V Reunión Nacional de avances en Cáncer de Próstata y Cáncer Renal

1. V Reunión Nacionalde avances en Cáncer de Próstata y Cáncer Renal Everolimus en Cáncer Renal Avanzado Guadalajara 18 y 19 de Junio de 2009 Dr. Daniel Castellano Servicio de Oncología Médica

2. Patogenesis de CCR

4. Everolimus Temsirolimus

5. mTOR mTORControls Cell Growth, Proliferation and Angiogenesis • mTOR is a kinase in the PI3-K/Akt signaling pathway • Integrates multiple signals • Growth factor receptor activity • Cellular energy, nutrients, and oxygen levels • Signals from other cellular signaling pathways • Estrogen receptor signaling • Controls production of proteins regulating cell growth, cell division, and angiogenesis in response to these signals Growth factor receptors (IGF-1R, VEGFR, ErbB) Oxygen, energy, and nutrients Ras/Raf pathway and Abl kinases Estrogen receptor Protein production Cell growth Angiogenesis Cell division

6. ↓Glucose ↓ATP ↑Glucose AMPK TSC1 ↑ATP TSC2 Amino Acids mTOR Integrates Growth Factor and Nutrient Signaling • mTOR pathway, PI3K-AKT-mTOR, is a downstream component of several growth factor signaling pathways1 • mTOR senses availability of amino acids, metabolic fuel, and energy (ATP) • mTOR activation turns on the synthesis of proteins involved in cell growth2 • mTOR is a critical integrator of signaling that coordinates cell growth control3 PI3K Growth Signaling Akt mTOR Protein Synthesis Cell Growth & Proliferation Bioenergetics Angiogenesis Targeting the mTOR pathway can impact the bioenergetics of the cell

9. mTOR Mutations in Cancer mTOR Coordinates Cancer Cell Growth Blood Vessel Nutrient Availability Production of Transporters IncreasedNutrient Uptake Secretion of Angiogenic Growth Factors GlucoseTransporter Amino AcidTransporter M G1 G2 Cancer Cell Cancer Cell Growth S

10. Ras/Raf, Abl, ER PI3-K TSC2 TSC1 Akt/PKB RAD001 S6K1 X X X Deregulation of the the mTOR Pathway Growth factors IGF-1, VEGF, ErbB, etc • In cancer cells, mTOR is often deregulated by • Excessive growth factor signaling • Gain-of-function mutations in up-stream kinases, eg, PI3-K and Akt • Loss of function of the negative regulators PTEN, TSC1/2, and LKB1 • Increased activity of kinases that stimulate the PI3-K/Akt pathway, eg, Ras/Raf, Abl, ER • mTOR inhibition counters many common defects in cancer cells PTEN Oxygen, energy, and nutrients Ras/Raf pathway kinases mTOR 4E-BP1 elF-4E S6 Protein production Cell growth Angiogenesis Cell division

11. mTOR mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways Blood Vessel Nutrient Availability DECREASED Secretion of Angiogenic Growth Factors GlucoseTransporter DECREASED Amino AcidTransporter M G1 G2 Cancer Cell Cancer Cell Growth S

12. mTOR InhibitionMolecular Rationale for Selected Cancers +++ Closely associated with pathogenesis in a high proportion of cancers ++ Contributes to the pathogenesis of many cancers+ Contributes to pathogenesis in some cancers, or contribution is not apparent

13. Active rapamycin derivative, not a prodrug Oral bioavailability T1/2 ≈ 30 hours CYP3A4 metabolism Broad antitumor activity in preclinical & phase 1 studies Inhibits cell growth and angiogenesis Enhances activity of chemotherapy, radiation, and molecular therapeutics O H O O O O O H N O O O O O O H O O RAD001An Oral mTOR Pathway Inhibitor RAD001 (everolimus)

14. RAD001Preclinical Summary • Potent inhibition of tumor & endothelial cell proliferation • In vivo activity vs many tumor types, including lung, colon, pancreatic, and epidermoid cancers and melanoma • Inhibition of tumor cell VEGF production in vitro & in vivo • Antiangiogenic effects in vivo • Enhances apoptosis induced by DNA damaging agents • Additive/synergistic in combination with cisplatin, gemcitabine, doxorubicin, paclitaxel, PTK/ZK, AEE788, and letrozole • p-Akt may indicate higher PI3-K pathway activation and increased sensitivity to RAD001 • PTEN status may predict antitumor response in certain tumor types (eg, glioblastoma multiforme [GBM])

15. RAD001(everolimus) Phase I Monotherapy Studies

16. RAD001Dose-Limiting Toxicity • DLTs of RAD001 are stomatitis and neutropenia *Study 2107: Phase 1 safety study in 55 patients with advanced cancer.

17. RAD001 Safety and Tolerability: Phase 1 Monotherapy • Adverse events (AEs) generally mild to moderate • Most common: rash/erythema (~ 46%), stomatitis/ mucositis (~ 40%) • Other common: fatigue (32%), nausea (25%), anorexia (24%), vomiting (16%), headache (14%), pruritus, infections, constipation (~ 10% each) • Stomatitis the most common serious toxicity • Toxicity profile nonoverlapping with many commonly used anticancer agents—no serious neuropathy, cardiotoxicity, edema, or alopecia has been seen • Long-term (≥ 3 years) safety and tolerability in more than 1,000 patients in transplantation applications using dosages similar to those used in oncology Data on file, Novartis.

18. RAD001Studies 2101/2 and 2107: Response* *Conventional imaging using RECIST criteria. GE = gastroesophageal.

19. RAD001Conclusions: Phase 1 Single-Agent Trials • DLTs are stomatitis, neutropenia, and hyperglycemia • Favorable PK profile • Oral bioavailability • t1/2~ 30 hours • Dose proportionality • Interpatient variability ~ 50% • Most common AEs are rash and stomatitis in ≥ 40% • Grade 3 in < 1% and 5%, respectively • PD and safety support recommended doses • 10 mg/d or 50–70 mg/wk • Tumor responses and prolonged disease stabilizations

20. RAD001Single Agent Activity in Renal Cell Cancer ASCO 2006: Dr Amato, Methodist Hospital – Houston (IIT) • 25 patients with disease progression after cytokine or cytotoxic therapy • 21 evaluable : 18 pts are progression-free at 3 mos • Median duration of RAD therapy is 8+ months (range 1+ to 9+) ASCO 2008: Dr J. Jac, Amato, Methodist Hospital – Houston (IIT) • 22 patients with disease progression after tyrosine kinase inhibitors • 22 evaluable : 3 PR (16%) and 14 pts (74%) are progression-free at 3 mos • Median PFS of RAD therapy is 5.5 + months (range 1+ to 8+) Phase 3 Study in 2nd/3rd Line Advanced RCC after VEGFr Inhibitor failure, RECORD-1

21. RAD001 (Everolimus) Plus Best Supportive Care (BSC) vs BSC Plus Placebo in Patients With Metastatic Renal Cell Carcinoma (RCC), After Progression on VEGFr-TKI Therapy R. Motzer, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, R. Figlin, J. Thompson, V. Grünwald, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud, for the RECORD-1 Study Group Supported by Novartis Pharmaceuticals

22. Objectives • Phase III randomized trial of everolimus vs placebo • 2:1 double-blind • Primary end point: progression-free survival • 33% risk reduction (hazard ratio = 0.67) • 290 events to achieve 90% power • Assessment by independent central review • Secondary end points: safety, response, patient-reported outcomes and overall survival

23. Key Eligibility Criteria • Metastatic RCC with clear cell component • Measurable disease • Progressive disease on or within 6 mos of treatment with sunitinib, sorafenib, or both • Prior bevacizumab and cytokines permitted • Adequate performance status, blood counts and serum chemistry

24. R A N D O M I Z A T I O N 2:1 Target N = 362 Stratification • Prior VEGFrTKI: 1 or 2 • MSKCC risk group1: favorable, intermediate, or poor Everolimus + BSC Upon Disease Progression Placebo + BSC Interim analysis Interim analysis • Interim analyses planned after ≈ 30% and 60% of targeted 290 events 1. Motzer et al. J Clin Oncol. 2004;22:454-463. Study Design Final analysis

25. R A N D O M I Z A T I O N 2:1 N = 410 Stratification • Prior VEGFrTKI: 1 or 2 • MSKCC risk group: favorable, intermediate, or poor Everolimus + BSC (n = 272) Upon Disease Progression Placebo + BSC (n = 138) Finalanalysis Interim analysis Interim analysis = Study Conduct 410 patients randomized between September 2006 and October 2007 Second interim analysis cut-off: October 15, 2007, based on 191 PFS events Independent Data Monitoring Committee recommended termination of study

26. Study Treatment • Repeated 28-day cycles • Response and safety assessments • Dose reduction for toxicity • Treatment continued unless progression or intolerance Arm A: everolimus10 mg po daily Arm B: matching placebo po daily vs

27. Baseline Characteristics 1. Motzer et al. J Clin Oncol. 2004;22:454-463.

28. Prior Therapies

29. Patient Disposition and Treatment Administered

30. 100 Hazard ratio = 0.30 95% CI [0.22, 0.40] Median PFS Everolimus: 4.0 moPlacebo: 1.9 mo Log rank P value < 0.001 Everolimus (n = 272) Placebo (n = 138) 80 60 Probability, % 40 20 0 6 12 0 2 4 8 10 Months Progression-Free Survival by Treatment Central Radiology Review Patients at Risk Everolimus272 132 47 8 2 0 0 Placebo138 32 4 1 0 0 0

31. Progression-Free Survival by Treatment Central Radiology Review > 25 %

32. Progression-Free Survival by Treatment Prior Sunitinib Central Radiology Review

33. Progression-Free Survival by Treatment Prior Sorafenib Central Radiology Review

34. Subgroup Analysis of Progression-Free Survival Central Radiology Review

35. 1 Subgroup Analysis of Progression-Free SurvivalCentral Radiology Review 1. Motzer et al. J Clin Oncol. 2004;22:454-463.

36. Maximum % Change in Target Lesions and Objective Response Rate* 100% Everolimus Placebo 75% 50% 25% 0% −25% Best Response n (%) PR 0 Stable 45 (32) PD 74 (53) NE 20 (14) Best Response n (%) PR 5 (2) Stable 185 (67) PD 57 (21) NE 30 (11) −50% −75% −100% NE = not evaluable *Central Radiology Review

37. Laboratory Abnormalities* *≥ 10% of everolimus patients†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < 0.05)

38. Treatment-Related Adverse Events* *≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05).

39. Pneumonitis with Everolimus Therapy Baseline Month 5 Month 11 Month 12

40. Overall Survival by Treatment

41. Standards for RCC Therapy by Phase III Trial ASCO 2007 *MSKCC risk status.

42. Standards for RCC Therapy by Phase III TrialASCO 2008 *MSKCC risk status.

43. Conclusions • Everolimus prolongs progression-free survival in RCC patients after progression on VEGFr-TKI therapies • Everolimus is the first and only agent with established clinical benefit for the treatment of patients with RCC after VEGFr-TKI therapy • Everolimus should be standard-of-care in this setting • FDA approved March 2009

44. Phase II study RAD001/Bevacizumab in Advanced RCC (Asco 2008) • 59 mClear-cell RCC patients (Aug 2006 - Nov 2007) • No previous targeted agents: 30 patients • Previous targeted agents: 29 patients • Sunitinib 15, Sorafenib 10, Sorafenib and sunitinib 2, IL-2 and sorafenib 2 • ECOG 0-1 • Maximum of 1 previous immunotherapy or chemotherapy regimen • No previous bevacizumab or M-TOR inhibitors • Motzer prognostic score: • Low: 12 (20%) • Intermediate: 45 (76%) • High:2 (4%) • Bevacizumab 10mg/kg IV infusion, every 2 weeks • RAD001 10mg PO daily

45. RAD001/Bevacizumab in Advanced RCC Treatment Received, Activity, Discontinuation • 13 of 15 patients previously treated with sunitinib had DCR: PR 4, SD 9 • Reasons for discontinuing treatment (N=45) • Progression: 24 • Toxicity: 9 (proteinuria, embolus, stomatitis, diarrhea) • Other: 12 (intercurrent illness, MD decision, Pt refusal)

46. RAD001/Bevacizumab in Advanced RCC Toxicity (N=59) Number of Patients (%) Toxicity Grade 1/2 3 4 Hematologic Neutropenia 10 (23%) 1 (2%) 0 Thrombocytopenia 25 (57%) 1 (2%) 0 Anemia 41 (93%) 0 0 Non-Hematologic Fatigue 35 (59%) 4 (7%) 1 (2%) Skin toxicity (rash, pruritus) 53 (90%) 0 0 Hypertension 14 (24%) 1 (2%) 0 Proteinuria 9 (15%) 10 (17%) 2 (3%) Mucositis/Stomatitis 28 (47%) 4 (7%) 0 Diarrhea 16 (27%) 5 (8%) 0 Hyperlipidemia 39 (66%) 2 (3%) 0 Nausea/vomiting 18 (31%) 0 0 Epistaxis 6 (10%) 0 0

47. RECORD-2Phase II Trial of RAD001 Plus Bevacizumab • First-line treatment of patients with metastatic clear-cell carcinoma of the kidney • Primary endpoint: Progression-free survival • Secondary endpoint: Overall survival RAD001 10 mg/dayplus Bevacizumab 10 mg/kg q 2 wk IV SCREEN N = 360 Randomized 1 : 1 IFN- dose escalation SC plusBevacizumab 10 mg/kg q 2 wk IV FPFV: 4Q08 SC = Subcutaneous; IFN- = Interferon alfa.

48. RECORD-3 Randomized Phase II Crossover Design • First-line treatment of patients with previously untreated mRCC • Stratified by MSKCC risk criteria • Primary endpoint: Progression-free survival • Secondary endpoint: Overall survival, safety, efficacy, QoL RAD001 10 mg/day Sunitinib 50 mg/day, 4 wk on/2 wk off SCREEN Disease progression Randomized 1 : 1 Sunitinib 50 mg/day, 4 wk on/2 wk off RAD001 10 mg/day MSKCC = Memorial Sloan-Kettering Cancer Center; QoL = Quality of life.

49. RAD001 10 mg/day RAPTORRAD001 as Monotherapy in the Treatment of Advanced Papillary Renal Cell Tumors • Phase II, multicenter, international study of RAD001 as first-line treatment for patients with metastatic papillary RCC • Type I/II metastatic papillary RCCN = 60 • Inclusion criteria: • ≥ 1 measurable lesion • ECOG PS 0 or 1 • Adequate bone marrow, liver, and renal function • Adequate lipid profile • No prior systemic therapy Study start date is January 2009.ECOG PS = Eastern Cooperative Oncology Group performance status.

50. Estudio multicéntrico, abierto, de acceso expandido de RAD001, en pacientes con carcinoma renal metastásico que han progresado a pesar de la terapia con  inhibidor de tirosina quinasas del receptor del factor de crecimiento endotelial vascular 30 centros en España abiertos para tratamiento