Advanced RCC 2008 : Therapeutic Approaches to Advanced Disease Ronald M. Bukowski MD Emeritus Consulting Staff CCF Taussig Cancer Center Professor of Medicine CCF Lerner College of Medicine of CWRU

ANDREW NOVICK (1948 – 2008) In Memorium :

Treatment of Advanced RCC Development of therapeutic approaches Systemic treatment approaches: - Untreated patients - Treatment refractory patients - Combination development - Sequential approches Biomarker assessment Summary

Developments in Therapy mRCC s1990s2000s Cytokines: Immunotherapy: IL-2 and IFN-α first to report activity 1 High-dose IL-2 FDA-approval: Phase II data VHL tumor suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors 2 VEGFr TKI FDA-approval: Sorafenib based on Phase III and Sunitinib based on Phase II data Temsirolimus FDA-approval: based on Phase III data Bevacizumab + IFN-  : EMEA-approval 1. Snow M et al. Urology 1982; 20:177– Latif F et al. Science 1993; 260:1317– Yang J et al. N Engl J Med July 31; 349(5): Bevacizumab Data established activity of anti- angiogenic agents in RCC 3 European approvals 2006: Sorafenib approval : Sunitinib approval : Temsirolimus approval Inpharma, Volume 1, Number 1616, , pp (1) 2008: Bevacizumab approval Inpharma, Volume 1, Number 1620, , pp (1) Prognostic Factors : described

Patient Subgroups - Metastatic RCC: Characteristics Affecting Therapy Decisions  Histologic variety : - Clear cell / clear cell component - Non-clear cell carcinoma - Sarcomatoid differentiation  Prior therapy status : - Treatment naïve - Prior therapy ( ? Number of regimens & therapy type) - Treatment refractory  Prognostic categories: - Favorable / intermediate - Poor - Role of prior therapy

4.5 months PR (11%) 14.6 months IR (70%) months FR (19%) 4.9 months PR (20%) 13.8 months IR (62%) months FR (18%) CCF Patients MSKCC Patients Prognostic Factor Models : Survival Advanced Renal Cell Carcinoma – Cytokine Era Favorable Risk (FR) Intermediate Risk (IR) Poor Risk (PR) Risk Factors : PS < 80%, LDH ≥1.5x ULN,↑ corrected Ca ++, DFI<1 yr, Hgb<LLN Risk Group Med. SurvivalRisk Group Med. Survival

RCC : Poor Risk Patients  Clinical criteria to define a poor risk population (previously treated vs untreated) are available  Use in a clinical trial setting and/or to determine therapy is reasonable  It is unclear whether this group of patients can be defined biologically : - VEGF levels - Histology - Molecular markers

Untreated RCC Patients First Line Therapy – no prior systemic treatment Formerly cytokine therapy, but currently < 10% patients receive IL-2 or IFNα Series of phase 3 trials – comparator arm IFNα Agents investigated : Sunitinib Bevacizumab Temsirolimus Sorafenib (phase 2)

Sunitinib versus Interferon : Phase 3 Trial (N=750) (n=375) Sunitinib 50 mg PO daily on 4/2 schedule IFN-α 3 MU sc tiw 1st week, 6 MU sc tiw 2nd week, 9 MU sc tiw 3rd week thereafter Eligibility Criteria ≥ 18 years of age Metastatic RCC Clear cell histology No prior systemic treatment Measurable disease by RECIST ECOG PS of 0 or 1 Adequate organ function RANDOMIZATIONRANDOMIZATION Motzer RJ, et al. N Engl J Med 2007;356:115–124 Progression Free Survival Overall Survival : Intent to Treat Primary Endpoint : PFS Motzer RJ, et JCO (submitted) 2008

Phase III First-Line Sunitinib vs. IFN: Efficacy Summary Figlin, ASCO 2008, abstract # Log Rank test; 2 Independent review ; 3 Investigator assessed Response of Pulmonary Metastases Response of Pancreatic Metastases Sunitinib (n=375) IFNα (n=375) p Value 1 ORR % 2 39% (47%) 3 8% (12%) 3 < Median PFS mos 5.0 mos <

Sunitinib vs IFN  in First-Line mRCC: PFS and Survival by MSK Risk Status Risk Group Median PFS (95% CI)Median OS (95% CI) N (%) Sunitinib (N=375) IFN  (N=375) N (%) Sunitinib (N=375) IFNα (N=375) Favorable (0 risk factors) 264 (35%) 14.5 mo ( ) 7.9 mo ( ) 270 (36%) NR* 91%/72% NR* 92%/76% Intermediate (1-2 risk factors) 421 (56%) 10.6 mo ( ) 3.8 mo ( ) 431 (57%) 20.7 mo** ( ) 15.4 mo** ( ) Poor (≥3 risk factors) 48 (6%) 3.7 mo ( ) 1.2 mo ( ) 49 (7%) 5.3 mo § ( ) 4.0 mo § ( ) Motzer. ASCO 2007 (abstr 5024); JCO 2008 (submitted) * Not reached; % alive at 1 and 2 years **HR 0.787, p = § HR 0.66, p = 0.173

Bevacizumab : Phase 3 Trials in Renal Cell Carcinoma Patient Population : Metastatic Clear Cell Ca No Prior Systemic Therapy CALGB N = 732 BO17705 (Avoren) N = 649 IFN  9.0 MU TIW + Bevacizumab 10 mg/kg d1,15 zRandomize IFNα 9.0 MU TIW + Bevacizumab 10 mg/kg d1,15 IFNα 9.0 MU TIW + Placebo 1 Rini, B : GU Malignancy Symposium, ASCO 2/08; 2 Escudier, B et al : The Lancet, 2007 Therapy IFNα IFNα + Bev IFNα ORR % 13.1% 25.5% 31.0% 13% PFS (mos) FR IR PR CALGB AVOREN 2

Bevacizumab ± IFN  in First-Line mRCC: Risk Group Analysis GroupN Bevacizumab + IFN  Placebo + IFN  IFNα Bevacizumab N + IFNα Progression Free Survival All Patients mo5.4 mo 5.2 mo 8.5 mo 732 Favorable 180 (28%) 12.9 mo7.6 mo 5.7 mo 11.1 mo 192 Intermediate 363 (56%) 10.2 mo4.5 mo 5.3 mo 8.4 mo 465 Poor542.2 mo2.1 mo 2.6 mo 3.3 mo 75 Median OS649Not reached19.8 mo TE TE 732 *Patients with measurable disease only. DOR=duration of response; NR=not reported. Escudier. Lancet. 2007;370:2103., Rini ; ASCO, 2/08, San Francisco (26%) (7%) (64%) (10%)

*Modified MSK poor risk; † Stratification by Country and Nephrectomy status IFN 3MU-18MU (n=207) CR + PR - 7% CR + PR + SD ‡ - 29% Med. OS 7.3 months § IFN 6MU + TEM 15mg QW (n=210) CR + PR – 11% CR + PR + SD – 41% Med. OS 8.4 months TEM 25mg QW (n=209) CR + PR – 9% CR + PR + SD – 46% Med. OS 10.9 months § Randomize † 3/6 Poor Risk Features LDH>1.5xULN Hgb < LLN Ca ++ (cor) >10 KPS <70% DFI <1 year Multiple sites of metastases Metastatic RCC (N=626) Temsirolimus : Phase III Trial in Poor Risk RCC* Proportion Surviving Months Surviving IFN TEMSR TEMSR + IFN (n=207) (n=209) (n=210) Arm 1 Arm 2 Arm 3 Median OS (mos) Comparisons Arms 2 : 1 Arms 3:1 Stratified Log Rank p TEMSR IFNα IFNα + TEMSR § SD≥16 wks p=

Phase III Trial Temsirolimus vs. IFN-α: Subset Analyses 1 HR : hazard ratio; 2 MSK prognostic groups Dutcher et al. ASCO, Median Survival IFN-αTEMSRHR 1 Intermediate Risk (n=51)13.0 (n=64)1.17 Poor Risk (n=156)10.2 (n=145)0.76 Clear Cell 8.2 (n=170)10.6 (n=169)0.85 Other 4.3 (n=36)11.6 (n=37)0.55

Escudier ASCO 2008 Figlin ASCO 2008 Multiple studies Temsirolimus Gore ASCO 2008 Kane Advances in PFS : Advanced RCC Median Progression-free survival Time (months) Best supportive care INF-α+ IL-2+5-FU Temsirolimus Sunitinib Bevacizumab + INF-α Sorafenib – Sorafenib Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Naxavar PI, Figlin et al. ASCO 2008, Escudier ASCO 2008 Bevacizumab + INF-α CALGB INF-α alone Present

Treatment of the Refractory Patient Nature of previous therapy : Cytokines VEGFR / VEGF Inhibitors mTOR Inhibitors – no data Role of prognostic factors - ? Are all refractory pts. poor risk Definitions of resistant and refractory - Biology of TKI and VEGF inhibitor resistance

Parameter p valueHR95% CI Alkaline Phosphatase – Corrected calcium < – LDH – Number of metastatic sites – Time from nephrectomy to metastatic disease < * 66 patients are missing data on one of the risk factors. Multivariate Analysis : Prognostic Factors Cytokine Refractory Patients Randomized trial in cytokine refractory patients (n = 300) Treatment arms : AE 941 (shark cartilage extract) vs placebo Median PFS : AE 941 – 58 days, placebo – 57 days Median OS : AE – 379 days, placebo – 376 days Escudier et al, J Urol, – No. Factors Med. OS (mos) ≥ 3 3.5

Metastatic RCC Cytokine Failure : Comparative Results Sorafenib 1 Sunitinib 2 Bevacizumab 3 Dose 400 mg BID 50 mg/d 4/6 wks 10 mg/kg IV q2wks Type Trial Phase 3 Phase 2 Phase 2 Pt. Nos ORR (%) 10% 34% 10% PFS 5.8 mos 8.4 mos 4.8 mos OS 17.3 mos 19.9 mos 15.5 mos 1 Bukowski et al, ASCO, 2007 ; 2 Rosenberg et al, ASCO, 2007; 3 Yang et al, NEJM, 2002.

Phase III Trial of Everolimus vs. Placebo: Results Motzer, ASCO 2008, abstract LBA5026 RANDOMIZERANDOMIZE Eligibility criteria: Metastatic RCC with clear cell histology Measurable disease Prior bevacizumab and cytokines permitted Stratify by: Prior VEGFR TKI (1 vs. 2) MSKCC risk group (favorable vs. intermediate vs. poor) Everolimus 10 mg/day p.o. BSC Placebo 10 mg/day p.o. BSC Primary endpoint: PFS Secondary endpoints: OS, safety, response, QOL (n = 410) 2: Percent Progression Free Months Hazard Ratio = % CI (0.22, 0.40) Median PFS : Everolimus 4.0 mos Placebo 1.9 mos P < Everolimus Placebo EverolimusPlacebo ORR 1% 0 SD 63% 32% 6 mo PF (%) 26% 2% Efficacy Summary

Future Directions RCC Trteatment Dose / schedule exploration Combination therapy Sequential treatment strategies Role of biomarkers? Novel agents – future role Adjuvant / neo-adjuvant treatment

Probability of PR or CR in mRCC Increased with Mean Daily Sunitinib Exposure P=0.023 for AUC AUCss sunitinib (ughr/mL) Probability of a response Mean 95% CI Houk et al., ASCO 2007

Sunitinib Continuous Schedule Evaluable Patientsn=103 Objective response, n (%) Partial response 15 (14.6%) Stable disease ≥ 3 mos68 (66.0) Progressive disease14 (13.6) Not evaluable/missing6 (5.8) Median PFS8.3 months (Srinivas et al., ASCO 2007) Phase 2 trial has examined activity & toxicity of sunitinib 37.5 mg/d given continuously Phase 3 trial in progress examining sunitinib 50 mg/d 4/2 schedule versus 37.5 mg/d continuous schedule (400 pts)

Why pursue combination therapy with targeted agents? Limitations of present therapy- ultimately uniform “resistance” May induce “better” responses –More complete responses with potential long-term disease-free remissions –More durable remissions- extend them from 8-16 months to months May allow use of less of each drug and bring costs down May diminish toxicity when both used at lower dose

25 mTOR Inhibitor (CCI-779, RAD001) HSP-90 antagonist (17-AAG), HDACI Bevacizumab Bevacizumab, VEGF Trap AZD2171, Sunitinib, Sorafenib, Axitinib, Pazopanib, etc HIF VEGF KDR Vertical Combinations- Targeting of VEGF at multiple levels O2O2 VEGF

Phase 1 Trials : Sunitinib Combinations Since sunitinib is the most active approved agent, examination of combination data is instructive Cytokines – IFNα Targeted agents : - Bevacizumab - Temsirolimus - Everolimus

Phase 1 Trial Sunitinib + IFNα 25 treatment naïve patients accrued Study schema : IFNα 3.0 → 9.0 MU TIW SQ Sunitinib 37.5 mg/d 4/2 wks Sunitinib 50 mg/d 4/2 wks 13 pts. 12 pts Toxicity – 25/25 pts. Experienced ≥ Gr 3/4 adverse events - Fatigue : 100% (≥ Gr 3 28%) - Thrombopenia : 32% (≥ Gr 3 20%) - Neutropenia : 48% (≥ Gr 3 36%) Efficacy – probably no different than sunitinib monotherapy - PR 3/25 (12%) - SD 20/25 (80%) Motzer et al, ASCO 2007

Phase 1 Trials Sunitinib + Bevacizumab Two trials conducted in USA – sites Memorial Cancer Center and Cleveland Clinic Cancer Center Site MSK CCF Patients Eligible RCC Solid Tumors Dose Levels 3 5 Patients Entered (RCC-6) Previous Rx 3/25 (12%) 27/38 (71%) Median No. Cycles (Range) 5 (NS) 2.5 (1-11) ORR (CR + PR) 13/25 (52%) 6/24 (25%) (3/6 RCC pts)

Phase 1 Trials : Sunitinib + Bevacizumab Study Designs Sunitinib Dose (mg/d) MSK 1 CCF 2 Bevacizumab Dose (mg/kg ) MSK CCF Cohort Cohort Cohort Cohort Cohort Sunitinib 4 weeks Sunitinib 4 weeks B B B B B B B B = bevacizumab 1.Feldman, 2008 ASCO 2. Cooney et al, 2008 ASCO

Phase 1 Trials Sunitinib + Bevacizumab : Toxicity Different patterns of toxicity reported : Toxicity Gr 1/2 MSK CCF Gr 3 MSK CCF Gr 4 MSK CCF Overall MSK CCF Fatigue80% 50% 8% 8% 4% - 92% 58% Hypertension32% 14% 48% 24%12% 3%92% 41% Thrombopenia60% 40% 24% 8% % 48% MAHA (Microangiopathic hemolytic anemia) 8% -12% % -

Phase 1 Trial Sunitinib + Bevacizumab : Toxicity MSK Trial 5 patients with findings suggesting an acquired MAHA (TTP like disorder) Hematologic findings : - Fragmented RBC’s and anemia (Hgb 7.8 to 11.2) - ↓ serum haptoglobin - Thrombopenia (26 to 52,000) ↑ Serum creatinine (1.5 to 2.6 mg/dL) 2/5 patients with RPLS

Conclusions- Sunitinib + Bevacizumab While activity against was observed across multiple RCC histologies, treatment at full doses was poorly tolerated in the Phase 1 trial in RCC pts. Chronic therapy resulted in a high proportion of patients experiencing Grade 3/4 hypertension The dose level of sunitinib 50 mg with bevacizumab 10 mg/kg as is not recommended for administration to RCC patients Reasons for differences between these 2 trials : - Patient population : RCC vs solid tumors - Differences in design with CCF trial using conservative dose escalation - Median duration of therapy different 32

Phase 1 Trial Sunitinib + Temsirolimus 3 patients with metastatic RCC (≤ 2 prior treatment regimens accrued Study schema : first cohort treated at following dose levels Temsirolimus 25 mg IV q1week + Sunitinib 25 mg/d 4/2 weeks 2/3 patients in first cohort experienced Gr 3 toxicity, no further patients accrued Toxicity – rash, thrombocytopenia Further investigation of combination not recommended Patel et al, manuscript in press Clin GU Cancer

Issues with Combination Therapy with Targeted Agents Is combination better than sequential therapy? –Information on results of sequencing and efficacy of second line targeted agent –Sunitinib is active in Bevacizumab- failures –Axitinib active in Sorafenib failures –Everolimus active in TKI failures –Sorafenib and Sunitinib can induce benefit in patients that fail the other Increase Toxicity? Increase Cost? How to test this concept?

RECORD 3 Phase II Crossover Trial of RAD001 and Sunitinib Patients : metastatic RCC, clear cell histology, no prior systemic therapy Stratified by MSK risk criteria Primary endpoint: combined progression-free survival (PFS 1 + PFS 2) Secondary endpoint: Overall survival, safety, efficacy, QoL 35 MSK = Memorial Sloan-Kettering Cancer Center; QoL = Quality of life. RAD mg/day Sunitinib 50 mg/day, 4 wk on/2 wk off Randomized 1 : 1 Sunitinib 50 mg/day, 4 wk on/2 wk off RAD mg/day Disease progression PFS 1 PFS 2

Biomarkers Clear Cell Ca : VHL & VEGF Pathway Adapted from Linehan, et al. J Urol 2003 Hypoxia HIFα HIFα accumulation VEGF TGFα, PDGF Angiogenesis Autocrine growth stimulation VHL protein VHL complex Tagged for degradation Normoxia HIFα degradation VHL mutation –prevents interaction with HIFα and therefore its degradation –causes HIFα accumulation and subsequent release of proangiogenic factors VEGF = vascular endothelial growth factor VHL = von Hippel-Lindau; HIF = Hypoxia-inducible factors TGF = transforming growth factor; PDGF = platelet-derived growth factor 1 2 3

Time (months) HR = % CI: 0.49–0.83 Low baseline VEGF (≤131pg/mL)High baseline VEGF (>131pg/mL) TARGET: Biomarker Analysis (Phase 3 Trial Sorafenib vs Placebo PFS (% patients) Sorafenib (n=180): 5.5 months Placebo (n=176): 3.3 months Sorafenib (n=184): 5.5 months Placebo (n=172): 2.7 months HR = % CI: 0.38–0.62 Both high and low baseline VEGF groups benefited from sorafenib Both high and low baseline VEGF groups benefited from sorafenib Time (months) PFS (% patients)

RESPONSE AND VHL STATUS Treatment TKI’s 3, Bevacizumab Pazopanib ORR Response 45/122 (37%) 32/70 (46%) VHL Status : Mutated + Methylated 71/122 (58%) 63/70 (90%) Wild Type 51/122 (32%) 7/70 (10%) ORR (CR + PR) : Mutated + Methylated 29/71 (41%) 29/63 (46%) Wild Type 16/51 (31%) 3/7 (42%) Factor Choueiri et al 1 Hutson et al 2 1 Choueiri et al, ASCO 2007; 2 Hutson et al, ASCO 2008 ; 3 Sunitinib - 63, axitinib - 15, sorafenib -28

Efficacy and VHL Status by Specific Drug VHL StatusSunitinibAxitinibSorafenib Bevacizumab Mutated18/32 (56%) 3/9 (33%) 2/10 (20%) 4/9 (44%) Methylated2/6 (33%)0/1 (0%)0/2 (0%)0/3 (0%) Wild-type13/25 (52%) 3/5 (60%) 0/16 (0%)0/5 (0%) 16/30 (53%) 0/21 (-) PFS - proportion Months WT – 9 mos Methylated – 11 mos Mutated – 12 mos Overall Response Rates Progression Free Survival Choueiri et al, 2007

HIF2α Tumor Levels & Response to Sunitinib in Clear Cell Ca 43 tumors - sunitinib treated patients : - HIF1α and HIF2α levels (immunoblot analysis) - Clinical responses (CR/PR vs SD/PD) HIF2α levels correlated with response Level HIF2α CR/PR (n=18) SD/PD (n=25) %ORR None % Low % High % HIF2α levels : low 50% of control PFS also correlated with HIF2α levels: p=0.001 Patel HR, et al: ASCO 2008 (abst 5008)

RCC Treatment Alogrithm : 2008 * Setting Therapy (Level 1) Options (≥ Level 2) Treatment Naïve Patient MSK Risk : Good or Intermediate MSK Risk : Poor Treatment Refractory Patient ( ≥ 2 nd Line) Cytokine Refractory Refractory to VEGF/VEGFR Inhibitors Sunitinib Bevacizumab + IFNα HD IL-2 Temsirolimus Sunitinib Sorafenib Sunitinib Bevacizumab Everolimus Investigational ?Sequential TKI’s or VEGF Inhibitor *Adapted from M Atkins, ASCO 2006 ; R Bukowski ASCO 2007; R Rini ASCO 2008 Refractory to mTOR inhibitors Investigational

Summary Increased understanding of angiogenesis both in normal and tumor-associated situations has led to introduction of avariety of angiogenesis inhibitors and other novel molecular targeted therapies. Clear cell RCC is a model for the effects of various angiogenesis inhibitors A variety of multi-kinase and VEGF inhibitors including bevacizumab, have significant activity in recently completed phase 2 & 3 clinical trials : - TKI’s (FDA approval) : sunitinib (↑PFS, ORR), sorafenib (  PFS,? survival)  - VEGF inhibitor : bevacizumab + IFNα (↑ PFS, ORR)  - mTOR inhibitor (FDA approval): temsirolimus (↑ OS, poor  risk)

VEGFR TKI’s : Phase 2 Results in Advanced RCC Agent Pt. # CR+PR (%) SD (%) PFS (mo) Axitinib 1 : Cytokine Ref (44%) 12 (23%) NS Sorafenib Ref (21%) 21 (34%) NS Pazopanib (35%) 103 (46%) 11.9 Cediranib (35%) 19 (51%) Rini et al, ASCO 2006 & 2007; 2 Hutson et al, ASCO 2008; 3 Sridhar et al, ASCO 2008

Phase II Trial: Sorafenib vs IFN  in First- Line mRCC Escudier et al, JCO 2008 (accepted) Primary endpoints: Period 1: PFS (sorafenib vs IFN  ) Period 2: PFS and clinical benefit Sorafenib 600 mg bid (N=44) Sorafenib 400 mg bid (N=50) Previously untreated clear cell RCC (N=189) PROGRESSION Period 1 Period 2 Sorafenib 400 mg bid (N=97) IFN  9 MIU tiw (N=92) Sorafenib=5.7 months IFN  =5.6 months HR (0.883 (95% CI: ) P=0.504 (log-rank test) PFS (% of patients) Time From Randomization (months) Efficacy Summary Sorafenib IFNα Number pts % Pts.↓ tumor 68% 39% CR / PR (%) 0 / 5.2% 1% / 7.6% SD 74.2% 55.4% PFS 5.7 mos 5.6 mos

Phase 3 Trials : Axitinib and Pazopanib * Patient Population: Patients with metastatic RCC following failure of one prior systemic first line regimen : Sunitinib OR Bevacizumab + INF alfa OR Temsirolimus OR Cytokines (IL-2, INF-α) N = 540 Prior therapy Primary end point : PFS Axitinib AXIS Trial COMPARZ Study RANDOMIZERANDOMIZE Arm 1 Pazopanib Arm 2 Sunitinib N = 876 No prior therapy Clear Cell Carcinoma Primary end point : PFS Patient Population : Metastatic RCC, no prior systemic treatment Clear cell component Measurable disease (RECIST)

Summary  Increased understanding of RCC biology has led to introduction of multi- kinase inhibitors and other novel molecular targeted therapies as a new treatment paradigm for advanced clear cell carcinoma.  A variety of multi-kinase and VEGF inhibitors have significant activity in recently completed phase 2 & 3 clinical trials : - Tyrosine kinase inhibitors : sunitinib, sorafenib (  PFS, survival)  - VEGF inhibitor : bevacizumab + IFNα (↑ PFS)  - mTOR inhibitors : temsirolimus (  PFS, survival – poor risk subset),  everolimus (↑ PFS – TKI refractory pts)  Studies underway in following areas : - Novel agents / combinations - Sequencing of targeted agents - Role of biomarkers : response/PFS prediction, prognostic - Mechanisms of action / resistance - Adjuvant / neoadjuvant therapy - Nonclear cell tumors

IFN Sunitinib 2008 Temsirolimus Nexavar Gore ASCO 2008 Kane Advances in Overall Survival : Advanced RCC Median Overall survival Time (months) Best supportive care Temsirolimus Sunitinib AVOREN TARGETs – INF-α+ IL-2+5-FU Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Naxavar PI, Figlin et al. ASCO 2008, Escudier ASCO 2008; Escudier et al. Lancet 2007;370: IFN Bevacizumab + IFN NR 18.7 IFN 7.3 IFN 21.8 Placebo Present

Overall Survival : Sunitinib vs IFNα Intent to Treat Analysis Crossover Patients (#25) Censored Figlin R, et al, ASCO 2008

Sunitinib vs IFNα : Effects of Secondary Therapy Sunitinib, n (%) (n=323) IFN- , n (%) (n=359) Any post-study treatment 182 (56)213 (59) Sunitinib36 (11)117 (33) Other VEGF Inhibitors 106 (33)115 (32) Cytokines63 (20)47 (13) mTOR Inhibitors28 (9)16 (4) Chemotherapy21 (6)20 (6) *Treatments received after discontinuation from the study Figlin, et al., 2008 Post-Study Therapy Received OS in Patients Not Receiving Post-Study Treatments

Sorafenib 400 mg bid ORR 10% SD 74% PFS 5.5 mos Major end points PFS (  =0.01) Survival (  =0.04) Escudier B, et al. NEJM, 2006; Bukowski et al, ASCO 2007 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs)Placebo* ORR 2% SD 53% PFS 2.8 mos (1:1) Randomization n~905 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 MSKCC group excluded Stratification MSKCC criteria Country Secondary end point : ORR *Crossover - initiated 6/05 Summary Survival Data Analysis Sorafenib Placebo p Value Final (9/06) 17.8 mos 15.2 mos Censored (6/05) 17.8 mos 14.3 mos 0.287