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Cora N. Sternberg, MD, FACP

Metastatic Renal Cell Carcinoma What’s Hot In The Treatment Of Renal Cell Carcinoma And Is There Hope?. Cora N. Sternberg, MD, FACP Chairman, Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy. Metastatic Kidney Cancer: Options.

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Cora N. Sternberg, MD, FACP

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  1. MetastaticRenalCellCarcinomaWhat’sHotInTheTreatmentOfRenalCellCarcinomaAndIsThereHope?MetastaticRenalCellCarcinomaWhat’sHotInTheTreatmentOfRenalCellCarcinomaAndIsThereHope? Cora N. Sternberg, MD, FACP Chairman, Department of Medical OncologySan Camillo and Forlanini Hospitals Rome, Italy

  2. MetastaticKidneyCancer:Options • Interferon- for good risk patients until recently • HD-IL-2 for intermediate and good risk patients. • Limited availability • Intensive treatment • Of value (long lasting CR) for a small group of patients • Patient selection required • Poor risk patients: no proven therapeutic options until recently • Second line: no proven therapeutic options until recently

  3. Treatment of Metastatic Kidney Cancer • Has our perception of RCC been changed with the advent of new drugs? • Can we commute a death sentence to a chronic disease that patients can learn to live with? • How have traditional criteria to measure response with cytotoxics led us astray? • Can we afford these expensive promising new treatments? Mancuso and Sternberg, BJU Int. Jun 2005 Mancuso and Sternberg, Can J Urol. Feb 2005

  4. a Von Hippel-Lindau SuppressorGene Inactivated in > 75% Sporadic RCC Critical Cofactor in the Ubiquitin Ligase Complex Regulated by hypoxia; No HIF1-a breakdown degradation of hypoxia inducible = pVHL HIF b Suppressor gene mTOR inhib, HSP 90 inhib Bevacizumab, VEGF TRAP PDGF periocytes TGFa VEGF angiogenesis autocrine growth factors EGFR KDR PDGFR Sunitinib, Sorafenib AG13736,Vatalanib Sunitinib, Sorafenib CCI-779 Sunitinib, Sorafenib Imatinib

  5. The VEGF Family Are Critical Tumor-Secreted Angiogenic Factors • The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis • There are five members of the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E) VEGF-E VEGF-A VEGF-D VEGF-C VEGF-B Bevacizumab binds VEGF A

  6. Time to Progression High-Dose Ab vs. Placebo (RR= 10%) 4.8 mos 2.5 mos Yang, NEJM 2003

  7. Survival Update Yang, NEJM 2003

  8. CALGB90206:RandomizedPhaseIIITrialofIFNαorIFNα+BevacizumabinAdvancedRCC(n=700)CALGB90206:RandomizedPhaseIIITrialofIFNαorIFNα+BevacizumabinAdvancedRCC(n=700) RANDOMI ZE IFNα9MUTIW No prior Rx Stratify Motzer Score VS IFNα9MUTIW+Bevacizumab10mg/KGD1andD15 1° Endpoint: Survival, 89% Power to Detect Improvement in OS of 13 to 17 mos

  9. Europe:RandomizedPhaseIIITrialofIFNαorIFNα+BevacizumabinAdvancedRCC(n=638)Europe:RandomizedPhaseIIITrialofIFNαorIFNα+BevacizumabinAdvancedRCC(n=638) RANDOMI ZE IFNα9MUTIW+placebo VS Nephrectomy Clear Cell > 50% IFNα9MUTIW+Bevacizumab10mg/KGD1andD15 1° Endpoint: Survival, 80% Power to Detect Improvement in OS of 13 to 17 mos

  10. Sunitinib Mechanism of Action in RCC Loss of VHL Protein Function ↑ VEGF ↑ PDGF VEGF PDGF VEGFR PDGFR Pericyte/Fibroblast/ Vascular Smooth Muscle Vascular Endothelial Cell Sunitinib Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation Inhibition of RCC pathogenesis and progression

  11. Best Response By RECIST Motzer R ,J Clin Oncol. 2006 Jan 1;24(1):16-24 Motzer R, JAMA. 2006 Jun 7;295(21):2516-24

  12. Two Types of Response Observed 2-Central Necrosis 1-Shrinkage Week0 Week12 Week32

  13. Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma Pre-planned analysis of primary endpoint PFS R A N D O M I Z A T I O N Sunitinib (N=375) N=750 Stratification Factors • LDH 1.5 vs >1.5xULN • ECOG PS 0 vs 1 • Presence vs Absence of Nephrectomy IFN- (N=375) 90% power to detect a 35% improvement in median PFS from 20 weeks to 27 weeks (4.6 months to 6.2 months; 2-sided unstratified log-rank test; significance level 0.05) Motzer R, ASCO 2006

  14. Outcome Summary *Sunitinib vs IFN-: P <0.000001

  15. Progression-Free Survival (Independent Central Review) 1.0 Sunitinib 0.9 Median: 11 months (95% CI: 10–12) 0.8 IFN- 0.7 Median: 5 months (95% CI: 4–6) 0.6 Progression Free Survival Probability 0.5 0.4 0.3 0.2 Hazard Ratio = 0.415 (95% CI: 0.320–0.539) 0.1 P <0.000001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (Months) No. at Risk Sunitinib:23590322 No. at Risk IFN-:15242180

  16. 1.0 0.9 0.8 0.7 0.6 Overall Survival Probability 0.5 0.4 0.3 Sunitinib (n=375) Median not reached 0.2 Hazard Ratio = 0.65 IFN- (N=375) Median not reached 0.1 (95% CI: 0.449–0.942) P = 0.0219* 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (Months) Overall Survival No. at Risk Sunitinib:34119084151 No. at Risk IFN-:29616266100 *The observed p-value did not meet the pre-specified level of significance for this interim analysis

  17. Laboratory Abnormalities * Greater frequency, P <0.05

  18. Treatment-Related Adverse Events * Greater frequency, P <0.05

  19. Conclusions • Sunitinib is a new reference standard for the first-line treatment of RCC • Mechanism-directed RCC therapy based on tumor-specific molecular features is validated • Sunitinib is a new treatment option providing hope for patients with RCC Motzer R, ASCO 2006

  20. Global ARCC Trial A Phase 3, Randomized, 3-Arm Study of Temsirolimus (TEMSR) or Interferon-Alpha (IFN) or the Combination of TEMSR + IFN in the Treatment of First-Line, Poor-Risk Patients With Advanced Renal Cell Carcinoma G Hudes, M Carducci, P Tomczak, J Dutcher, R Figlin, A Kapoor, E Staroslawska, T O’Toole, S Kong, and L Moore 2006 ASCO Presentation

  21. Temsirolimus: Mechanism of Action GrowthFactors extracellular membrane PI-3 Kinase PI-3K/AKT Activation PTEN PTEN Loss Akt mTOR Temsirolimus S6K 4EBP1 Translation cMyc overexpression Cyclin D1 overexpression HIF-1, HIF-2 overexpression

  22. Global ARCC Trial IFN: escalating to 18 MU SC TIW R A N D O M I Z E Stratification by: n = 207 TEMSR: 25 mg IV QW n = 209 TEMSR: 15 mg IV QW + IFN: 6 MU TIW n = 210 Phase 3 Study of TEMSR and IFN in Advanced RCC • 626 patients with advanced metastatic RCC with poor-risk features • 209 sites (26 countries) • Geographic Regions: • WEU + AU + CA (22%) • US (30%) • EEU + Other (48%) • Nephrectomy: • Yes (67%) • No (33%)

  23. Overall Survival by Treatment Arm Arm 2: Temsirolimus Probability of Survival Arm 1: IFN Arm 3: IFN + Temsirolimus Time from Randomization, Months

  24. Global ARCC Trial Overall Survival by Treatment Arm *O’Brien-Fleming boundary for significance = 0.0155

  25. Global ARCC Trial • Thisisthefirststudytodemonstrateastatisticallysignificantimprovementinsurvivalinadvancedpoor-riskRCCpatients • Theresultsofthisglobalphase3trialdemonstratethatmTORisanimportanttherapeutictargetinRCC

  26. P P Raf kinase Ras MEK Sorafenib (BAY 43-9006) Inhibits survival of tumor cells Targets proliferation + angiogenesis GF P P P P Potent inhib c-RAF Other targets: - VEGFR-2 - VEGFR-3 - FLT-3 - PDGFR - c-kit BAY 43-9006 ERK Nucleus

  27. Sorafenib (BAY 43-9006)Randomized Discontinuation Trial Schema (n=202) > 25% Shrinkage Continue BAY 43-9006Open Label BAY 43-9006 >-25% to <25% Randomized Tumor Assessment 12 Week Induction Placebo* > 25% Growth Off study Baseline 12 weeks 24 weeks Ratain, ASCO 2005 Eisen T, Br J Cancer. 2006 Sep 4;95(5):581-6 * May cross over to BAY 43-9006

  28. (1:1) Randomization n~905 Stratification • Motzer criteria • Country TARGETs: Pretreated Patients Study Design Eligibility criteria • Histologically/cytologically confirmed, unresectable and/or metastatic disease • Clear-cell histology • Measurable disease • Failed one prior systemic therapy in last 8 months • ECOG PS 0 or 1 • Good organ function • No brain metastasis • Poor risk Motzer group excluded Sorafenib400 mg bid • Major endpoints • Survival (alpha=0.04) • PFS (alpha=0.01) Placebo Treatment Approaches in RCC Global Evaluation Trial Escudier, ASCO and ECCO 2005

  29. Maximum Percent Reduction in Tumor Measurement* Placebo Sorafenib 100 80 60 Maximum Percent Reduction in Tumor Measurement 40 20 250 100 150 200 250 0 50 100 150 200 50 -20 Patient number Patient number -40 -60 -80 -100 20% 74% *Independently assessed measurements available for 574 patients

  30. 1.00 0.75 Proportion of patients progression free 0.50 0.25 0 0 2 4 6 8 10 12 14 16 18 20 Time from randomization (months) TARGETsProgression-Free Survival Benefit Median PFS Sorafenib = 5.5 months Placebo = 2.8 months Hazard ratio (S/P) = 0.51 Sorafenib 2.8 mos 5.5 mos Placebo Censored observation *Based on investigator assessment Escudier, ECCO, October 2005

  31. Overall Survival Analysis 6 Months Post-crossover* 1.00 0.75 Survival distribution function 0.50 MedianOS Placebo=15.9months Sorafenib=19.3months Hazardratio=0.77(95%CI:0.63,0.95) p-value=0.015** 0.25 0 0 5 10 15 20 25 Time from randomization ( months) Of 367 events, a total of 122 deaths were reported in the low-risk and 245 in the intermediate-risk groups *At 367 events, Nov. 30, 2005**O’Brien-Fleming stopping boundary for significance was p<0.0094 Eisen T, ASCO 2006

  32. Pazopanib Preclinical Summary • Potent Multi-target tyrosine kinase inhibitor • Selectively inhibits • VEGFR-1, 2 and 3 • PDGFR- and - • c-kit • IC50 of 10, 30, 47, 71, 84 and 74 nM respectively (high affinity for all receptors)

  33. Pazopanib Phase III Trial (VEG105192) Design (n=350) R A N D O M I Z E Eligibility Prior cytokines* Stratification ECOG PS 0 vs 1 Prior nephrectomy Pazopanib 800mg qd Matching Placebo 2:1 1° Endpoint PFS, 2° survival and RR

  34. Adjuvant Therapy • ASSUREtrial(n=1,332)IntergroupECOG.AfternephrectomypatientsarestratifiedbyUISSstage(II-V)andhistologicsubtype(clearcellornonclearcell)among3armsto1yearofadjuvantsunitinib,sorafeniborplacebo.Theprimaryendpointisdiseasefreesurvival. • SOURCEtrial(n=1,420),MRC.Afternephrectomy,patientswithhigh-andintermediate-riskRCCwillberandomizedto3yearsofsorafenib,1yearofsorafeniband2yearsofplacebo,or3yearsofplacebo.Theprimaryendpointismetastasesfreesurvival.

  35. Unaddressed Questions • Is any one agent better than the other? • Are they cross-resistant? • Are the studied doses/schedules optimal? • Can combination therapy improve outcome? • Can novel imaging modalities identify “benefiting” patients? • What is the role of these agents in the adjuvant setting? • What is the role of these agents in non-clear cell RCC?

  36. What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope? • OralVEGFR/PDGFRandmTORinhibitorsareextremelyactiveinclearcellRCC • TheyaremuchbettertoleratedthanIFNorIL2butthereistoxicityassociatedwiththeseagents • Theseagentshavechangeshowwetreatthisdisease • Completeresponsesareextremelyrareandthevastmajorityofpatientseventuallyprogress

  37. What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope? • Strong rationale for targeting multiple pathways particularly angiogenesis in patients with advanced RCC • Novel signal transduction inhibitors have demonstrated an increase in PFS in 1st and 2nd line and an increase in survival in poor risk therapy naive patients • Some of these agents have been recently approved and others are still awaiting trial results • They are defining a new standard of care

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