,6 with synergistic antitumor effects with hormonal therapy7

MEK

PI3K

RAS

mTOR

ERK

RAFAKT

Cell Proliferation

TSC2 TSC1

Cell Growth

Metabolism

Angiogenesis

ER

ER

ER

IGF-1R, EGFR

1. Chan et al. J Clin Oncol. 2005;23:5314-5322. 2. Tabernero et al. J Clin Oncol. 2008;26:1603-110.3. Ellard et al. J Clin Oncol. 2007;25(18s):141s. Abstract 3513. 4. Boulay et al. Clin Cancer Res. 2005;11:5319-5328. 5. deGraffenreid et al. Clin Cancer Res. 2004;10:8059-8067. 6. Ghayad et al. Cancer Sci. 2008;99:1992-2003.7. Lisztwan et al. Breast Cancer Res. 2008;10:R56. 48

Feb 2009

RAD001 in Advanced ER+ Breast Cancer

49

Phase I Trial of RAD001 in Combination With Letrozole

18 patients with metastatic breast cancer stable or progressing on letrozole alone

Phase I open-label combination of letrozole and RAD001 at 5 mg/day or 10 mg/day

Well tolerated—1 DLT with RAD001 10 mg/day—grade 3 thrombocytopenia

• Other AEs consistent with previous studies with RAD001—stomatitis, fatigue, anorexia, diarrhea, headache, rash

No PK interactions between RAD001 and letrozole

1 CR (RAD001 10 mg/day) with a duration of 22.3 months

9 SD with durations from 8 to 23 months

1. Awada et al. Eur J Cancer. 2008;44:88-91.

Daily therapy with RAD001 and letrozole isfeasible with evidence of clinical activity

50

RAD001/Femara Clinical Program in Breast Cancer

128 patients

SCREEN

RANDOMIZE

Femara 2.5 mg/day

RAD001 10 mg/day

Femara 2.5 mg/day

Placebo

128 patients

16 weeks

Surgery

Tumor biopsies(pretreatment)

Tumor biopsies (2 weeks)

Tumor tissue (surgery)

•Newly diagnosed, untreated, patients with ER+ localized breast cancer likely to benefit from hormonal therapy

•Palpable tumor: > 2 cm diameter

Phase II – neoadjuvant treatment (CRAD001C2222):

51

Phase II Neoadjuvant Study of Letrozole ± RAD001 in Patients With ER+ Breast Cancer

270 postmenopausal women received 4 months of letrozole 2.5 mg qd + RAD001 10 mg qd or placebo

Responses Everolimus +

Letrozolen = 138

Placebo + Letrozolen = 132 P

Palpation 68.1% 59.1% .062

Ultrasound

58.0 % 47.0 % .035

Supports the use of RAD001 with letrozole in a neoadjuvant setting

The combination is tolerable and more active than letrozole alone

Biomarker analysis: subgroup of patients with higher level of mTOR activity at baseline (high levels of pS6) had a higher RR (82% vs 60%). Technical challenges, however, don’t allow the selection of patients based on pS6 values

1. Baselga et al. submitted.52

PR and cyclin D1 downregulated in response to letrozole; pS6 levels dramatic downregulation with RAD001

-140

-120

-100

-80

-60

-40

-20

0

20

40

Ch

ang

e i

n H

Sco

re (

% P

osi

tive

fo

r K

i67)

Everolimus + letrozoleLetrozole

CyclinD1 pS6235PR Ki67 pS6240ER

pAkt

1. Baselga et al. submitted.

53

Feb 2009

A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination with Exemestane in the Treatment of Postmenopausal Women with Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer who are Refractory to Letrozole or Anastrozole

54

< 21 days prior to day 1

SCREEN

2:1

N = 705

Randomize

RAD001 10 mg po daily

Exemestane 25mg po daily

Placebo 10 mg po dailyExemestane 25mg po daily

2009 2010 20112008 20132012 2014

705 ptsY2301

BOLERO-2: ER+ ABC, Exemestane RAD001 after recurrence or progression on anastrozole or letrozole

Postmenopausal women with ER+ locally advanced or metastatic breast cancer with prior recurrence or progression on letrozole or anastrozole

Stratification by sensitivity to prior hormonal therapy and visceral metastases PFS

Survival ORR, CBRPS

QoLSafety

PKBiomarkers

55

ER+ Breast Cancer: Summary and Conclusions

80% of breast cancers express ER or PR

Long-term efficacy of hormonal therapy is limited by acquired resistance, which may be caused by enhanced signaling through growth factor receptors reducing dependence on estrogen to stimulate cell growth and proliferation

• Targeted therapies are being investigated to overcome resistance to hormonal therapy

mTOR is a key regulator of the stimuli driving growth of the hormone-resistant breast cancers

RAD001 has shown antitumor activity in breast cancer as a single agent, and also in combination with hormonal therapy

57