1. Sunitinib (Sutent) for Renal Cell Cancer Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer

2. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer Anti-VEGF agents have somewhat similar toxicities High-Dose Interleukin-2 can cure some patients with metastatic kidney cancer

3. T.E., 50 yr old male c kidney cancer July 2004 Nephrectomy clear cell cancer venous margin + December 2004 Partial excision tumor in vena cava February 2005 Brain metastases Rx cyberknife April 2005 Liver, lung metastases Rx Subcu IL-2---PD August 2005 Rx sorafenib --PD October 2005 GI bleeding bowel invasion Rx weekly transfusion December 2005 Rx sunitinib 50mg/day April 2006 Grade 2-3 Hand-foot syndrome dose 37mg/day June 2006 CT’s show 47% recist PR in lung mets leaves town for 3000 mile motocycle trip

5. Sunitinib Mechanism of Action in RCC RCC pathogenesis and progression ↑ VEGF ↑ PDGF Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation Loss of VHL protein function VEGFPDGF VEGFRPDGFR Vascular endothelial cell Pericyte/fibroblast/ vascular smooth muscle Sunitinib

12. Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma RJ Motzer, TE Hutson, P Tomczak, MD Michaelson, RM Bukowski, O Rixe, S Oudard, ST Kim, CM Baum, RA Figlin and the SU11248 Study Group Supported by Pfizer Inc.

13. Randomization Scheme N=750 Stratification Factors: LDH >1.5 vs.  1.5 x ULN ECOG PS 0 vs. 1 Presence vs. absence of nephrectomy RANDOMIZATIONRANDOMIZATION Sunitinib (n=375) IFN-  (n=375)

14. Patient Characteristics Characteristics Sunitinib (n=375) IFN-  (n=375) Median age 62 59 ECOG PS 0/1 (%) 62/38 61/39 Prior nephrectomy (%) 91 89 Prior radiation therapy (%) 14 Sites of disease involvement (%) Lung 78 80 Liver 26 24 Bone 30

15. Best Response by RECIST (Independent Central Review) ResponseSunitinib IFN-  Pts with measurable disease at baseline* (n) 335 327 Overall response** Complete response Partial response 103 (31%) 0 103 20 (6%) 0 20 Stable disease160 (48%)160 (49%) Progressive disease or not evaluable 72 (21%)147 (45%) ** Sunitinib vs. IFN-  : p <0.000001 * 88 patients not yet assessed by central review;

16. Progression-free Survival (Independent Central Review) No. at Risk Sunitinib:23590322 No. at Risk IFN-  :15242180

17. Overall Survival No. at Risk Sunitinib:34119084151 No. at Risk IFN-  :29616266100 * The nominal level of significance for this pre-planned analysis was p <0.0031

18. Laboratory Abnormalities Sunitinib (%) IFN-  (%) Event All grade Grade 3/4All grade Grade 3/4 Neutropenia7211/1467 Anemia71 3/<1644/<1 Thrombocytopenia65 8210 Lymphopenia59126322 Hyperlipasemia5213/3435/1 Hypophosphatemia364/<1326 Hyperamylasemia31 4/1282/<1

19. Treatment-Related Adverse Events Event Sunitinib (%) IFN-  (%) All gradeGrade 3/4All gradeGrade 3/4 Fatigue517 11/<1 Diarrhea53513 0 Nausea44333 1 Stomatitis251 2<1 Hypertension248 1<1 Dermatitis/HFS205 1 0 Ejection fraction decline102 3 1 Pyrexia 7134 0 Chills 6129 0 Myalgia 5<116<1 Flu-like symptoms 10 8<1

20. Sunitinib Dermatological Toxicity

21. Outcome Summary Sunitinib IFN-  Median Progression-free Survival* (95% C.I.) Independent Review Investigator 11 mos (10, 12) 11 mos (8, 14) 5 mos (4, 6) 4 mos (4, 5) Overall response* (95% C.I.) Independent Review Investigator 31% (26, 36) 37% (32, 42) 6% (4, 9) 9% (6, 12) SafetyAcceptable Patient-reported OutcomesSuperior- * Sunitinib versus IFN-  : p <0.000001

22. Unusual Side effects of Sunitinib (sutent) Hand-foot syndrome with skin blisters or ulcers Hypothyroidism and adrenal insufficiency Decreased cardiac function?? Hypertension Pulmonary hemorrhage seen in lung cancer patients Hypophosphatemia

29. High-dose IL-2 at California Pacific: 5 of 50 patients in 10 years Patient number age Date Rx Sites of disease # of IL-2 Other therapyDisease -free since 8467/97Brain,bone, Liver,adrenal 5 Craniotomy, adrenalectomies 2000 143211/98Brain,bone, liver 8craniotomy1999 26543/01Bone2Radiation2003 37639/02Lung, liver8Thoracotomy2003 40571/03Lung52003

30. Indications for high-dose IL-2 before January 2006 after January Renal cell cancer Age < 65 P.S 0--1.5 Brain metastases if resected Motivated patient Clear cell renal cell Age <55 P.S. 0--0.5 No brain metastses Very motivated patient Clinical trials if available

31. Overall Survival Temsirolimus vs IFN TEMSR ± IFN 3-Arm Phase III Study 05101520253035 0 1.00 0.75 0.50 0.25 Time from randomization (months) Probability of survival Arm 1: IFN Arm 3: IFN + temsirolimus Arm 2: Temsirolimus Parameter IFN Arm1 TEMSR Arm 2 TEMSR + IFN Arm 3 n207209210 ComparisonsArm 2: Arm 1Arm3: Arm 1 Stratified log-rank P0.00690.6912 Adapted from: Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.

32. Sorafenib (Nexavar) and Sunitinib (Sutent): Differences  Sorafenib given BID  Sorafenib probably less toxic  Dispensed via mail-order pharmacies only  Onyx/Bayer pharmaceuticals  In trial in combinations  Sunitinib given daily 4 weeks on, 2 weeks off  Sunitinib probably more potent but more toxic with fatigue and mild hematologic toxicity  Dispensed via local pharmacies  Sugen/Pfizer pharmaceuticals  In trial in combinations

33. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer Anti-VEGF agents have somewhat similar toxicities High-Dose Interleukin-2 can cure some patients with metastatic kidney cancer