1. Feb 2009 RAD001 – registrational program in Advanced HER2 + and ER+ Breast Cancer Cristian Massacesi, M.D. Sr Medical Director, CIL RAD001 BC

2. Feb 2009 mTOR Inhibition in HER2 + Breast Cancer 23

3. mTOR Is a Key Regulator of the PI3K/AKT Pathway Stimulated by HER2 Angiogenesis mTOR AKT AMPK TSC1 TSC2 PTEN LKB1 Cell Growth & Cell Growth &Proliferation Cell Metabolism Metabolism PI3K RHEB IGF-1R EGFR/HER2 Nutrients  mTOR is an intracellular serine/threonine kinase in the PI3K/Akt signaling pathway 1  mTOR is a central regulator that senses changes in Growth factor signaling 1,2 Nutrients and energy 1-3  mTOR activation promotes Cell growth and proliferation 3 Angiogenesis 4 Cancer cell metabolism through increased nutrient uptake and utilization 3,5 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. Trastuzumab 24

4. RAD001 Counters the Effects of Molecular Changes in Signaling Pathways Conferring Trastuzumab Resistance Angiogenesis mTOR AKT AMPK TSC1 TSC2 PTEN LKB1 Cell Growth & Cell Growth &Proliferation Cell Metabolism Metabolism PI3K RHEB IGF-1R EGFR/HER2 Increased signaling through IGF-1R Constitutive PI3K/Akt activation Elevated AKT or pAKT Absent or low PTEN Truncated HER2 Nutrients Downstream inhibition with RAD001 counters these resistance mechanisms RAD001 1. Widakowich et al. Anticancer Agents Med Chem. 2008,8:488-496. 25

5. RAD001 Inhibits Growth and Proliferation of Breast Cancer Cells and Endothelial Cells RAD001 VEGF VEGFR RAD001 Protein Synthesis mTOR Hypoxic Stress Genes HIF Blood Vessel Protein Synthesis mTOR Hypoxic Stress Genes HIF VHL 26

6. Feb 2009 RAD001 in Advanced HER2 + Breast Cancer 27

7. RAD001 Single Agent Phase II Study of Daily and Weekly Dosing in Advanced Breast Cancer  48 patients with ≤ 1 prior therapy for metastatic disease 1 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 2009 2. 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 pharmacodynamic 2,3 and modeling studies 4 28

8. Phase I RAD001 + Weekly Paclitaxel and Trastuzumab in HER2 + Patients With Prior Resistance to Trastuzumab  31 patients, 96% trastuzumab resistant; median 5 prior regimens 1 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 implication RAD001 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

9. 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+727+39211529+33+402512 CRPR SD PD Due to New Lesion PD Due to New Lesion Weeks on treatment 30

10. Regression of a Brain Metastasis in a patient with Taxane- / Trastuzumab-refractory tumor BaselineMonth 5Month 1 31

11. Phase I RAD001 + Vinorelbine and Trastuzumab in HER2 + Patients With Prior Resistance to Trastuzumab  41 patients, all trastuzumab resistant; median of 3 prior chemotherapy regimens 1 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 tolerable with 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

12. 4 pts at 20 mg qw, 9 pts at 30 mg qw 13 pts at 5 mg qd CRPR SD PRSD PDSD PD Ω 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% -1.2 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 20 mg 30 mg5 mg 30 mg 30 mg 30 mg5 mg 30 mg5 mg 20 mg5 mg 30 mg5 mg 30 mg5 mg 20 mg 20 mg5 mg 30 mg 30 mg5 mg Dose regimen strongest tumor regression from Baseline (sum of target lesions - decrease in %) Resistant to Taxanes and to Lapatinib Resistant 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

13. 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

14. †* After a loading dose of 4 mg/kg on day 1, cycle 1 < 14 days prior to day 1 1 cycle = 28 days SCREENSCREEN 2:1 RAD:Placebo N = 717 Randomize RAD001 10 mg po daily Paclitaxel 80 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg * days 1, 8, 15, 22 Placebo 10 mg po daily Paclitaxel 80 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg * days 1, 8, 15, 22 PFS Survival Response Clin. Ben. Safety 200920102011200820132012 99 pts 717 pts 2014 BOLERO-1 (J2301) First line: Paclitaxel + Trastuzumab  RAD001  HER2-overexpressing, unresectable locally advanced or metastatic breast cancer, no prior therapy for advanced disease  Stratification by prior adjuvant or neoadjuvant trastuzumab and by presence of visceral metastases 35

15. 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

16. * 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 SCREENSCREEN 1:1 N = 572 Randomize RAD001 5.0 mg po daily Vinorelbine 25 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg † days 1, 8, 15 Placebo 5.0 mg po daily Vinorelbine 25 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg † days 1, 8, 15 1 cycle = 21 days 200920102011200820132012 2014 572 pts W2301 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 PK Biomarkers 39

17. 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

18. 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 Complete 5 y TAM AI to complete 5 y or longer Complete 5 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 complete 5 y or longer AI x 5y 42

19. Selection of the First-line Regimen for Postmenopausal ER+ Advanced Breast Cancer AgentStudy DesignPivotal 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 = 0.0002 Survival: 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 ExemestaneNot 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

20. 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

21. GfK Research Matters AGBreast Cancer Treatment Tracker 2008 – Global ReportFebruary 2009 21 Hormonal therapy in pre/peri-menopausal women (2 nd line) 5‘090 patients in 2008 Hormonal therapy in post- menopausal women (2 nd 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 hormone3% 42% 1% Total of all patients receiving AIs46%55% Total of all patients receiving a LHRHa45% Second Line Hormonal Therapy in Metastatic Breast Cancer Patients - USA Base:All Part II physicians giving hormonal therapy as 2 nd line (US pre/peri-menopausal n=129, post-menopausal n=134) Q122a1, Q122b Q122a2 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

22. GfK Research Matters AGBreast Cancer Treatment Tracker 2008 – Global ReportFebruary 2009 22 Hormonal therapy in pre/peri-menopausal women (2 nd line) 5‘790 patients in 2008 Hormonal therapy in post- menopausal women (2 nd 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 … Tamoxifen20% 33% 14% Arimidex22% 50% 20% Femara18% 46% 19% Aromasin17% 44% 27% Faslodex17% 25% 18% LHRHa alone5%0% Other hormone1% 100% 0% Total of all patients receiving AIs58%54% Total of all patients receiving a LHRHa49% Second Line Hormonal Therapy in Metastatic Breast Cancer Patients - Europe (t5) Base:All Part II physicians giving hormonal therapy as 2 nd line (US pre/peri-menopausal n=129, post-menopausal n=134) Q122a1, Q122b Q122a2 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

23. Feb 2009 mTOR Inhibition in ER+ Breast Cancer 47

24. mTOR Inhibition Combines Effectively With Hormonal Therapy in Breast Cancer  Objective responses and stable disease in patients with BC treated with mTOR inhibitors alone 1-3  Combination mTOR inhibition and hormonal therapy reduced cell proliferation and induced apoptosis in BC cells to a greater extent than either agent alone 4  mTOR inhibition reverses resistance to hormonal therapy in BC 5,6 with synergistic antitumor effects with hormonal therapy 7 MEK PI3K RAS mTOR ERK RAF AKT Cell Proliferation TSC2 TSC1 Cell Growth Metabolism Angiogenesis 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

25. Feb 2009 RAD001 in Advanced ER + Breast Cancer 49

26. 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 is feasible with evidence of clinical activity 50

27. RAD001/Femara Clinical Program in Breast Cancer 128 patients SCREENSCREEN RANDOMIZERANDOMIZE 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

28. 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 + Letrozole n = 138 Placebo + Letrozole n = 132 P Palpation68.1%59.1%.062 Ultrasound58.0 %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

29. 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 Change in H Score (% Positive for Ki67) Everolimus + letrozole Letrozole CyclinD1pS6 235 PRKi67 pS6 240 ER pAkt 1. Baselga et al. submitted. 53

30. 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

31. < 21 days prior to day 1 SCREENSCREEN 2:1 N = 705 Randomize RAD001 10 mg po daily Exemestane 25mg po daily Placebo 10 mg po daily Exemestane 25mg po daily 200920102011200820132012 2014 705 pts Y2301 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, CBR PS QoL Safety PK Biomarkers 55

32. 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