1. Expert Insight Into Optimal Treatment for Individuals With Advanced Renal Cell Cancer Jointly sponsored by Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC This program is supported by an educational grant from Image: ISM/Copyright©2012 Phototake All Rights Reserved

2. Robert Motzer, MD Attending Physician Memorial Sloan-Kettering Cancer Center New York, New York Therapeutic Decision Making in Advanced Renal Cell Carcinoma: A 2012 Perspective Image: ISM/Copyright©2012 Phototake All Rights Reserved

3. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

4. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Faculty Disclosure Robert Motzer, MD, has disclosed that he has received consulting fees from Pfizer.

5. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Outline  Renal cell carcinoma incidence and biology  Interactive Decision Support Tool  First-line therapy  Salvage therapy  Management of treatment-related adverse events  Surgery in advanced RCC  Nonclear-cell RCC  Future directions

6. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Background  ~ 64,770 new cases of kidney/renal pelvis cancers will be diagnosed in the US in 2012 with an estimated 13,570 deaths [1] ~ 75% are clear-cell RCC [2] ~ 25% to 30% of pts with RCC are diagnosed with metastatic disease [2] Background and Treatment of mRCC Before the Era of Targeted Agents  Cytokine-based therapy was associated with a median PFS of 3-5 mos [3-5] and median OS of 13 mos [6] Current Situation  Targeted agents have resulted in substantial improvements in treatment outcomes for patients with mRCC [5,7,8] 1. Siegel R, et al. CA Cancer J Clin. 2012;62:10-29. 2. Motzer RJ, et al. N Engl J Med. 1996;335:865-875. 3. Rini BI, et al. J Clin Oncol. 2008;26:5422-5428. 4. Escudier B, et al. Lancet. 2007;370:2103-2111. 5. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 6. Coppin C, et al. Cochrane Database Syst Rev. 2005;1:CD001425. 7. Mulders P. Eur Urol Suppl. 2008;7:577-578. 8. Ljungberg B, et al. Eur Urol. 2010;58:398-406.

7. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment The Biology of Clear-Cell RCC: VHL Gene Mutation Bratslavsky G, et al. Clin Cancer Res. 2007;13:4667-4671. Elongin B Elongin C Rbx1 E2 CUL2 β-domain VHL complex disrupted VHL protein HIFα accumulation VEGF PDGF Glut1 Mutant α-domain Activation of hypoxia-inducible genes Angiogenesis Glucose Transport Autocrine Growth Stimulation

8. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment VEGF VEGFR Everolimus Temsirolimus Bevacizumab HIF Kaelin WG Jr. Clin Cancer Res. 2004;10:6290S-6295S. Mutant pVHL PDGF PDGFR mTOR Sunitinib Sorafenib Pazopanib Axitinib RCC Therapy: Targeting VEGF at Multiple Levels

9. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Patient Management and Therapy Selection in Advanced RCC: Considerations  Previous nephrectomy –Patients with intact primary tumor may benefit from surgical resection  Tumor histology –Evidence supporting the current therapeutic paradigm is largely limited to clear-cell RCC  Extent of metastases –Patients with 1-3 metastatic sites or those with metastases affecting QoL may benefit from additional treatment interventions including surgery, radiation, and/or bone-modifying agents  Previous systemic therapy  Preexisting comorbidities  Patient considerations –Cost –Convenience vs compliance

10. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Interactive Decision Support Tool (IDST): 1 Tool, 3 Expert Recommendations In the IDST (available at: http://clinicaloptions.com/RCCInsight), the above variables were used to make treatment decisions.

11. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Experts Were Asked How They Would Treat Patients, With the Following Options  Axitinib  Bevacizumab/interferon  Everolimus  Interferon  High-dose interleukin-2  Pazopanib  Sorafenib  Sunitinib  Temsirolimus  No treatment RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

12. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment An Expert Insight Is Shown With Each Expert’s Treatment Recommendations RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

13. First-line Therapy

14. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Case 1  72-yr-old greenhouse worker returned for a follow-up exam after a partial nephrectomy 14 mos ago for a 5.6-cm tumor on his right kidney  PMH –Diabetes, HTN; both controlled with medication  Current evaluation –ECOG PS 0 –Lab values normal except for anemia (Hb: 7.8 g/dL) –CT scan: new metastases to both lungs, multiple lymph nodes, and bone lesions to the pelvis, ribs, and vertebrae

15. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Which agent would you recommend for this patient?  Axitinib  Bevacizumab/interferon  Everolimus  Interferon  High-dose interleukin-2  Pazopanib  Sorafenib  Sunitinib  Temsirolimus  No treatment

16. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment IDST Expert Insight Results: Case 1  First choice –Expert 1: pazopanib –Expert 2: sunitinib –Expert 3: sunitinib  Patient characteristics –Extensive metastatic clear-cell RCC –No previous systemic therapy –MSKCC intermediate risk (anemia) –ECOG PS 0  Alternative agents recommended by the 3 experts for this patient included bevacizumab plus interferon, high-dose IL-2, or sorafenib –High-dose IL-2 was recommended as an option only for patients with the highest PS scores RCC IDST. Available at: http://clinicaloptions.com/RCCtInsight.

17. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Case 2  76-yr-old retired nurse presents with lower left back pain and hematuria  PMH is unremarkable except for arthritis and osteoporosis  Her current workup reveals –8-cm mass on the left kidney, lesions in the liver and right lung –ECOG PS 1 –Laboratory tests identify anemia, LDH 3 x ULN, and serum calcium 10.5 mg/dL –Biopsy results confirm clear-cell RCC

18. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Which agent would you recommend for this patient?  Axitinib  Bevacizumab/interferon  Everolimus  Interferon  High-dose interleukin-2  Pazopanib  Sorafenib  Sunitinib  Temsirolimus  No treatment

19. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment IDST Expert Insight Results: Case 2  All 3 experts selected temsirolimus as their first choice for this patient  The alternate choices for this patient were pazopanib (1 expert) or sunitinib (2 experts)  Patient characteristics –Extensive metastatic clear-cell RCC –No previous systemic therapy –MSKCC poor risk (anemia, elevated LDH, elevated serum calcium) –ECOG PS 1 RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

20. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Poor Risk Factors in Advanced Untreated RCC: MSKCC Criteria  Independent validation at the Cleveland Clinic identified 2 additional prognostic factors [2] –Previous radiotherapy –Presence of lung, hepatic, retroperitoneal nodal metastasis  Platelet and neutrophil counts > ULN identified as adverse prognostic factors for patients treated with VEGF-targeted therapies [3] 1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296. 2. Mekhail TM, et al. J Clin Oncol. 2005;23:832 841. 3. Heng DY, et al. J Clin Oncol. 2009;27:5794-5799. Risk Group by No. of Risk Factors Favorable0 Intermediate1 or 2 Poor3-5 MSKCC Criteria 2002 [1] KPS< 80% Time from diagnosis to treatment with IFN-α < 12 mos Hemoglobin< LLN LDH> 1.5 x ULN Corrected serum calcium> 10.0 mg/dL

21. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Tumor ResponseIL-2 + IFN (n = 91) HD IL-2 (n = 95) P Value Patients% % Overall response99.92223.2.018 CR33.388.4.214 PR66.61414.7 Durable 3-yr CR0077.4.014 Response by stratification criteria Liver or bone metastases1/392.610/4422.7.008 Primary tumor in place0/2706/2920.7.024 High-Dose IL-2 vs Subcutaneous IL-2 + IFN for Patients With mRCC: Phase III Trial  Grade 3, 4 toxicities more common in HD IL-2 arm vs IL-2 + IFN –Hypotension: 56.8% vs 1.1% –Neurologic AEs: 14.7% vs 3.3% –Hematologic, pulmonary, renal/electrolytes: 13.7% vs 0%, 1.1%, 3.3%, respectively McDermott DF, et al. J Clin Oncol. 2005;23:133-141.

22. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment First-line Treatment of RCC Overview StudyNORR vs IFN-α, % Median PFS vs IFN-α, Mos Final Median OS vs IFN-α, Mos Sunitinib vs IFN-α [1] 75047.0 vs 12.011 vs 5* P <.001 26.4 vs 21.8 P =.051 Bevacizumab + IFN-α vs IFN-α [2] 64931.0 vs 12.010.4 vs 5.5* P <.0001 23.3 vs 21.3 P =.1291 Bevacizumab + IFN-α vs IFN-α [3] 73225.5 vs 13.18.4 vs 4.9 P <.0001 18.3 vs 17.4 P =.069 Sorafenib vs IFN-α [4] (phase II) 1895.2 vs 8.75.7 vs. 5.6* P =.504 NA Pazopanib vs placebo [5] 23332.0 vs 4.011.1 vs 2.8 P <.0001 NA Temsirolimus vs IFN-α [6] (poor risk) 6268.6 vs 4.85.5 vs 3.1* P <.001 10.9 vs 7.3 P =.008 1. Motzer RJ, et al. J Clin Oncol. 2009;27:3584-3590. 2. Escudier BJ, et al. ASCO 2009. Abstract 5020. 3. Rini BI, et al. J Clin Oncol. 2009. Abstract LBA5019. 4. Escudier BJ, et al. J Clin Oncol. 2009;27:1280-1289. 5. Sternberg CN, et al. J Clin Oncol. 2010;28:1061-1068. 6. Hudes G, et al. N Engl J Med. 2007;356:2271-2281. *Independent assessment.

23. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Quality of Life for Patients With mRCC Receiving First-line Sunitinib vs IFN-α  QoL superior across all endpoints with sunitinib vs IFN-α  Patients receiving sunitinib reported better scores for FKSI-DRS vs those receiving IFN-α –Primary QoL endpoint –Indicates that patients receiving sunitinib experienced fewer disease-specific symptoms  Outcomes similar for patient groups in the US and EU, indicating minimal variation in QoL reporting or treatment experience Cella D, et al. ASCO 2009. Abstract 6529.

24. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Pazopanib vs Sunitinib as First-line Tx for Clear-Cell mRCC: Phase III COMPARZ  Primary endpoint: PFS  Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL Patients with locally advanced or mRCC clear-cell histology, no previous systemic therapy, measurable disease by CT/MRI (N = 927) ClinicalTrials.gov. NCT00720941. Pazopanib 800 mg/day Sunitinib 50 mg/day (schedule 4/2) RANDOMIZATIONRANDOMIZATION

25. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment 1.0 0.8 0.6 0.4 0.2 0 Survival Distribution Function 05101520253035 Time to Death (Mos) Arm 3: IFN + Tem Arm 2: Tem Arm 1: IFN *Modified MSKCC poor risk. † Stratified by country and nephrectomy status. ‡ SD  24 wks. Hudes G, et al. N Engl J Med. 2007;356:2271-2281. RANDOMIZATION†RANDOMIZATION† IFN-α 3 MU-18 MU (n = 207) CR + PR: 4.8% CR + PR + SD ‡ : 15.5% Tem 25 mg QW (n = 209) CR + PR: 8.6% CR + PR + SD: 32.1% 3/6 Poor-Risk Features:  LDH > 1.5 x ULN  Hb < LLN  Ca ++ (corrected) > 10 mg/dL  KPS 60-70  Initial diag to random < 1 yr  Multiple sites of metastases mRCC (N = 626) IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1% CR + PR + SD: 28.1% ParameterIFN Arm 1 (n = 207) Tem Arm 2 (n = 209) Tem + IFN Arm 3 (n = 210) Median survival, Mos 7.310.98.4 ComparisonsArm 2 to Arm 1 Arm 3 to Arm 1 Stratified log-rank P.008.70 Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment

26. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Temsirolimus vs IFN-α: Correlation With Survival in First-line, Poor-Risk mRCC Hudes G, et al. N Engl J Med. 2007;356:2271-2281. Dutcher JP, et al. Med Oncol. 2009;26:202-209. Dutcher JP, et al. ASCO 2007. Abstract 5033. Histology Clear cell Other 287 129 115 301 Age < 65 yrs ≥ 65 yrs Prognostic Risk Intermediate Poor Subgroup nHR (95% CI) 339 73 00.51.01.52.0 Temsirolimus BetterIFN-α Better

27. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment PFS in Untreated RCC by Risk Group *Included patients classified as intermediate risk per MSKCC (31% of temsirolimus group). 1. Motzer RJ, et al. J Clin Oncol. 2009;27:3584-3590. 2. Motzer RJ, et al. ASCO 2007. Abstract 5024. 3. Sternberg CN, et al. J Clin Oncol. 2010;28:1061-1068. 4. Escudier B, et al. Lancet. 2007;370:2103-2111. 5. Rini BI, et al. J Clin Oncol. 2008;26:5422-5428. 6. Escudier B, et al. J Clin Oncol. 2009;27:1280-1289. 7. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

28. Salvage Therapy

29. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Case 3  61-yr-old high school athletic director diagnosed with metastatic clear-cell RCC 8 mos ago  Initiated sunitinib –Achieved SD as best response  Returns complaining of fatigue with an ECOG PS of 1  CT scans show progression at multiple sites

30. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Which agent would you recommend for this patient?  Axitinib  Bevacizumab/interferon  Everolimus  Interferon  High-dose interleukin-2  Pazopanib  Sorafenib  Sunitinib  Temsirolimus  No treatment

31. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment IDST Expert Insight Results: Case 3  First choice –Expert 1: axitinib –Expert 2: everolimus –Expert 3: axitinib  Patient characteristics –Extensive metastatic clear-cell RCC –Previous sunitinib –ECOG PS 1  For this patient, either axitinib or everolimus were the first 2 choices of each of the 3 experts  Alternative agents recommended by at least 1 out of the 3 experts for this patient included bevacizumab plus interferon, pazopanib, or sorafenib RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

32. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Case 3  The athletic director is treated with everolimus but returns 5 mos later with a deteriorating ECOG PS  CT scans show further evidence of disease progression

33. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Which agent would you recommend for this patient now?  Axitinib  Bevacizumab/interferon  Everolimus  Interferon  High-dose interleukin-2  Pazopanib  Sorafenib  Sunitinib  Temsirolimus  No treatment

34. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment IDST Expert Insight Results: Case 3  First choice –Expert 1: axitinib –Expert 2: sorafenib –Expert 3: axitinib  Patient characteristics –Extensive metastatic clear- cell RCC –Previous sunitinib and everolimus –ECOG PS 2  Alternative agents recommended by at least 1 out of the 3 experts for this patient included bevacizumab plus interferon, or pazopanib (2 experts)  1 expert recommended no further therapy for this patient  All of the experts agreed that a clinical trial, if available, would be a reasonable option RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

35. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Sorafenib Activity in Patients With TKI- Refractory mRCC AgentPopulationNTTP/PFS, MosOS, Mos Sorafenib [1] Sunitinib refractory523.77.3 Sorafenib* [2] Sunitinib refractory274.4 16 Bevacizumab refractory 203.7 1. Di Lorenzo G, et al. J Clin Oncol. 2009;27:4469-4474. 2. Garcia JA, et al. Cancer. 2010;116:5383-5390. *Tumor burden reduction ≥ 5% observed in 30% of patients (43% of patients had SD).

36. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment 100 80 60 40 20 0 02468101624 Mos Everolimus vs Placebo: Survival Outcomes of RECORD-1 Patients at Risk, n Everolimus27719211551261010 Placebo139471562000 Patients at Risk, n Everolimus2772672402041641551311016130600 Placebo139131117100887456432713300 Probability (%) HR: 0.87 (95% CI: 0.65-1.17) Kaplan-Meier Median, Mos Everolimus : 14.78 Placebo: 14.39 Log-rank P =.162 HR: 0.33 (95% CI: 0.25-0.43) Median PFS, Mos Everolimus : 4.90 Placebo: 1.87 Log-rank P <.001 Everolimus (n = 277) Placebo (n = 139) PFS Central Radiology Review OS Everolimus (n = 277) Placebo (n = 139) Motzer RJ, et al. Cancer. 2010;116:4256-4265. 100 80 60 40 20 0 02468101214 Mos 1214182022

37. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment RECORD-1: Previous Therapies Previous Treatment, %Everolimus (n = 277) Placebo (n = 139) Nephrectomy9796 Radiotherapy3127 VEGFR-TKI therapy  Sunitinib4543  Sorafenib2931  Both26 Other systemic therapy  Immunotherapy6567  Chemotherapy1316  Hormone therapy24  Other53 Motzer RJ, et al. Cancer. 2010;116:4256-4265.

38. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment More potent Less potent Potency: IC50 (nM) VEGFR-1 VEGFR-2 VEGFR-3 Sunitinib [3] Pazopanib [4] Sorafenib [2] Axitinib [1] 0.01 0.1 1 10 100 1000 Most Potent for VEGFR-1, -2, and -3Most Selective for VEGFR -1, -2, and -3 Target Selectivity Axitinib [1] Sorafenib [2] Sunitinib [3] Pazopanib [4] VEGFR-2++++ PDGFR b+++ c-kit+++ FLT-3++ CSF-1RND++ Raf-1ND+ 1. Hu-Lowe DD, et al. Clin Cancer Res. 2008;14:7272-7283. 2. Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109. 3. Roskoski R. Biochem Biophys Res Commun. 2007;356:323-328. 4. Kumar R, et al. Mol Cancer Ther. 2007;6:2012-2021. +: inhibition of receptor kinase comparable (≤ 5 times) to potency for VEGFR-2 ND: not determined Axitinib: Recently Approved Potent and Selective VEGFR TKI

39. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Treat until PD, unmanageable AE, or withdrawal of consent Axitinib* 5 mg BID (n = 361)  Primary endpoint: PFS (independent review committee [IRC])  Secondary endpoints: OS, ORR (RECIST), duration of response, safety, QoL Patients with clear-cell mRCC, refractory to 1 previous first-line therapy (N = 723) Sorafenib 400 mg BID (n = 362) Stratified by previous regimen, ECOG PS (0 vs 1) * Starting dose 5 mg BID with option for dose titration to 10 mg BID. Rini BI, et al. Lancet. 2011;378:1931-1939. Phase III AXIS Study : Axitinib vs Sorafenib as Second-line Therapy for mRCC

40. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment 361256202145966438201010 3622241571005128126310 Patients at Risk, n Axitinib Sorafenib 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0246810 Mos Stratified HR: 0.665 (95% CI: 0.544-0.812; log-rank P <.0001) 1214161820 Axitinib Sorafenib mPFS, Mos 6.7 4.7 95% CI 6.3-8.6 4.6-5.6 Probability of PFS Rini BI, et al. Lancet. 2011;378:1931-1939. AXIS Trial: PFS (IRC Assessment)

41. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment AXIS Trial: Efficacy Results Previous Treatment Regimen Axitinib (n = 361) Sorafenib (n = 362) HRP Value* Cytokines (n = 251)  IRC  Investigator 12.1 12.0 6.5 8.3 0.464 0.636 <.0001.0049 Sunitinib (n = 389)  IRC  Investigator 4.8 6.5 3.4 4.5 0.741 0.636.0107.0002 Temsirolimus (n = 24)  IRC  Investigator 10.1 2.6 5.3 5.7 0.511 1.210.1425.6342 Bevacizumab (n = 59)  IRC  Investigator 4.2 6.5 4.7 4.5 1.147 0.753.6366.2126 Rini BI, et al. Lancet. 2011;378:1931-1939. PFS by Previous Regimen *1-sided log-rank test stratified by ECOG PS.

42. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Temsirolimus vs Sorafenib for Patients With Advanced RCC Failing Sunitinib Patients with mRCC, RECIST-defined PD while receiving first-line sunitinib, measurable disease, no CNS metastases, no previous therapy other than sunitinib (estimated enrollment N = 508) Temsirolimus 25 mg IV/wk  Primary endpoints: PFS (independent assessment), safety, and tolerability  Secondary endpoints: PFS (investigator assessment), RR (CR & PR), OS, PFS at 12, 24, 36 wks (independent assessment), duration of response  Phase III international, prospective, randomized, open-label, outpatient, multicenter study Sorafenib 400 mg PO BID ClinicalTrials.gov. NCT00474786. Stratified by nephrectomy status, MSKCC prognostic group, duration sunitinib response, RCC tumor histology

43. Treatment-Related Adverse Events and Their Management

44. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Treatment-Related Toxicities in Advanced Renal Cell Carcinoma  VEGF blockade (bevacizumab and VEGFR TKIs) –HTN, proteinuria, wound healing, bleeding –Higher incidence of grade 3/4 HTN with TKIs vs bevacizumab  VEGFR TKI class toxicities –Rash, HFSR, hair/skin depigmentation, cardiac dysfunction, myelosuppression, hypothyroidism, liver dysfunction –Incidence and severity vary with specific TKI  Other VEGF/VEGFR agent toxicities, predominantly grade 1/2 –Diarrhea, nausea/vomiting, fatigue, asthenia  mTOR class toxicities –Hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypophosphatemia, pneumonitis Schmidinger M, et al. Cancer Treat Rev. 2010;36:416-424.

45. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Comparative VEGF TKI Toxicity in Recent Trials of Advanced RCC  Pazopanib vs sunitinib [1] –Diarrhea, elevated ALT and bilirubin more common with pazopanib –HFS, mucositis, stomatitis, myelosuppression, dysgeusia, and fatigue (by FACIT-F) more common with sunitinib –HTN, AST elevation similar with each  Axitinib vs sorafenib [2] –HTN, fatigue, nausea more common with axitinib –HFS, rash, hypophosphatemia more common with sorafenib –Diarrhea, myelosuppression, ALT/AST elevations similar with each 1. Escudier BJ, et al. ASCO 2012. Abstract CRA4502. 2. Rini BI, et al. Lancet. 2011;378:1931-1939.

46. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Incidence of Metabolic Abnormalities With mTOR Inhibitors Across Trials Grade ≥ 3 Adverse Events, % Everolimus [1] (n = 269) Temsirolimus [2] (n = 208) Hyperglycemia1211 Hyperlipidemia/hypertriglyce ridemia < 13 Hypophosphatemia4NR Hypercholesterolemia31 1. Motzer RJ, et al. Lancet. 2008;372:449-456. 2. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

47. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Key Issues in Treatment-Related Toxicity Management in Advanced RCC  Maximizing exposure to therapeutic agents correlates with improved clinical outcomes for patients with advanced RCC  Dose reduction or discontinuation should be limited to patients experiencing severe (grade 3/4) toxicities that do not resolve to grade 1 or lower by withholding therapy  Emergent adverse events should be aggressively managed –Monitor LFTs in patients receiving TKI therapy (especially pazopanib) –Symptomatic management of dermatological and gastrointestinal toxicities such as rash, diarrhea, mucositis Houk BE, et al. Cancer Chemother Pharmacol. 2010;66:357-371. Eisen T, et al. J Natl Cancer Inst. 2012;104:93-113.

48. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Treatment-Related Toxicity Management in Advanced RCC: Comorbidities  Patients with history of diabetes –Optimize glycemic control before treatment –Monitor during treatment, especially with mTOR inhibitors  Patients with history of heart disease –Pretreatment evaluation for signs of heart failure, subclinical cardiovascular disease –On-treatment monitoring –Ongoing evaluation for heart failure –Exclude pulmonary embolism, hypothyroidism, or other causes of heart failure Eisen T, et al. J Natl Cancer Inst. 2012;104:93-113.

49. The Role of Surgery in Metastatic RCC

50. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment 1. Flanigan RC, et al. N Engl J Med. 2001;345:1655-1659. 2. Mickisch GH, et al. Lancet. 2001;358:966-970. Cytoreductive Nephrectomy SWOG [1] Median Survival, Mos IFN-  + nephrectomy (n = 120) 11.1 IFN-  (n = 121) 8.1 EORTC [2] Median Survival, Mos IFN-  + nephrectomy (n = 42) 17.0 IFN-  (n = 42) 7.0 Mos P =.05 P =.03 0 20 40 60 80 100 Survival (%) 024487296 0 20 40 60 80 100 Survival (%) 0122436 Mos

51. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Cytoreductive Nephrectomy: Guidelines  > 75% tumor debulking  No CNS metastases  Adequate pulmonary and cardiac function  ECOG PS 0 or 1  Predominantly clear-cell histology  Quantify the tumor’s biology and its affect on the patient –Performance score –Tumor distribution –Comorbidity Index Culp SH, et al. Cancer. 2010;116:3378-3388.

52. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Cytoreductive Nephrectomy: Factors Associated with Adverse Outcome  Serum LDH > ULN  Serum albumin < LLN  Retroperitoneal or supradiaphragmatic adenopathy  Symptomatic presentation due to metastases  ≥ T3 tumor  Liver metastasis Culp SH, et al. Cancer. 2010;116:3378-3388.

53. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Metastasectomy in Renal Cell Carcinoma  Characteristics associated with improved survival in patients undergoing metastasectomy for first recurrence –Disease-free interval > 1 yr –Single site of metastasis –Lung better than brain  5-yr survival of 44% –Similar 5-yr survival rates with curative resection upon second and third recurrence Kavolius JP, et al. J Clin Oncol. 1998;16:2261-2266.

54. Nonclear-Cell Renal Cell Carcinoma

55. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Nonclear-Cell RCC Histologic Subtypes and Resistant Phenotypes Type [1] Frequency Gene Clear cell 75% VHL Papillary type 1 5% c-Met Papillary type 2 10% FH Chromophobe 5% BHD Oncocytoma 5% BHD Sarcomatoid variant is an aggressive form of RCC that can occur in any histology subtype [2] 1. Linehan WM, et al. J Urol. 2003;170:2163-2172. 2. Chowdhury S, et al. Hematol Oncol Clin North Am. 2011;25:853-869.

56. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Nonclear-Cell RCC: Prognosis and Treatment  5-yr survival rates [1] –Chromophobe: 87.9% (localized) –Papillary: 79.4% (localized), 10.3% (nonlocalized)  Treatment –Clinical trial recommended by all 3 experts –No current standard of care –Targeted therapy –Agents that may be active include sunitinib, sorafenib, temsirolimus, and erlotinib (papillary) [2] –Lower efficacy than in clear-cell RCC –Current evidence limitations: retrospective analyses, small patient populations, lack of confirmed histology 1. Patard JJ, et al. J Clin Oncol. 2005;23:2763-2771. 2. Chowdhury S, et al. Hematol Oncol Clin North Am. 2011;25:853-869.

57. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Future Directions  New agents  Combination therapy  Markers of efficacy

58. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Investigational Agents in Trials AgentClassTarget(s)Trial Phase Tivozanib [1,2] TKIVEGFRIII Dovitinib [2] TKIFGFR, VEGFR, PDGFRIII (ongoing) Lenvatinib [3] TKIFGFR, VEGFR, PDGFRII (ongoing) GDC-0980 [4] Kinase inhibitormTOR, PI3 kinaseII (planned) MDX-1106 [1] MoAbPD-1II, III (planned) AGS-003 [5] Dendritic cellTumor antigensII, III (planned) IMA901 [6] VaccineMultipeptideIII (ongoing) 1. Gross-Goupil M, et al. Curr Urol Rep. 2012;13:16-23. 2. Motzer RJ, et al. ASCO 2012. Abstract 4501. 3. Boss DS, et al. Br J Cancer. 2012;106:1598-1604. 4. Wallin JJ, et al. Mol Cancer Ther. 2011;10:2426-2436. 5. Amin A, et al. ASCO 2010. Abstract 4588. 6. Rini BI, et al. ASCO 2011. Abstract TPS183.

59. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Phase III TIVO-1: Tivozanib (AV-951) vs Sorafenib for Patients With Advanced RCC  Primary endpoint: PFS  Secondary endpoints: ORR, safety Tivozanib 1.5 mg/day PO, 3 wks of 4-wk cycle (n = 260) Sorafenib 400 mg PO BID (n = 257) Motzer RJ, et al. ASCO 2012. Abstract 4501. Patients with recurrent or metastatic clear-cell RCC, previous nephrectomy, ≤ 1 previous systemic therapy, no previous VEGF or mTOR-targeting treatment, ECOG PS 0-1 (N = 517) Stratified by previous treatments (0, 1), number of metastatic sites (1 vs ≥ 2), geographic region

60. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment TIVO-1: Efficacy  Advantage in median PFS with tivozanib –ITT population: 11.9 vs 9.1 mos (HR: 0.797; P =.042) –Previously untreated population: 12.7 vs 9.1 mos (HR: 0.756; P =.037)  ORR improved with tivozanib –33% vs 23% (P =.014) Motzer RJ, et al. ASCO 2012. Abstract 4501.

61. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment TIVO-1: Toxicity Toxicity, %Tivozanib (n = 259)Sorafenib (n = 257) All GradesGrade 3 (4)All GradesGrade 3 (4) More with sorafenib  Diarrhea 222326  HFS 1325417  Alopecia 20210 More with tivozanib  HTN 4424 (2)3417 (< 1)  Dysphonia 21050  Back pain 14372 Significantly fewer dose interruptions (18% vs 35%) and dose reductions (12% vs 43%) with tivozanib compared with sorafenib (P <.001 for both comparisons). Motzer RJ, et al. ASCO 2012. Abstract 4501.

62. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Dovitinib (TKI258): FGFR as a Target in RCC  Preclinical studies indicate that FGF is a possible escape mechanism after the initiation of anti-VEGF therapy [1]  Phase I: dovitinib in VEGF-refractory RCC [2] –N = 18 –1 PR, 2 prolonged SD  MTD: 500 mg 5 days on/2 days off  Modulation of VEGFR-2 and FGFR  Toxicities: nausea, vomiting, diarrhea, hypertension 1. Casanovas O, et al. Cancer Cell. 2005;8:299-309. 2. Angevin E, et al. ASCO 2009. Abstract 3563. Enzymatic Assay Target TKI258 IC 50 nM FGFR-18 FGFR-240 FGFR-39 FLT31 c-KIT2 VEGFR-110 VEGFR-213 VEGFR-38 PDGFR-β12 CSFR-115

63. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment Phase II TORAVA: Temsirolimus + Bevacizumab for Patients With mRCC  For patients receiving combination temsirolimus and bevacizumab –51% discontinued treatment for reasons other than disease progression –77% experienced grade ≥ 3 AEs –No evidence of synergistic or additive efficacy Négrier S, et al. Lancet Oncol. 2011;12:673-680. *Dosing: temsirolimus 25 mg/wk IV, bevacizumab 10 mg/kg IV q2wks, sunitinib 50 mg/day PO 4 wks on/2 wks off, IFN-α 9MU SC TIW. Patients with clear-cell mRCC, measurable disease, ECOG PS 0-2; previously untreated (N = 171) 2 1 1 Stratified by center, ECOG PS (0-1 vs 2) Temsirolimus* + Bevacizumab* (n = 88) Sunitinib* (n = 42) Bevacizumab* + IFN-α* (n = 41) RANDOMIZERANDOMIZE

64. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment INTORACT: Bevacizumab + Temsirolimus vs Bevacizumab + IFN-α for Advanced RCC  Primary endpoints: PFS (independently assessed)  Secondary endpoints: safety, PFS (investigator assessed), ORR, and OS ClinicalTrials.gov. NCT00631371. Bevacizumab 10 mg/kg IV q8w + Temsirolimus 25 mg IV weekly Bevacizumab 10 mg/kg IV q8w + IFN-α 9MU SC TIW Patients with clear-cell, advanced RCC, no CNS metastases, and no previous systemic treatment (Estimated N = 790)  Phase IIIb, randomized, open-label study

65. clinicaloptions.com/oncology Expert Insight Into Advanced RCC Treatment OS by HTN Status (DBP ≥ 90 mm Hg) on Sunitinib Probability of OS Mos With HTN (n = 363) Median OS: 32.2 mos Without HTN (n = 171) Median OS: 14.9 mos Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 05051015202530354045 P <.0001

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