1. Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma May 19, 2006 Atlanta, Georgia

2. Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Nicholas J. Vogelzang, MD Director Nevada Cancer Institute Las Vegas, Nevada

3. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  Von Hippel-Lindau (VHL) syndrome is characterized by germline mutation of chromosome 3p, development of renal cell carcinoma (RCC)  Noninherited clear-cell RCC characterized by VHL gene tumor suppressor gene inactivation, leads to –Constitutive expression of oxygen-regulated transcription factor (HIFa) –Induction of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF)  VEGF overexpression promotes tumor angiogenesis Biology of RCC

4. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  VHL gene inactivation in clear-cell RCC: selected series* Author VHL Gene Methylation Herman 199419.0% (5/26) Clifford 199815.0% (7/45) Kondo 20025.4% (11/202) Brauch 20007.0% (10/151) Total8.0% (33/424) Author VHL Gene Mutation Gnarra 199457% (56/98) Gallou 199956% (73/130) Brauch 200045% (68/151) Shuin 1994 & Kondo 2002 51% (104/202) Schraml 200234% (38/113) Total49% (339/694) *No significant VHL gene mutation (1%) or methylation (2%) observed in nonclear-cell RCC. Rini B, et al. J Clin Oncl. 2005;23:1028-1043. Clear-Cell RCC Is Characterized by VHL Gene Inactivation

5. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Rini B, et al. J Clin Oncl. 2005;23:1028-1043. Hypoxia or Abnormal pVHL Function Induction of hypoxia-inducible genes, eg, VEGF, PDGF Constitutively expressed HIF  translocates into the nucleus Proteasome Normoxia and Normal pVHL Function Ubiquitin attachment HIF  degradation AB pVHL hp HIF  HIF 

6. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma VEGF mRNA and Protein Expression in Clear Cell RCC Rini B, et al. J Clin Oncl. 2005;23:1028-1043. AuthorVEGF mRNAVEGF protein Takahashi 1994 96%NR Nicol 1997 100%93% Tomisawa 1999 100%NR Hemmerlein 2001 100%NR Lee 2001 NR81% Igarashi 2002 63%NR Na 2003 NR100%

7. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Therapeutic Inhibition of VEGF in RCC  Binding antibodies to the VEGF protein –Bevacizumab  VEGFR inhibitors –Sunitinib –Sorafenib –Others under investigation (eg, valatinib, axitinib)

8. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Rini B, et al. J Clin Oncl. 2005;23:1028-1043. Akt/PKB PI3K p38MAPK Raf MEK Erk VEGFR-2 PPPP Vascular permeability Endothelial cell survival Endothelial cell migration Endothelial cell proliferation Vascular endothelial cell plasma membrane VEGF

9. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Rini B, et al. J Clin Oncl. 2005;23:1028-1043. Akt/PKB PI3K p38MAPK Raf MEK Erk VEGFR-2 PPPP Vascular permeability Endothelial cell survival Endothelial cell migration Endothelial cell proliferation Vascular endothelial cell plasma membrane VEGF Sorafenib Axitinib Sorafenib Sunitinib Bevacizumab

11. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Bevacizumab  Bevacizumab: a recombinant anti-VEGF antibody –Created by transferring the VEGF-binding regions of the murine antibody to a humanized IgG 1 framework (93% human, 7% murine) –Produces a humanized IgG  Mediates blockade of VEGF protein (ligand) –Binds and neutralizes all biologically active isoforms of VEGF

12. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Placebo Q2W (n = 40) Yang JC, et al. N Engl J Med. 2003;349:427-434. Patients with treatment-refractory, metastatic RCC Bevacizumab in RCC Bevacizumab 3 mg/kg Q2W (n = 37) Bevacizumab 10 mg/kg/kg Q2W (n = 39) PD

13. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Yang JC, et al. N Engl J Med. 2003;349:427-434. *P =.041 vs placebo. † P <.001 vs placebo. Placebo Low-Dose Bevacizumab High-Dose Bevacizumab Response rate0% 10% TTP (months)2.53.0*4.8 † OS (months)13.015.115.5 Bevacizumab in RCC

14. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Yang JC, et al. N Engl J Med. 2003;349:427-434. *P ≤.05 vs placebo. Treatment-Related Toxicity, Any Grade (Grade 3) Placebo Low-Dose Bevacizumab High-Dose Bevacizumab Hypertension5%3%36%* (21%*) Proteinuria38%41% (5%)64%* (8%) Epistaxis3%14%21%* Hematuria0%3%13% Hemoptysis5%3% Pulmonary embolism3%0% Bevacizumab in RCC

15. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Change in RCC Tumor Burden During Bevacizumab Therapy Elaraj DM, et al. J Immunother. 2004;27:259-264. Placebo 0 20 40 60 80 100 120 140 160 180 200 020406080 Tumor Burden Compared With Baseline (%) High Dose 020406080 Low Dose 020406080 Weeks of Treatment

16. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Sorafenib Sunitinib PDGF-R Cell survival, proliferation, migration Pericyte/fibroblast vascular smooth muscle Vascular endothelial cell/ tumor cell Vascular formation, maturationVascular permeability RCC pathogenesis and progression PPPP VEGF PDGF VEGFR PPPP X X

17. Sunitinib

18. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor of VEGFR (-1, -2, and -3), PDGFR (-  and -  ), KIT, RET, and FLT3 receptors  By inhibiting VEGF and PDGF signaling pathways, sunitinib may inhibit tumor growth in RCC  Antitumor activity of sunitinib was observed early in phase I studies in RCC and other tumor types  FDA approved for advanced RCC, January 2006 Faivre S, et al. J Clin Oncol. 2006;24:25-35. Sunitinib

19. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Sunitinib: Phase II Trials in RCC  Eligibility (Trial 1) –Any RCC histology –Prior cytokine failure –Measurable disease –Adequate PS, blood counts, and chemistries –Normal organ function  Eligibility (Trial 2) –Clear cell RCC –Prior cytokine failure –Radiographic documentation of progression –Prior nephrectomy –Measurable disease –Adequate PS, blood counts, and chemistries –Normal organ function Motzer RJ, et al. 2005 ASCO. Abstract 4508.

20. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Sunitinib: Best Response by RECIST In Phase II Trials Trial 1 (n = 63) Trial 2 (n = 106) ORR, % 44* 36 † 43* 35 † Median duration of response, wks5427 ‡ *Investigator review † Independent review ‡ Immature data Motzer RJ, et al. 2005 ASCO. Abstract 4508.

21. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma ToxicityTrial 1, %Trial 2, % Fatigue11 Diarrhea33 Nausea30 Stomatitis25 Hand-foot syndrome07 Hypertension26 Motzer R, et al. Eur J Cancer. 2005;3(suppl):227. Abstract 797. Grade 3 Adverse Events

22. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Motzer R, et al. Eur J Cancer. 2005;3(suppl):227. Abstract 797. EventTrial 1, %Trial 2, % Neutropenia1316 Anemia106 Thrombocytopenia 06 Hyperlipidemia2117 HyperamylasemiaNR Grade 3/4 Laboratory Abnormalities

23. Sorafenib (BAY 43-9006)

24. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  Originally identified through inhibitory effects on Raf-1, a serine/threonine kinase [1]  Further activity against B-Raf and additional receptor tyrosine kinases, including VEGF-R2, PDGF-R, FLT-3, and c-KIT [2]  Broad-spectrum, antitumor activity in a number of tumor xenograft models, including renal adenocarcinoma [2]  FDA approved for advanced RCC, December 2005 1. Wilhelm S, et al. Curr Pharm Des. 2002;8:2255-2257. 2. Wilhelm S, et al. Cancer Res. 2004;64:7099-7109. Sorafenib

25. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  Primary endpoint: proportion of patients progression-free at 12 wks postrandomization  Secondary endpoints: PFS postrandomization, overall PFS from Day 1, RR, safety Patients with tumor shrinkage < 25% after 12 wk induction with sorafenib 400 mg BID (n = 65) Randomization (1:1) Patients with advanced RCC (N = 202) Placebo Sorafenib 400 mg BID Ratain MJ, et al. 2005 ASCO. Abstract 4544. Randomized Discontinuation Trial: Study Design

26. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Ratain MJ, et al. 2005 ASCO. Abstract 4544. 0.00 0.25 0.50 0.75 1.00 Survival Distribution Function - 84 050 100150 200 250 300 350 12-week run-in period Days From Randomization 450400 Median PFS from randomization: Placebo = 6 weeks Sorafenib = 24 weeks P =.0087 Sorafenib (n = 32) Placebo (n = 33) Censored Randomized Discontinuation Trial: PFS

27. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma TARGET: Study Design  Eligibility criteria –Clear-cell histology – Measurable disease –ECOG PS 0 or 1– Good organ function –No brain metastasis– Poor risk Motzer group excluded –Failed 1 prior systemic therapy in last 8 months Stratification by MSKCC criteria Country Randomization (1:1) Patients with histologically/ cytologically confirmed, unresectable and/or metastatic disease (N > 900) Escudier B, et al. 2005 Eur J Cancer. 2005;3(suppl):227. Abstract 794.  Major Endpoints –Survival (alpha =.04) –PFS (alpha =.01) Placebo Sorafenib 400 mg BID

28. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma *Patients randomized at least 6 weeks before data cutoff of January 28, 2005. Escudier B, et al. 2005 Eur J Cancer. 2005;3(suppl):227. Abstract 794. Best Response (RECIST), n (%) Sorafenib (n = 335)* Placebo (n = 337)* Partial response7 (2%)0 (0%) Stable disease261 (78%)186 (55%) Progressive disease29 (9%)102 (30%) Missing38 (11%)49 (15%) TARGET: Objective Responses by Independent Review

29. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma *Based on investigator assessment. Escudier B, et al. 2005 Eur J Cancer. 2005;3(suppl):227. Abstract 794. Proportion of Patients Progression Free 0 0.25 0.50 0.75 04102026812141618 Median PFS Sorafenib = 5.5 months Placebo = 2.8 months Hazard ratio (S/P) = 0.51 1.00 Time From Randomization (mos) TARGET: Progression-Free Survival Benefit* Censored observation Placebo Sorafenib

30. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma *Results are from a planned interim analysis as per protocol (220 events) and are considered preliminary. † Threshold for significance of interim analysis was P <.0005 Escudier B, et al. 2005 Eur J Cancer. 2005;3(suppl):227. Abstract 794. Time From Randomization (mos) Overall Survival 04102026812141618 0 0.25 0.50 0.75 1.00 Median OS Sorafenib = Not reached Placebo = 14.7 months Hazard ratio (S/P) = 0.72 P = 0.018 † (NS) TARGET: Planned Interim Analysis of Overall Survival* Censored observation Placebo Sorafenib

31. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma Escudier B, et al. 2005 Eur J Cancer. 2005;3(suppl):227. Abstract 794. Sorafenib (n = 384)Placebo (n = 384) Cardiovascular Any GradeGrades 3/4Any GradeGrades 3/4 Hypertension 30 (8%)4 (1%)1 (< 1%)– Constitutional symptoms Fatigue 70 (18%)7 (2%)54 (14%)5 (1%) Gastrointestinal Diarrhea116 (30%)5 (1%)27 (7%)3 (1%) Nausea 54 (14%)1 (< 1%)41 (11%)1 (< 1%) Anorexia 33 (9%)2 (1%)21 (6%)2 (1%) Vomiting 31 (8%)–21 (6%)1 (< 1%) Mucositis 27 (7%)2 (1%)1 (< 1%)– Dermatologic Rash/desquamation 120 (31%)3 (1%)43 (11%)1 (< 1%) Hand-foot skin reaction101 (26%)20 (5%)18 (5%)– Neurologic Sensory neuropathy33 (9%)1 (< 1%)9 (2%)– TARGET: Incidence of Drug-Related Adverse Events > 5%

32. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  VEGF targeting –Valatinib –AMG706 –Axitinib  mTOR targeted –Rad001 –Temsirolimus Additional Agents

33. clinicaloptions.com/oncology Novel Agents: Unique Therapeutic Targets in Advanced Renal Cell Carcinoma  VHL gene inactivation is a frequent event in clear-cell RCC leading to VEGF overexpression  Therapeutic inhibition of VEGF via antibody or receptor blockade results in antitumor activity in metastatic RCC  New clinical options that target VEGF ligand or VEGF receptor currently available –Both approaches appear effective  Other potential targets being investigated –New studies underway in this area Conclusions