Expert Insight Into Optimal Treatment for Individuals With Advanced Renal Cell Cancer This program is supported by an educational grant from

Therapeutic Decision Making in Advanced Renal Cell Carcinoma: A 2012 Perspective Robert Motzer, MD Attending Physician Memorial Sloan-Kettering Cancer Center New York, New York

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Faculty Disclosure Robert Motzer, MD, has disclosed that he has received consulting fees from Pfizer.

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 RCC, renal cell carcinoma.

Background and Treatment of mRCC ~ 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] 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] mRCC, metastatic renal cell carcinoma; OS, overall survival; PFS, progression-free survival. 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.

The Biology of Clear-Cell RCC: VHL Gene Mutation CUL2 Rbx1 VHL complex disrupted Elongin B Elongin C VHL protein β-domain Mutant α-domain HIFα accumulation Activation of hypoxia-inducible genes HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau gene. VEGF PDGF Glut1 Autocrine Growth Stimulation Angiogenesis Glucose Transport Bratslavsky G, et al. Clin Cancer Res. 2007;13:4667-4671.

RCC Therapy: Targeting VEGF at Multiple Levels Everolimus Temsirolimus Mutant pVHL HIF mTOR Bevacizumab VEGF PDGF HIF, hypoxia-inducible factor; mTOR, mammalian target or rapamycin; PDGF, platelet-derived growth factor; RCC, renal cell carcinoma; VEGF, vascular endothelial growth Factor. Sunitinib Sorafenib Pazopanib VEGFR PDGFR Axitinib Kaelin WG Jr. Clin Cancer Res. 2004;10:6290S-6295S.

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 QoL, quality of life; RCC, renal cell carcinoma.

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.

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.

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

First-line Therapy

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 CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; HTN, hypertension; PMH, past medical history; PS, performance status.

Which agent would you recommend for this patient? Axitinib Bevacizumab/interferon Everolimus Interferon High-dose interleukin-2 Pazopanib Sorafenib Sunitinib Temsirolimus No 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 ECOG, Eastern Cooperative Oncology Group; IL-2, interleukin-2; MSKCC, Memorial Sloan-Kettering Cancer Center; PS, performance status; RCC, renal cell carcinoma. RCC IDST. Available at: http://clinicaloptions.com/RCCtInsight.

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 ECOG, Eastern Cooperative Oncology Group; PMH, past medical history; LDH, lactate dehydrogenase; PS, performance status; RCC, renal cell carcinoma; ULN, upper limit of normal.

Which agent would you recommend for this patient? Axitinib Bevacizumab/interferon Everolimus Interferon High-dose interleukin-2 Pazopanib Sorafenib Sunitinib Temsirolimus No 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 ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center; PS, performance status; RCC, renal cell carcinoma. RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

Poor Risk Factors in Advanced Untreated RCC: MSKCC Criteria 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 Risk Group by No. of Risk Factors Favorable Intermediate 1 or 2 Poor 3-5 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] IFN, interferon; KPS, Karnofsky performance status; LDH, lactate dehydrogenase; LLN, lower limit of normal; MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma; ULN, upper limit of normal. 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.

High-Dose IL-2 vs Subcutaneous IL-2 + IFN for Patients With mRCC: Phase III Trial Tumor Response IL-2 + IFN (n = 91) HD IL-2 (n = 95) P Value Patients % Overall response 9 9.9 22 23.2 .018 CR 3 3.3 8 8.4 .214 PR 6 6.6 14 14.7 Durable 3-yr CR 7 7.4 .014 Response by stratification criteria Liver or bone metastases 1/39 2.6 10/44 22.7 .008 Primary tumor in place 0/27 6/29 20.7 .024 AE, adverse event; CR, complete response; HD, high dose; IFN, interferon; IL-2, interleukin-2; mRCC, metastatic renal cell carcinoma; PR, partial response. 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.

First-line Treatment of RCC Overview Study N ORR vs IFN-α, % Median PFS vs IFN-α, Mos Final Median OS vs IFN-α, Mos Sunitinib vs IFN-α[1] 750 47.0 vs 12.0 11 vs 5* P < .001 26.4 vs 21.8 P = .051 Bevacizumab + IFN-α vs IFN-α[2] 649 31.0 vs 12.0 10.4 vs 5.5* P < .0001 23.3 vs 21.3 P = .1291 Bevacizumab + IFN-α vs IFN-α[3] 732 25.5 vs 13.1 8.4 vs 4.9 P < .0001 18.3 vs 17.4 P = .069 Sorafenib vs IFN-α[4] (phase II) 189 5.2 vs 8.7 5.7 vs. 5.6* P = .504 NA Pazopanib vs placebo[5] 233 32.0 vs 4.0 11.1 vs 2.8 P < .0001 Temsirolimus vs IFN-α[6] (poor risk) 626 8.6 vs 4.8 5.5 vs 3.1* P < .001 10.9 vs 7.3 P = .008 IFN, interferon; NA, data not provided in the original study; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma. *Independent assessment. 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. 22 22

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 FKSI-DRS, Function Assessment of Cancer Therapy - Kidney Symptom Index - Disease-Related Symptoms; IFN, interferon; mRCC, metastatic renal cell carcinoma; QoL, quality of life. Cella D, et al. ASCO 2009. Abstract 6529.

Pazopanib vs Sunitinib as First-line Tx for Clear-Cell mRCC: Phase III COMPARZ Pazopanib 800 mg/day Patients with locally advanced or mRCC clear-cell histology, no previous systemic therapy, measurable disease by CT/MRI (N = 927) RANDOM I Z A T ON CT, computed tomography; mRCC, metastatic renal cell carcinoma; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life. Sunitinib 50 mg/day (schedule 4/2) Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL ClinicalTrials.gov. NCT00720941. 24

Survival Distribution Function Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment R A N D O M I Z T N† 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-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% IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1% CR + PR + SD: 28.1% 1.0 Parameter IFN Arm 1 (n = 207) Tem Arm 2 (n = 209) Tem + IFN Arm 3 (n = 210) Median survival, Mos 7.3 10.9 8.4 Comparisons Arm 2 to Arm 1 Arm 3 to Arm 1 Stratified log-rank P .008 .70 0.8 CR, complete response; IFN, interferon; KPS, Karnofsky Performance Scale; LDH, lactate dehydrogenase; LLN, lower limit of normal; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; MU, million units; OS, overall survival; PR, partial response; QW, each week; SD, stable disease; Tem, temsirolimus; ULN, upper limit of normal. 0.6 Survival Distribution Function Arm 2: Tem 0.4 Arm 1: IFN 0.2 Arm 3: IFN + Tem 5 10 15 20 25 30 35 Time to Death (Mos) *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. 25

Temsirolimus vs IFN-α: Correlation With Survival in First-line, Poor-Risk mRCC Subgroup n HR (95% CI) Histology Clear cell Other 339 73 Age < 65 yrs ≥ 65 yrs 287 129 Prognostic Risk Intermediate Poor 115 301 CI, confidence interval; HR, hazard ratio; IFN, interferon; mRCC, metastatic renal cell carcinoma. 0.5 1.0 1.5 2.0 Temsirolimus Better IFN-α Better 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.

PFS in Untreated RCC by Risk Group Agent(s) PFS, Mos Good Intermediate Poor HR vs IFN Sunitinib[1,2] 11.0 14.5 10.6 3.7 0.54 Pazopanib[3] 11.1 -- 0.40 (vs placebo) Bev + IFN (AVOREN)[4] 10.2 12.9 2.2 0.63 Bev + IFN (CALGB 90206)[5] 8.5 8.4 3.3 0.71 Sorafenib[6] 5.7 Trend for improved PFS (HR:1.16) 0.88 Temsirolimus[7] 3.8 NA 3.8* NR Bev, bevacizumab; HR, hazard ratio; IFN, interferon; MSKCC, Memorial Sloan-Kettering Cancer Center; NA, not applicable; NR, not reported; PFS, progression-free survival; RCC, renal cell carcinoma. *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. 27

Salvage Therapy

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 CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PS, performance status; RCC, renal cell carcinoma; SD, stable disease.

Which agent would you recommend for this patient? Axitinib Bevacizumab/interferon Everolimus Interferon High-dose interleukin-2 Pazopanib Sorafenib Sunitinib Temsirolimus No 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 ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; PS, performance status; RCC, renal cell carcinoma. RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

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 CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PS, performance status.

Which agent would you recommend for this patient now? Axitinib Bevacizumab/interferon Everolimus Interferon High-dose interleukin-2 Pazopanib Sorafenib Sunitinib Temsirolimus No 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 ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; PS, performance status; RCC, renal cell carcinoma. RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

Sorafenib Activity in Patients With TKI-Refractory mRCC Agent Population N TTP/PFS, Mos OS, Mos Sorafenib[1] Sunitinib refractory 52 3.7 7.3 Sorafenib*[2] 27 4.4 16 Bevacizumab refractory 20 *Tumor burden reduction ≥ 5% observed in 30% of patients (43% of patients had SD). mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SD, stable disease; TKI, tyrosine kinase inhibitor; TTP, time to progression. 1. Di Lorenzo G, et al. J Clin Oncol. 2009;27:4469-4474. 2. Garcia JA, et al. Cancer. 2010;116:5383-5390. 35

Everolimus vs Placebo: Survival Outcomes of RECORD-1 PFS Central Radiology Review OS 100 HR: 0.33 (95% CI: 0.25-0.43) Median PFS, Mos Everolimus : 4.90 Placebo: 1.87 Log-rank P < .001 100 HR: 0.87 (95% CI: 0.65-1.17) Kaplan-Meier Median, Mos Everolimus : 14.78 Placebo: 14.39 Log-rank P = .162 80 80 60 60 Probability (%) Everolimus (n = 277) Placebo (n = 139) 40 40 Everolimus (n = 277) 20 20 Placebo (n = 139) CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. 2 4 6 8 10 12 14 2 4 6 8 10 12 14 16 18 20 22 24 Mos Mos Patients at Risk, n Everolimus 277 192 115 51 26 10 1 Placebo 139 47 15 6 2 Patients at Risk, n Everolimus 277 267 240 204 164 155 131 101 61 30 6 Placebo 139 117 100 88 74 56 43 27 13 3 Motzer RJ, et al. Cancer. 2010;116:4256-4265.

RECORD-1: Previous Therapies Previous Treatment, % Everolimus (n = 277) Placebo (n = 139) Nephrectomy 97 96 Radiotherapy 31 27 VEGFR-TKI therapy Sunitinib 45 43 Sorafenib 29 Both 26 Other systemic therapy Immunotherapy 65 67 Chemotherapy 13 16 Hormone therapy 2 4 Other 5 3 Motzer RJ, et al. Cancer. 2010;116:4256-4265.

Axitinib: Recently Approved Potent and Selective VEGFR TKI Most Potent for VEGFR-1, -2, and -3 Most Selective for VEGFR -1, -2, and -3 More potent 0.01 Target Selectivity   Axitinib[1] Sorafenib[2] Sunitinib[3] Pazopanib[4] VEGFR-2 + PDGFR b c-kit FLT-3 CSF-1R ND Raf-1 Axitinib[1] 0.1 Sunitinib[3] Pazopanib[4] Sorafenib[2] 1 Potency: IC50 (nM) 10 +: inhibition of receptor kinase comparable (≤ 5 times) to potency for VEGFR-2 ND: not determined c-KIT, v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog; FLT, FMS-like tyrosine kinase; CSF, colony-stimulating factor; ND, not determined; PDGFR, platelet-derived growth factor; Raf, v-raf-1 murine leukemia viral oncogene homolog 1;TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. 100 Less potent VEGFR-1 VEGFR-2 VEGFR-3 1000 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.

Treat until PD, unmanageable AE, or withdrawal of consent Phase III AXIS Study : Axitinib vs Sorafenib as Second-line Therapy for mRCC Stratified by previous regimen, ECOG PS (0 vs 1) Axitinib* 5 mg BID (n = 361) Patients with clear-cell mRCC, refractory to 1 previous first-line therapy (N = 723) Treat until PD, unmanageable AE, or withdrawal of consent AE, adverse event; BID, twice daily; ECOG, Eastern Cooperative Oncology Group; mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors. Sorafenib 400 mg BID (n = 362) *Starting dose 5 mg BID with option for dose titration to 10 mg BID. Primary endpoint: PFS (independent review committee [IRC]) Secondary endpoints: OS, ORR (RECIST), duration of response, safety, QoL Rini BI, et al. Lancet. 2011;378:1931-1939. 39

AXIS Trial: PFS (IRC Assessment) 1.0 mPFS, Mos 6.7 4.7 95% CI 6.3-8.6 4.6-5.6 0.9 Axitinib Sorafenib 0.8 0.7 Stratified HR: 0.665 (95% CI: 0.544-0.812; log-rank P < .0001) 0.6 Probability of PFS 0.5 0.4 0.3 0.2 CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; mPFS, median progression-free survival. 0.1 2 4 6 8 10 12 14 16 18 20 Mos Patients at Risk, n Axitinib 361 256 202 145 96 64 38 20 10 1 Sorafenib 362 224 157 100 51 28 12 6 3 1 Rini BI, et al. Lancet. 2011;378:1931-1939.

AXIS Trial: Efficacy Results PFS by Previous Regimen Previous Treatment Regimen Axitinib (n = 361) Sorafenib (n = 362) HR P Value* Cytokines (n = 251) IRC Investigator 12.1 12.0 6.5 8.3 0.464 0.636 < .0001 .0049 Sunitinib (n = 389) 4.8 3.4 4.5 0.741 .0107 .0002 Temsirolimus (n = 24) 10.1 2.6 5.3 5.7 0.511 1.210 .1425 .6342 Bevacizumab (n = 59) 4.2 4.7 1.147 0.753 .6366 .2126 ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival; PS, performance status. *1-sided log-rank test stratified by ECOG PS. Rini BI, et al. Lancet. 2011;378:1931-1939.

(estimated enrollment Temsirolimus vs Sorafenib for Patients With Advanced RCC Failing Sunitinib Phase III international, prospective, randomized, open-label, outpatient, multicenter study Stratified by nephrectomy status, MSKCC prognostic group, duration sunitinib response, RCC tumor histology 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 Sorafenib 400 mg PO BID BID, twice daily; CNS, central nervous system; CR, complete response; IV, intravenous; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; PR, partial response; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; RR, response rate. 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 ClinicalTrials.gov. NCT00474786.

Treatment-Related Adverse Events and Their Management

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 HFSR, hand-foot skin reaction; HTN, hypertension; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Schmidinger M, et al. Cancer Treat Rev. 2010;36:416-424.

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 ALT, alanine aminotransferase; AST, aspartate aminotransferase; HFS, hand-foot syndrome; HTN, hypertension; TKI, tyrosine kinase inhibitor; 1. Escudier BJ, et al. ASCO 2012. Abstract CRA4502. 2. Rini BI, et al. Lancet. 2011;378:1931-1939.

Incidence of Metabolic Abnormalities With mTOR Inhibitors Across Trials Grade ≥ 3 Adverse Events, % Everolimus[1] (n = 269) Temsirolimus[2] (n = 208) Hyperglycemia 12 11 Hyperlipidemia/hypertriglyceridemia < 1 3 Hypophosphatemia 4 NR Hypercholesterolemia 1 NR, not reported. 1. Motzer RJ, et al. Lancet. 2008;372:449-456. 2. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

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 LFT, liver function test; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor. Houk BE, et al. Cancer Chemother Pharmacol. 2010;66:357-371. Eisen T, et al. J Natl Cancer Inst. 2012;104:93-113.

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 RCC, renal cell carcinoma. Eisen T, et al. J Natl Cancer Inst. 2012;104:93-113.

The Role of Surgery in Metastatic RCC RCC, renal cell carcinoma.

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) 7.0 100 100 80 P = .05 80 P = .03 60 60 Survival (%) Survival (%) 40 40 EORTC, European Organization for the Research and Treatment of Cancer; IFN, interferon; SWOG, Southwest Oncology Group. 20 20 24 48 72 96 12 24 36 Mos Mos 1. Flanigan RC, et al. N Engl J Med. 2001;345:1655-1659. 2. Mickisch GH, et al. Lancet. 2001;358:966-970. 50

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 CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status. Culp SH, et al. Cancer. 2010;116:3378-3388.

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 LDH, lactate dehydrogenase; LLN, lower limit of normal; ULN, upper limit of normal Culp SH, et al. Cancer. 2010;116:3378-3388.

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.

Nonclear-Cell Renal Cell Carcinoma

Nonclear-Cell RCC Histologic Subtypes and Resistant Phenotypes Frequency Gene Clear cell 75% VHL Papillary type 1 5% c-Met Papillary type 2 10% FH Chromophobe 5% BHD Oncocytoma 5% BHD BHD, Birt-Hogg-Dube syndrome gene; FH, fumarate hydratase gene; RCC, renal cell carcinoma; VHL, von Hippel-Lindau gene. 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.

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 RCC, renal cell carcinoma. 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.

Future Directions New agents Combination therapy Markers of efficacy

Investigational Agents in Trials Class Target(s) Trial Phase Tivozanib[1,2] TKI VEGFR III Dovitinib[2] FGFR, VEGFR, PDGFR III (ongoing) Lenvatinib[3] II (ongoing) GDC-0980[4] Kinase inhibitor mTOR, PI3 kinase II (planned) MDX-1106[1] MoAb PD-1 II, III (planned) AGS-003[5] Dendritic cell Tumor antigens IMA901[6] Vaccine Multipeptide FGFR, fibroblast growth factor receptor; MoAb, monoclonal antibody; mTOR, mammalian target of rapamycin; PD-1, programmed death-1; TKI, tyrosine kinase inhibitor. 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.

Tivozanib 1.5 mg/day PO, 3 wks of 4-wk cycle Phase III TIVO-1: Tivozanib (AV-951) vs Sorafenib for Patients With Advanced RCC Stratified by previous treatments (0, 1), number of metastatic sites (1 vs ≥ 2), geographic region 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) Tivozanib 1.5 mg/day PO, 3 wks of 4-wk cycle (n = 260) Sorafenib 400 mg PO BID (n = 257) BID, twice daily; ECOG PS, ECOG , Eastern Cooperative Oncology Group performance score; ORR, objective response rate; PFS, progression-free survival; PO, orally; RCC, renal cell carcinoma. Primary endpoint: PFS Secondary endpoints: ORR, safety Motzer RJ, et al. ASCO 2012. Abstract 4501.

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) HR, hazard ratio; ITT, intent-to-treat; ORR, objective response rate; PFS, progression-free survival. Motzer RJ, et al. ASCO 2012. Abstract 4501.

TIVO-1: Toxicity Toxicity, % Tivozanib (n = 259) Sorafenib (n = 257) All Grades Grade 3 (4) More with sorafenib Diarrhea 22 2 32 6 HFS 13 54 17 Alopecia 21 More with tivozanib HTN 44 24 (2) 34 17 (< 1) Dysphonia 5 Back pain 14 3 7 HFS, hand-foot syndrome; HTN, hypertension. 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.

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 Enzymatic Assay Target TKI258 IC50 nM FGFR-1 8 FGFR-2 40 FGFR-3 9 FLT3 1 c-KIT 2 VEGFR-1 10 VEGFR-2 13 VEGFR-3 PDGFR-β 12 CSFR-1 15 FGF, fibroblast growth factor; MTD, maximum tolerated dose; PR, partial response; RCC, renal cell carcinoma; SD, stable disease; VEGF, vascular endothelial growth factor. Casanovas O, et al. Cancer Cell. 2005;8:299-309. 2. Angevin E, et al. ASCO 2009. Abstract 3563.

Phase II TORAVA: Temsirolimus + Bevacizumab for Patients With mRCC Stratified by center, ECOG PS (0-1 vs 2) Temsirolimus* + Bevacizumab* (n = 88) R A N D O M I Z E Patients with clear-cell mRCC, measurable disease, ECOG PS 0-2; previously untreated (N = 171) 2 1 Sunitinib* (n = 42) 1 Bevacizumab* + IFN-α* (n = 41) *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. AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance score; IFN, interferon; IV, intravenous; mRCC, metastatic renal cell carcinoma; MU, million units; PO, orally; q2wks, every 2 weeks; SC, subcutaneously; TIW, every 3 weeks. 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.

INTORACT: Bevacizumab + Temsirolimus vs Bevacizumab + IFN-α for Advanced RCC Phase IIIb, randomized, open-label study Bevacizumab 10 mg/kg IV q8w + Temsirolimus 25 mg IV weekly Patients with clear-cell, advanced RCC, no CNS metastases, and no previous systemic treatment (Estimated N = 790) Bevacizumab 10 mg/kg IV q8w + IFN-α 9MU SC TIW CNS, central nervous system; IFN, interferon; IV, intravenous; MU, million units; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q8wks, every 8 weeks; RCC, renal cell carcinoma; SC, subcutaneously; TIW, three times weekly. Primary endpoints: PFS (independently assessed) Secondary endpoints: safety, PFS (investigator assessed), ORR, and OS ClinicalTrials.gov. NCT00631371.

OS by HTN Status (DBP ≥ 90 mm Hg) on Sunitinib With HTN (n = 363) Median OS: 32.2 mos 1.0 0.9 Without HTN (n = 171) Median OS: 14.9 mos 0.8 0.7 P < .0001 0.6 Probability of OS 0.5 0.4 0.3 DBP, diastolic blood pressure; HTN, hypertension; OS, overall survival. 0.2 0.1 5 10 15 20 25 30 35 40 45 50 Mos Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773. 65

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