Updates on Renal Cell Cancer Sandy Srinivas.M.D Stanford University & David Minor.M.D CPMC

Educational Objectives Describe the intracellular signaling cascades associated with VEGFR, PDGFR, and Ras/Raf kinases in tumor cells and tumor vasculature Discuss Clinical trials and data on Sorafenib Discuss the national clinical trial on adjuvant and metastatic disease Discuss Clinical trials and data on Sutent Role of High dose IL-2 Describe mTor Inhibitors FR=platelet-derived growth factor; RCC=renal cell carcinoma; VEGFR=vascular endothelial growth factor

Histological Classification of Human Renal Epithelial Neoplasms RCC Clear cell 75% Type Incidence (%) Associated mutations VHL Papillary type 1 5% c-Met Papillary type 2 10% FH Chromophobe BHD Oncocytoma Common epithelial neoplasms of the kidney can be either familial or sporadic Mutations in the gene for VHL, c-Met, FH, or BHD are common in both the familial and sporadic forms of kidney neoplasms.1,2 Cases of familial neoplasm arise from inherited germline mutations earlier than cases of sporadic neoplasm. Familial neoplasm requires only one additional mutation to inactivate the gene while sporadic neoplasm requires multiple subsequent mutations in order to inactivate the gene.1 Clear-cell RCC is the predominant histological type (75%).1,2 There are two types of papillary renal cell cancer: Type II is very aggressive; Type I less so. Oncocytoma is no longer considered to be malignant tumor, it is a benign neoplasm.3 BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol. 2003;170:2163-2172. References 1. Linehan WM et al. The genetic basis of cancer of the kidney. J Urol. 2003;170:2163-2172. 2. Kim WY. J Clin Oncol. Role of VHL gene mutation in human cancer. 2004;22:4991-5004. 3. Kidney Cancer Association. Kidney cancer subtypes. Available at: http://www.curekidneycancer.org/index.cfm?pageID=85. Accessed March 21, 2006.

American Joint Committee on Cancer (AJCC) 2002 Clinical Staging System Stage Description 5-Year Survival (%) Stage I T1, N0, M0 95 Stage II T2, N0, M0 88 Stage III T1-2, N1 or T3, N0-1 59 Stage IV T4 (any N or M) or N2 (any T or M) or M1 20 5-year survival rates by clinical stage of RCC. Revisions of the AJCC-TNM Staging System The AJCC system was revised in 1997. The most significant change was an increase in size cutoff between T1 and T2 tumors from 2.5 cm to 7 cm. This modification also induced a corresponding change in 5-year survival rate for tumors at stage II between 1987 and 1997 staging systems (from 94% to 88%). Both the 1987 and 1997 staging systems are similar in predicting patient outcome, but the revised system permits better stratification of cases based on survival. Advanced stages of RCC are associated with worsening prognosis. Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477-2490. Reference Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477-2490.

MSKCC Risk Factor Model in mRCC 0 risk factors (n=80 patients) 1 or 2 risk factors (n=269 patients) 3, 4, or 5 risk factors (n=88 patients) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Risk factors associated with worse prognosis KPS <80 Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) High corrected calcium (10 mg/dL) High LDH (300 U/L) Time from Dx to IFN- <1 yr Proportion Surviving The Memorial Sloan-Kettering risk-factor model is predictive of patient long-term prognosis This retrospective study was performed on 670 patients with mRCC treated at Memorial Sloan-Kettering Cancer Center. The subsequent model that was developed, identifies prognostic factors that predicted survival for patients with mRCC. Risk factors associated with shorter survival (no prior nephrectomy) were: KPS <80 Low serum hemoglobin (13 g/dL in males,11.5 g/dL in females) High corrected calcium (10 mg/dL) High lactate dehydrogenase (300 U/L) The model predicts that patient prognosis declines as the number of risk factors increases. 6 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time From Start of IFN- (years) Motzer RJ et al. J Clin Oncol. 2002;20:289-296. Reference Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M, et al. Interferon-alfa as a comparitive treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-286.

Historical Management Strategies for RCC: Summary Chemotherapy RCC is highly resistant, <10% ORR1 IFN- 15% ORR, but responses rarely complete or durable2 HD IL-2 15% ORR in stage IV patients, only 5% were CR3 Urgent need for additional options in late-stage RCC Historical management strategies for RCC: summary RCC is highly resistant to current chemotherapeutic agents, which have yielded a disappointing response rate of less than 10%.1 Treatment with IFN- yields an objective response rate of 15% in advanced patients, but the responses are rarely complete or durable.2 High-dose IL-2 has elicited a 15% objective response rate in stage IV patients, but only 5% were complete responses. In this small group of patients achieving a complete response with high-dose IL-2, responses appear to be durable, with a median duration in excess of 80 months.3 1. Krown SE. Cancer. 1987;59:647-651. 2. Muss HB. Semin Oncol. 1988;15:30-34. 3. Rosenberg SA et al. JAMA. 1994;271:907-913. References 1. Krown SE. Interferon treatment of renal cell carcinoma. Cancer. 1987;59:647-651. 2. Muss HB. The role of biological response modifiers in renal cell carcinoma. Semin Oncol. 1988;15:30-34. 3. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913.

Role of VHL in RCC Progression Paracrine Function Pericyte RAS RAF MEK ERK Autocrine Function Tumor cell VHL HIF-1 HIF-1 RAS RAF MEK ERK Scene 1 RCC is a highly vascularized tumor Scene 2 Three cell types play a role in the progression of RCC The 1° effector is the tumor cell itself Mutation or inactivation of VHL in the tumor cell allows for accumulation of HIF-1 protein. Increased levels of HIF-1 result in an overexpression of angiogenic and cellular growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). Scene 3 Through a paracrine function, VEGF travels to regional endothelial cells where it binds to the VEGF-receptor, initiating a signal for the stabilization of blood vessels and the further proliferation of tumor cells. Scene 4 Through a paracrine function, PDGF travels to regional pericytes where it binds to the PDGF-receptor, initiating a signal for the growth of blood vessels and the further proliferation of tumor cells. Scene 5 Through an autocrine function, EGF travels back to the tumor cell where it binds to the EGF-receptor, initiating a signal for the growth of the tumor. Paracrine Function HIF-1 RAS RAF MEK ERK Endothelial cell HIF-1 VEGF VEGF EGF EGF PDGF PDGF EGF VEGF PDGF Reference Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109.

Rational Targets in RCC (cont’d) EGF PDGF VEGF Pericyte Endothelial cell Tumor cell HIF-1 VHL HIF-1 RAS RAF MEK ERK Sorafenib Sunitinib Approved and investigational kinase inhibitors have multiple molecular targets in RCC Bevacizumab binds to the VEGF, inhibiting its ability to bind to its receptor. Sorafenib binds to the kinase domain of the VEGF and PDGF, inhibiting their ability to initiate cell-signaling cascades. Sorafenib also inhibits RAF kinase. Sunitinib binds to the kinase domain of the VEGF and PDGF, inhibiting their ability to initiate cell-signaling cascades. Bevacizumab

Bevacizumab for mRCC: Phase II Study Design High dose = 10 mg/kg (n=39) mRCC patients (N=116) ECOG PS <2 All patients have prior therapy (mostly IL-2) Low dose = 3 mg/kg (n=37) Placebo (n=40) 1° end points: TTP and ORR 2° end point: OS Study arms were balanced for demographics Phase 2 study of efficacy and safety of bevacizumab in mRCC This was a randomized, double-blind phase 2 trial. 116 patients received either 3 mg/kg or 10 mg/kg of bevacizumab, or placebo, every 2 weeks. Patients initially receiving placebo were permitted to cross over to treatment with bevacizumab. Primary end points in this study were TTP and ORR. Overall survival was a secondary end point in this study. Patients were well-matched for all groups. 116 previously treated, metastatic RCC patients were randomized to three groups: high dose (10 mg/kg), low dose (3 mg/kg), and placebo. ECOG PS were ≤2, which is a relatively fit patient population. Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide. Yang JC et al. N Engl J Med. 2003;349:427-434. Reference Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.

Bevacizumab for mRCC: Progression-Free Survival Median PFS (months) High dose, 10 mg/kg(n=39) 4.8 (P<.001) Low dose, 3 mg/kg (n=37) 3.0 (P<.041) Placebo (n=40) 2.5 100 90 80 70 60 Patients Free of Tumor Progression (%) 50 40 Bevacizumab increased PFS in patients with mRCC to a median of 4.8 months Significant increases in the PFS were observed in patients treated with both dosages of bevacizumab. High-dose median PFS was almost twice that of patients receiving placebo, 4.8 months vs 2.5 months (P<.001). Partial responses were seen in 10% (4 patients) of patients treated with high­dose bevacizumab. No responses were reported in patients receiving low­dose bevacizumab or placebo. No complete responses were observed. This study was terminated early, at the second interim by the National Cancer Institute (NCI) Data Safety and Monitoring Board because of the significant difference in the TTP between patients treated with high-dose bevacizumab (10 mg/kg) and patients in the placebo group. 30 Partial Response-10% 20 10 6 12 18 24 30 36 Time (months) Adapted from Yang JC et al. N Engl J Med. 2003;349:427-434. Reference Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.

Bevacizumab + Erlotinib for mRCC: Phase II Study Design Bevacizumab 10 mg/kg IV q 2 wks + erlotinib 150 mg PO qd mRCC patients, no prior therapy (N=104) Bevacizumab 10 mg/kg IV q 2 wks + placebo 150 mg PO qd 1° end points: PFS and ORR Results Bevacizumab +Erlotinib Bevacizumab + Placebo # Patients 51 53 ORR (CR+PR) 7(14%) 7(13%) Stable Disease 34(68%) 36(68%) PFS (months) 9.9 8.5 P=0.58 Preliminary data from a bevacizumab in combination with erlotinib phase 2 trial suggest no significant improvement over erlotinib alone 104 mRCC patients with no prior therapy were enrolled in a multicenter, randomized, placebo-controlled, double-blind phase 2 trial. Patients were treated with either bevacizumab at 10 mg/kg IV q 2 weeks plus erlotinib at 150 mg PO qd or bevacizumab 10 mg/kg IV q 2 weeks plus 150 mg PO qd. The primary end points were PFS and ORR. Based on the preliminary data, there were no significant differences in PFS between the 2 arms. Bukowski , Srinivas ASCO 2006 Reference Genentech press release, Tuesday, October 18, 2005. Available at: http://www.gene.com/gene/news/ press-releases/display.do?method=detail&id=8967. Accessed March 20, 2006.

Sorafenib (Nexavar®) CF3 CI NH O N CH3 N H Small-molecule receptor TKI1 Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinases1 Formulation: 200 mg tablets2 Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)2 FDA approved December 20, 2005 for advanced RCC3 N H O N CI CF3 NH CH3 Sorafenib targets multiple pathways involved in RCC tumorigenesis Sorafenib is an orally administered, small-molecule receptor TKI that targets VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, and Raf kinases.1 Although sorafenib is a potent inhibitor of Raf, there is little or no evidence to suggest that Raf plays a role in the oncogenesis of RCC.2 FDA approved December 20, 2005 for treatment of advanced RCC.3 Wilhelm SM et al. Cancer Res. 2004;10:7099-7109. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006. References Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.

Sorafenib for mRCC: Phase II (RDT) Study Design ≥25% tumor shrinkage  continue sorafenib Solid tumors (N=502) mRCC patients (n=202) Sorafenib Stable patients (-25% to +25%) randomized Placebo* >25% tumor growth  off-study 1° end points PFS from day 1 PFS 12 weeks post-randomization, tumor response rate, safety All patients treated with sorafenib 400 mg bid during the open-label run in phase Patients evaluated at 12 weeks: Responding patients (≥25% tumor shrinkage) continue sorafenib Stable patients (-25% to +25%) randomized in double-blind fashion to sorafenib vs placebo Progressing patients (>25% tumor growth) off-study 69 patients had tumor stabilization and were randomized either to continue treatment with sorafenib or to placebo. Of the patients randomized to sorafenib, 50% had stable disease at 24 weeks vs 18% of patients receiving placebo. The difference was statistically significant (P=.0077). RDT=randomized discontinuation trial. *May cross over to sorafenib. Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL. Reference Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a phase 2, placebo-controlled, randomized discontinuation trial of sorafenib (BAY-43-9006) in patients with advanced renal cell carcinoma. Presented at: ASCO; May 13-17, 2005; Orlando, FL.

Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival 1.00 Sorafenib (n=33) Placebo (n=32) Censored 0.75 Median PFS from randomization Sorafenib=24 weeks Placebo=6 weeks P=.0087 Proportion of Patients Progression-Free 0.50 Patients receiving sorafenib had a median PFS of 24 weeks Twelve weeks after patient randomization, 50% of the patients receiving sorafenib remained progression free, while 18% of patients in the placebo group were progression free. During the initial 12 weeks of sorafenib treatment, 71% of patients experienced tumor shrinkage or stabilization of disease. There were no deaths attributed to treatment toxicity in this trial; however, 5% of patients experienced a serious drug-related AE. AEs were similar between the randomized treatment groups. 0.25 84 100 200 300 400 500 12-week period Time From Randomization (days) Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL. Reference Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a phase 2, placebo-controlled, randomized discontinuation trial of sorafenib (BAY-43-9006) in patients with advanced renal cell carcinoma. Presented at: ASCO; May 13-17, 2005; Orlando, FL.

Sorafenib for mRCC: Phase II (RDT) Drug-Related Adverse Events Any grade % Grade 3/4 Any event 98 48 Cardiovascular 38 25 Hypertension 35 24 Dermatology 90 15 Rash/desquamation 62 2 Hand-foot skin reaction 60 13 Alopecia 50 – Other Dry skin 21 Flushing Constitutional symptoms 68 6 Fatigue 55 4 Weight loss Sorafenib for mRCC: Phase 2 (RDT) Drug-Related Adverse Events The major drug-related adverse events seen in the sorafenib RDT were hypertension, rash, hand-foot syndrome, fatigue, and alopecia. The incidence of adverse experiences was similar between treatment groups post-randomization. Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL. Reference Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a phase 2, placebo-controlled, randomized discontinuation trial of sorafenib (BAY-43-9006) in patients with advanced renal cell carcinoma. Presented at: ASCO; May 13-17, 2005; Orlando, FL.

Sorafenib for mRCC: Phase III Study Design (TARGET) Unresectable and/or mRCC, 1 prior systemic Tx in last 8 months, ECOG PS 0/1 (N=903*) Sorafenib, 400 mg bid (n=451) Placebo (n=452) 1° end point: OS 2° end points: ORR, PFS, safety, HR-QoL Demographics MSKCC good or intermediate risk patients Clear-cell carcinoma The efficacy of sorafenib in patients with unresectable, refractory or mRCC was assessed in the TARGET phase 3 trial TARGET is the largest phase 3 randomized, placebo-controlled trial to date in patients with advanced RCC. A total of 905 patients with unresectable or metastatic RCC who had already failed at least one systemic therapy were enrolled. The primary end point of this trial was OS. The secondary end points were overall response rate, PFS, safety, and patient quality of life. Patients who had failed while on placebo were permitted to cross over to sorafenib treatment after interim analysis was completed. *Out of 905 patients randomized by February 15, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Reference Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY-43-9006) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Response Rate* (TARGET) Best Response by RECIST Sorafenib (n=451) n (%) Placebo (n=452) n (%) Complete response 1 (<1) — Partial response 43 (10) 8 (2) Stable disease 333 (74) 239 (53) Progressive disease 56 (12) 167 (37) Missing 18 (4) 38 (8) A significant percentage of patients treated with sorafenib displayed some level of tumor response Sorafenib has significantly higher PR and SD rates than placebo (10% vs 2%, 74% vs 53%, respectively). * Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Reference Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY-43-9006) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Tumor Reduction* (TARGET) Placebo (n=452) Sorafenib (n=451) 50 100 150 -50 -100 50 100 150 -50 -100 Change From Baseline (%)* Change From Baseline (%)* Patients treated with sorafenib had a more significant increase in clinical benefit vs patients treated with placebo Sorafenib was significantly more effective in reducing tumor size than placebo. Clinical benefit referrers to changes in the tumor. Volume vs character changes 25% 76% Tumor Reduction Tumor Reduction PD (20% increase, RECIST); PR (30% or reduction, RECIST). * Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Reference Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY-43-9006) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Progression-Free Survival* (TARGET) 1.00 Censored observation Placebo (n=452) Sorafenib (n=451) 0.75 PFS Median (months) Sorafenib Placebo 5.5 2.8 Hazard ratio 0.51 Proportion of Patients Progression Free 0.50 0.25 Sorafenib increases the progression-free survival of patients with unresectable refractory mRCC The hazard ratio for disease progression was reduced by almost half in patients with mRCC who were treated with sorafenib. A significant reduction in the hazard ratio for progression was found in all patient subgroups. Sorafenib extended median patient PFS to 5.5 months. Independent assessment at planned interim analysis (ASCO) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P<.000001). 2 4 6 8 10 12 14 16 18 20 Time From Randomization (months) * Investigator assessment. Independent assessment at planned interim analysis (ASCO 2005) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P<.000001). Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Reference Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY-43-9006) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Overall Survival* (TARGET) 1.00 Censored observation Placebo (n=452) Sorafenib (n=451) 0.75 Proportion of Patients Overall Survival 0.50 OS Median (months) Sorafenib Placebo Not reached 14.7 Hazard ratio (S/P) 0.72 P=.018 Sorafenib increases the overall survival of patients with unresectable refractory mRCC The hazard ratio for OS was significantly reduced to 0.72 (P=.018) in patients with mRCC who were treated with sorafenib. To date, the median OS has not yet been reached in patients treated with sorafenib. Following interim analysis, patients who have been on placebo were allowed to crossover to sorafenib even in absence of disease progression. 0.25 2 4 6 8 10 12 14 16 18 20 Time From Randomization (months) *Interim analysis. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Reference Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY-43-9006) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Adverse Events Profile (TARGET) Placebo (n=452) Sorafenib (n=451) <1 <1 <1 Any Grade Grade 3 Sorafenib treatment was well tolerated with limited adverse events The most common AEs observed were: Diarrhea (43%) Rash/desquamation (40%) Fatigue (37%) Hand-foot skin reaction (30%) Hand-foot skin reaction (6%) and fatigue (5%) were the most frequent grade 3 AEs. Patients (%) Patients (%) 7% grade 4 toxicities in sorafenib-treated patients vs 6% grade 4 toxicities in placebo-treated patients. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005. Reference Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.

Sorafenib for mRCC: Laboratory Toxicities (TARGET) Placebo (n=452) Sorafenib (n=451) Any Grade Grade 3 Sorafenib treatment was well tolerated with limited laboratory abnormalitites The most frequent laboratory abnormalities associated with sorafenib treatment were hypophosphatemia (45%), anemia (44%), elevated lipase (41%). Hypophosphatemia (13%), lymphopenia (13%), and elevated lipase (12%) were the most frequent grade 3 laboratory abnormalities associated with sorafenib treatment. Patients (%) Patients (%) Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005. Reference Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.

TARGETs Hand–Foot Skin Reaction Early in treatment and reversible. hypersensitivity of foot, soreness

Sorafenib for mRCC: Conclusion First MKI approved for treatment of advanced RCC December 20, 2005 More than doubles PFS compared to placebo Therapeutic response Radiographic response vs disease stabilization OS survival trend at planned interim analysis (P<.018) Mild to moderate toxicity profile Sorafenib is a valuable therapeutic option in mRCC Sorafenib is the first in class approved multikinase inhibitor (MKI) for the management of advanced RCC. FDA approval on December 20, 2005. Treatment with sorafenib more than doubled the PFS in patients vs placebo. Adverse event toxicities observed with sorafenib were mild to moderate. Front-line data forthcoming for sorafenib vs IFN-.

Response in Treatment naïve patients(32) PR 6(18.8%) MR 8(25%) SD 10(31.3%) PD 3(9%) Uneval 5(15%) 32 of the 202 patients in the RDT had no prior therapy PFS in this group was 40 weeks -10 months Overall response of 75% Escudier ASCO 2006

Phase II Randomized Trial- First Line G I S T A O N P R O G E S I N SORAFENIB 400MG BID SORAFENIB 600MG BID MET RCC CLEAR CELL NO PRIOR RX ECOG 0/1 NO BRAIN METS ALL MSKCC RISK GROUPS N=189 IFN-α 9 M TIW SORAFENIB 400MG BID Accrual completed; too few events for results Escudier, ASCO 2006

Randomized phase III trial of Sorafenib: Impact of Crossover o survival OS @ Cross over OS@6 months Cross over OS@ 6 mos Crossover with placebo censored Placebo 14.7 15.9 14.3 Sorafenib NR 19.3 Hazard Ratio 0.72 0.77 0.74 P-value 0.018 0.015 0.01 O-Brien-Flemming SR 0.0005 0.0094 357 events as of 11/05; Mature data when 540 events Eisen, ASCO 2006

Summary-PFS (months) First Line Second Line Bevazizumab 8.5 4.8 Sorafenib 9 5.5

ECOG 2805: Adjuvant Trial 1° end point: Disease-free survival (DFS) Group A: (sunitinib) Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles† Stratify TNM Intermediate high risk Very high risk Histologic Subtype Clear cell Non-clear cell (except collecting duct or medullary) ECOG Performance Status 1 Surgery Laparoscopic Open Nephrectomy Group B: (Nexavar) Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and placebo for sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles† Preregister Randomization (N=1332) Group C: (placebo) Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and placebo for sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles†

Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial 1º end point: Disease-free survival 2º end points: RCC-specific survival time, toxicity, QOL, and biomarkers (1.5:1.5:1) Randomization (N=1656) High and intermediate risk, resected RCC Nephrectomy Preregister Placebo for 3 years (n=414) Nexavar for 1 year Placebo for 2 years (n=621) Nexavar