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 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

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

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

VEGF-B VEGF-A VEGF-E VEGF-C VEGF-D Bevacizumab binds VEGF A 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) The VEGF Family Are Critical Tumor-Secreted Angiogenic Factors

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

Survival Update Yang, NEJM 2003

CALGB 90206: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=700) IFNα 9MU TIW IFNα 9MU TIW + Bevacizumab 10 mg/KG D1 and D15 VS R A N D O MI Z E 1° Endpoint: Survival, 89% Power to Detect Improvement in OS of 13 to 17 mos No prior Rx Stratify Motzer Score

Europe: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=638) IFNα 9MU TIW + placebo IFNα 9MU TIW + Bevacizumab 10 mg/KG D1 and D15 VS R A N D O MI Z E 1° Endpoint: Survival, 80% Power to Detect Improvement in OS of 13 to 17 mos Nephrectomy Clear Cell > 50%

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

Best Response By RECIST Response Trial 1 n (%) Trial 2 n (%) Patients63106 Overall response Complete response Partial response 25 (40) 0 25 (40) 44 (42) 1 (1) 43 (41) Stable disease (SD) 3 months18 (28)22 (21) Progression, SD <3 months16 (25)33 (31) Not evaluable4 (6)7 (7) Motzer R,J Clin Oncol Jan 1;24(1):16-24 Motzer R, JAMA Jun 7;295(21):

Two Types of Response Observed Week 32 1-Shrinkage 2-Central Necrosis Week 0 Week 12

Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma N=750 Stratification Factors ● LDH  1.5 vs >1.5xULN ● ECOG PS 0 vs 1 ● Presence vs Absence of Nephrectomy RANDOMIZATIONRANDOMIZATION Sunitinib (N=375) 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) Pre-planned analysis of primary endpoint PFS Motzer R, ASCO 2006

Outcome Summary Sunitinib IFN-  Median Progression-free Survival*, mos (95% CI) Independent Review Investigator 11 (10-12) 11 (8-14) 5 (4-6) 4 (4-5) Objective response*, % (95% CI) Independent Review Investigator 31 (26-36) 37 (32-42) 6 (4-9) 9 (6-12) SafetyAcceptable— Patient-reported OutcomesSuperior— *Sunitinib vs IFN-  : P <

No. at Risk Sunitinib: No. at Risk IFN-  : Time (Months) Progression Free Survival Probability Sunitinib Median: 11 months (95% CI: 10–12) IFN-  Median: 5 months (95% CI: 4–6) Hazard Ratio = (95% CI: 0.320–0.539) P < (Independent Central Review) Progression-Free Survival

No. at Risk Sunitinib: No. at Risk IFN-  : *The observed p-value did not meet the pre-specified level of significance for this interim analysis Overall Survival

Laboratory Abnormalities Sunitinib (%) IFN-  (%) EventAll gradeGrade 3/4All gradeGrade 3/4 Neutropenia 7211/1*467 Anemia 71 3/<1644/<1 Thrombocytopenia 65 8*210 Lymphopenia * Hypophosphatemia 364/<1326 Hyperamylasemia 31 4/1*282/<1 * Greater frequency, P <0.05

Treatment-Related Adverse Events Event Sunitinib (%) IFN-  (%) All gradeGrade 3/4All gradeGrade 3/4 Fatigue517 11/<1* Diarrhea535*13 0 Nausea Stomatitis251 2<1 Hypertension248* 1<1 Hand-foot syndrome205* 1 0 Ejection fraction decline Pyrexia Chills Myalgia 5<116<1 Flu-like symptoms 10 8<1 * Greater frequency, P <0.05

Motzer R, ASCO 2006 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

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

Temsirolimus: Mechanism of Action PI-3 Kinase Akt mTOR PTEN S6K4EBP1 HIF-1 , HIF-2  overexpression PTEN Loss Translation PI-3K/AKT Activation cMyc overexpression extracellular membrane Cyclin D1 overexpression Temsirolimus Temsirolimus Growth Factors

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

Overall Survival by Treatment Arm Arm 3: IFN + Temsirolimus Arm 2: Temsirolimus Arm 1: IFN Time from Randomization, Months Probability of Survival ParameterIFN Arm 1 TEMSR Arm 2 TEMSR + IFN Arm 3 n ComparisonsArm 2:Arm 1Arm 3:Arm 1 Stratified Log-Rank p

IFN Arm 1 n=207 TEMSR Arm 2 n=209 TEMSR + IFN Arm 3 n=210 Deaths, n Median Survival, months (95% CI) 7.3 ( ) 10.9 ( ) 8.4 ( ) Arm 2: Arm 1Arm 3: Arm 1 Increase in Median Survival 49%15% Hazard Ratio (95% CI) 0.73 ( ) 0.95 ( ) Stratified Log-Rank p0.0069* Overall Survival by Treatment Arm *O’Brien-Fleming boundary for significance = Global ARCC Trial

This is the first study to demonstrate a statistically significant improvement in survival in advanced poor-risk RCC patients The results of this global phase 3 trial demonstrate that mTOR is an important therapeutic target in RCC Global ARCC Trial

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

* May cross over to BAY Week Induction >-25% to <25% Randomized > 25% Shrinkage Continue BAY Open Label > 25% Growth Off study BAY Placebo* Tumor Assessment Baseline12 weeks24 weeks Ratain, ASCO 2005 Eisen T, Br J Cancer Sep 4;95(5):581-6 Sorafenib (BAY ) Randomized Discontinuation Trial Schema (n=202)

Sorafenib 400 mg bid Placebo Major endpoints Survival (alpha=0.04) PFS (alpha=0.01) (1:1) Randomization n~905 Stratification Motzer criteria Country 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 Escudier, ASCO and ECCO 2005 Treatment Approaches in RCC Global Evaluation Trial TARGETs: Pretreated Patients Study Design

*Independently assessed measurements available for 574 patients Placebo Sorafenib 74%20% Maximum Percent Reduction in Tumor Measurement Patient number Patient number Maximum Percent Reduction in Tumor Measurement*

Proportion of patients progression free Time from randomization (months) Censored observation Placebo Sorafenib Median PFS Sorafenib = 5.5 months Placebo = 2.8 months Hazard ratio (S/P) = 0.51 *Based on investigator assessment Escudier, ECCO, October mos2.8 mos TARGETs Progression-Free Survival Benefit

*At 367 events, Nov. 30, 2005 **O’Brien-Fleming stopping boundary for significance was p< Time from randomization ( months) Survival distribution function Median OS Placebo = 15.9 months Sorafenib = 19.3 months Hazard ratio = 0.77 (95% CI: 0.63, 0.95) p-value = 0.015** Of 367 events, a total of 122 deaths were reported in the low-risk and 245 in the intermediate-risk groups Eisen T, ASCO 2006 Overall Survival Analysis 6 Months Post-crossover*

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)

Pazopanib 800mg qd Matching Placebo RANDOMIZERANDOMIZE 1° Endpoint PFS, 2° survival and RR 2:1 Pazopanib Phase III Trial (VEG105192) Design (n=350) Eligibility Prior cytokines* Stratification ECOG PS 0 vs 1 Prior nephrectomy

Adjuvant Therapy ASSURE trial (n=1,332) Intergroup ECOG. After nephrectomy patients are stratified by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) among 3 arms to 1 year of adjuvant sunitinib, sorafenib or placebo. The primary endpoint is disease free survival. SOURCE trial (n = 1,420), MRC. After nephrectomy, patients with high- and intermediate-risk RCC will be randomized to 3 years of sorafenib, 1 year of sorafenib and 2 years of placebo, or 3 years of placebo. The primary endpoint is metastases free survival.

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?

What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope? Oral VEGFR/PDGFR and mTOR inhibitors are extremely active in clear cell RCC They are much better tolerated than IFN or IL2 but there is toxicity associated with these agents These agents have changes how we treat this disease Complete responses are extremely rare and the vast majority of patients eventually progress

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