Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

Part III – Renal Cell Carcinoma Thursday, September 13, :30 PM – 8:30 PM ET RTP TV: A Live CME Webcast Series Focused on Emerging Data Sets and Novel Therapeutic Strategies in the Management of Common Cancers

Thomas E Hutson, DO, PharmD Director, GU Oncology Program Co-Director, GU Center of Excellence, Texas Oncology, PA Charles A Sammons Cancer Center and Baylor University Medical Center Professor of Medicine, Texas A&M Health Science Center College of Medicine Co-Chair of GU Research, US Oncology Dallas, Texas Robert J Motzer, MD Medical Oncologist Memorial Sloan-Kettering Cancer Center New York, New York Neil Love, MD Research To Practice Miami, Florida

Agenda — Renal Cell Carcinoma New Developments in mRCC –Anti-PD-1 –Tivozanib –Axitinib –Cabozantinib –Pazopanib Algorithm for Selecting Systemic Therapy Management of Toxicities with Novel Agents –mTOR inhibitors –TKIs

New Developments in mRCC

At this time, there is no known tissue or serum predictor of response to anti-PD-1.

Blockade of T-Cell Signaling in Tumor Immunotherapy Ribas A et al. N Engl J Med 2012;366(26):

Clinical activity and safety of anti-PD-1 (BMS , MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC) McDermott DF et al. Proc ASCO 2012;Abstract 4505.

Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer Topalian SL et al. N Engl J Med 2012;366(26): Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer Brahmer JR et al. N Engl J Med 2012;366(26):

Phase I Studies of Anti-PD-1/PD-L1 Agents: Advanced RCC Patient Subgroup Clinical parameter Anti-PD-1 a Anti-PD-L1 b 10 mg/kg (n = 17) 1 mg/kg (n = 17) 10 mg/kg (n = 16) Objective response rate 4 (24%)5 (31%)2 (12%) Stable disease at ≥24 weeks 4 (24%)5 (31%)7 (41%) Duration of response (range) >17.5 mo8.4 - >22.3 mo mo PFS rate at 24 weeks47%67%53% a Topalian SL et al. N Engl J Med 2012;366(26): b Brahmer JR et al. N Engl J Med 2012; 366(26):

Anti-PD-1 Treatment-Related Adverse Events: Advanced RCC Patient Subgroup (n = 34) Adverse event (AE)*All gradesGrades 3-4 † Any adverse event82%18% Fatigue38%0% Rash24%0% Pruritis18%3% Diarrhea15%0% Decreased appetite9%0% Nausea6%0% McDermott DF et al. Proc ASCO 2012;Abstract * All doses of anti-PD-1 † Most common Grade 3-4 AEs were respiratory system disorders (2 pts) and hypophosphatemia (2 pts).

Agent IC 50 (nM) VEGFR-1VEGFR-2VEGFR-3 Tivozanib Axitinib Sunitinib21017 Pazopanib Dovitinib10138 SorafenibNot reported9020 Eskens FALM et al. Proc AACR 2008;Abstract LB-201; Nakamura K et al. Cancer Res 2006;66: ; Chow LQ et al. J Clin Oncol 2007;25:884-96; Lee SH et al. Clin Cancer Res 2005;11: Relative Potencies of TKIs

Tivozanib is associated with fewer side effects and is more tolerable than sorafenib.

Tivozanib: Summary of Key Attributes Potent pan-VEGFR inhibitor Highly selective TKI for the VEGF receptors Favorable pharmacokinetic profile that enables once-daily dosing Oral administration Chow LQ et al. J Clin Oncol 2007;25: Eskens FALM et al. Proc AACR 2008;LB-201.

Tivozanib versus Sorafenib as Initial Targeted Therapy for Patients with Advanced Renal Cell Carcinoma: Results from a Phase III Randomized, Open- Label, Multicenter Trial Motzer RJ et al. Proc ASCO 2012;Abstract 4501.

Primary endpoint: Progression-free survival superiority of tivozanib TIVO-1: A Phase III Trial of First-Line Tivozanib versus Sorafenib in Advanced RCC Tivozanib (n = 260) Tivozanib (n = 260) R Advanced RCC Clear cell histology Prior nephrectomy No prior VEGF or mTOR therapy Sorafenib (n = 257) Sorafenib (n = 257) Crossover to tivozanib via separate protocol Progression Motzer RJ et al. Proc ASCO 2012;Abstract 4501.

TIVO-1: Progression-Free Survival With permission from Motzer RJ et al. Proc ASCO 2012;Abstract Time (months) Probability of PFS NMedian PFSHRp-value Tivozanib mo Sorafenib mo

TIVO-1: Treatment-Emergent Adverse Events Adverse event, % Tivozanib (n = 259) Sorafenib (n = 257) All gradeGrade 3 (4)All gradeGrade 3 (4) Diarrhea Hand-foot syndrome Alopecia20210 Hypertension4424 (2)3417 (<1) Dysphonia21050 Motzer RJ et al. Proc ASCO 2012;Abstract Fewer dose interruptions and reductions and treatment discontinuations occurred on the tivozanib arm.

Sorafenib: Reported Progression-Free Survival Values Over Time With permission from Eisen T. ASCO 2012 Discussant Japan (PH2) RDD (PH2) Target (PH3) NA-ARCCS (Expanded Access) Sorafenib vs IFN (PH2) AXIS/Prior Cytokine (PH3) EU-ARCCS Overall (Expanded Access) Italian Clinical Experience AMG 386 (PH2) and Japan CI. Exp. EU-ARCCS ECOG-0 (Expanded Access) Yellow = includes treatment naïve patients Gray = prior treatment with cytokine therapy and/or selective therapy targeting the angiogenesis pathway Publication Year Reported Median PFS (Months)

Sorafenib Studies Safety TARGET Ph IIIAMG 386TIVO-1 Hypertension (Grade 3-4) %17 (4)46 (14)34 (17) Fatigue (Grade 3-4) % 37 (5)22 (0) 16 (4) HFS (Grade 3-4) %30 (6)54 (28)54 (17) Diarrhea (Grade 3-4) %43 (2)56 (8)32 (6) Overall AEs (Grade 3-4) %95 (38)100 (86)NR Dose reduction/ interruption % 13 DR 21 DI 35 DR 61 DI 43 DR 35 DI Eisen T. ASCO 2012 Discussant

Primary endpoint: Patient preference for tivozanib or sunitinib after having received both in sequence Secondary endpoints: Safety, frequency of dose modifications and quality of life TAURUS: A Phase II Crossover-Controlled Study of First-Line Tivozanib versus Sunitinib in Advanced RCC Tivozanib Sunitinib R Untreated, advanced RCC Target Accrual: 160 (Open) 1:1 Tivozanib Sunitinib Accessed September 2012.

Primary outcome measures: Correlation of predefined biomarkers for tivozanib activity present in blood and tumor tissue with clinical activity and/or treatment-related toxicity Progression-free survival rate at 6 months BATON: A Phase II Biomarker Assessment of Tivozanib in Oncology Trial in Patients with Advanced RCC Tivozanib Unresectable locally recurrent or metastatic RCC Prior nephrectomy ≤1 prior systemic therapy (no prior VEGF- or mTOR-targeted therapy) Trial Identifier: NCT Target Accrual: 105 (Closed) Hutson TE et al. Proc ASCO 2012;Abstract TPS4686.

There is a significant association between the development of hypertension and the antitumor benefit with axitinib.

Comparative Effectiveness of Axitinib versus Sorafenib in Advanced Renal Cell Carcinoma (AXIS): A Randomised Phase 3 Trial Rini B et al. Lancet 2011;378(9807):

AXIS: Progression-Free Survival in Patients with RCC Receiving Second-Line Axitinib or Sorafenib Rini B et al. Lancet 2011;378(9807): AxitinibSorafenib Median PFS6.7 mo4.7 mo Stratified hazard ratio0.665 p-value<0.0001

Axitinib for First-Line Metastatic RCC: Overall Efficacy and Pharmacokinetic Analyses from a Randomized Phase II Study Rini BI et al. Proc ASCO 2012;Abstract 4503.

Clinical Outcome According to Diastolic Blood Pressure on Cycle 1 Day 15 Rini BI et al. Proc ASCO 2012;Abstract Blood pressure parametermPFSORR AUC 12 ng.h/mL a ΔdBP ≥10 mmHg, n = 39 <10 mmHg, n = mo 8.3 mo 59% 45% ΔdBP ≥15 mmHg, n = 20 <15 mmHg, n = mo 11.1 mo 60% 51% ΔdBP ≥90 mmHg, n = 17 <90 mmHg, n = mo 13.7 mo 65% 50% a Geometric mean dBP = diastolic blood pressure (per ambulatory blood pressure monitoring); ΔdBP = change in dBP from baseline

Cabozantinib has resulted in bone scan and symptom improvements in prostate cancer but no other solid tumor.

Efficacy of Cabozantinib (XL184) in Patients with Metastatic, Refractory Renal Cell Carcinoma Choueiri TK et al. Proc ASCO 2012;Abstract 4504.

Partial Bone Scan Resolution and Pain Relief in a Symptomatic Patient with Bone Metastases With permission from Choueiri TK et al. Proc ASCO 2012;Abstract Patient substantially reduced narcotic use by 7 weeks; continued on reduced narcotics until week 25 Another patient with bone metastases and pain at baseline reported complete resolution of pain by 4 weeks -Pain free 90+ weeks on study Prior therapies include sorafenib, everolimus, and sunitinib Baseline7-week follow-up

Cabozantinib Efficacy Summary Clinical parameter Cabozantinib (N = 25) Objective response rate, n (%) Confirmed partial response Stable disease 7 (28%) 13 (52%) DCR at 16 weeks18 (72%) Median duration of responseNot yet estimable Median PFS14.7 mo Median OSNot reached DCR = disease control rate defined as partial response + stable disease at 16 weeks Choueiri TK et al. Proc ASCO 2012;Abstract 4504.

Pazopanib has about the same efficacy as sunitinib as first-line treatment but is strongly preferred by patients.

Patient Preference between Pazopanib (Paz) and Sunitinib (Sun): Results of a Randomized Double-Blind, Placebo- Controlled, Cross-Over Study in Patients with Metastatic Renal Cell Carcinoma (mRCC) — PISCES Study, NCT Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.

Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502. Study Design Pazopanib 800 mg OD Sunitinib 50 mg 4/2 a Sunitinib 50 mg 4/2 a Sunitinib 50 mg 4/2 a Sunitinib 50 mg 4/2 a Patient preference for further treatment 10 weeks2-week washout End of study Time (weeks) Stratification factors: ECOG PS (0 vs 1) Metastatic sites (1 vs ≥2) R 10 weeks Period 1Period 2 Pazopanib 800 mg OD Double-blind phase 1:1 N = a 4 weeks on treatment  2 weeks matching placebo  4 weeks on treatment. ECOG PS, Eastern Cooperative Oncology Group performance status

Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502. Study Design Pazopanib Sunitinib Patient preference for further treatment R Period 1Period 2 Pazopanib 1:1 N = 169 Week Patient preference EQ-5D FACIT-F SQLQ CTCT*CT * Could occur earlier if the patient crossed over early due to AE

Primary Endpoint: Patient Preference Primary Analysis Population With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA % 22% 8% Percent of Patients Difference (pazopanib vs sunitinib)49.3% 90% CI for difference37.0% % p-value<0.001

With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502. Which Reasons Influenced Their Choice Primary Analysis Population Patients were able to select >1 option Number of Patients

Primary endpoint: Progression-free survival COMPARZ: A Phase III Trial of Pazopanib versus Sunitinib in Locally Advanced or Metastatic RCC Pazopanib R Untreated, advanced or metastatic RCC Clear cell component histology Sunitinib Trial Identifier: NCT Target Accrual: 927 (Closed) 1:1 Accessed September 2012.

Algorithm for Selecting Systemic Therapy

For patients with asymptomatic primary RCC and symptomatic mets, do you generally recommend nephrectomy?

What is your likely initial systemic treatment for RCC in a younger (age 55), otherwise healthy patient with low-volume asymptomatic mets?

What is your likely initial systemic treatment for RCC in an elderly (age 78), otherwise healthy patient with low-volume asymptomatic mets?

Management of Toxicities with Novel Agents

A patient about to receive sunitinib asks what the chance is that the drug will need to be held or stopped due to toxicity?

A patient about to receive everolimus asks what the chance is that the drug will need to be held or stopped due to toxicity?

An International Expanded-Access Programme of Everolimus: Addressing Safety and Efficacy in Patients with Metastatic Renal Cell Carcinoma Who Progress After Initial Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy Grünwald V et al. REACT Study Group. Eur J Cancer 2012;48(3):

REACT: Efficacy and Safety of Everolimus Everolimus (n = 1,367) Partial response1.7% Stable disease51.6% Grade 3 or 4 adverse event Anemia13.4% Fatigue6.7% Dyspnea6.5% Hyperglycemia5.5% Stomatitis5.4% Pneumonia4.2% Pneumonitis2.7% Grünwald V et al. Eur J Cancer 2012;48(3): In the REACT study, safety findings and tumor responses were consistent with those observed in RECORD-1.

Dabydeen DA et al. Eur J Cancer 2012;48: Best Response with Everolimus/Temsirolimus in Relation to Pneumonitis No. of patients Stable Disease Progressive Disease Pneumonitis1485.7%14.3% No Pneumonitis %56.3%

Primary endpoint: Progression-free survival after first-line therapy (noninferiority) RECORD-3: A Phase II Study of Everolimus as First- and Second-Line Treatments for Metastatic RCC Everolimus R Metastatic RCC Sunitinib Trial Identifier: NCT Target Accrual: 460 (Closed) Accessed September Sunitinib Everolimus

Primary endpoint: Overall survival Secondary endpoint: Progression-free survival, objective response rate, toxicity CALGB 90802: A Phase III Trial of Everolimus with or without Bevacizumab for Advanced RCC Everolimus + Bevacizumab Everolimus + Bevacizumab Metastatic, unresectable RCC, some clear cell histology Treated with ≥1 prior VEGF TKI, progressed/intolerant to therapy No active brain metastases Metastatic, unresectable RCC, some clear cell histology Treated with ≥1 prior VEGF TKI, progressed/intolerant to therapy No active brain metastases Everolimus + Placebo Everolimus + Placebo Trial Identifier: NCT Target Accrual: 700 (Open) R Accessed September 2012.

Faculty Case: Dr Motzer A 70-year-old man 2008: Nephrectomy: conventional clear cell type RCC –pT3b tumor grossly extended into renal vein(s) or vena cava –Mets: right adrenal, left psoas muscle, left inguinal nodes Sunitinib: PR 18 months –Dose reduction to 37.5 mg for fatigue and hand-foot reaction At progression: Everolimus: SD 6 months –Grade 1 fatigue, weight loss, dyspnea on exertion, rash, chills, nausea, vomiting, bleeding gums and myalgias –Bilateral pulmonary infiltrates but no respiratory symptoms

Faculty Case: Dr Hutson A 67-year-old man s/p sunitinib, tivozanib (trial) On Phase II trial of everolimus for 11 months

Faculty Case: Dr Motzer A 43-year-old woman 2008: Laparoscopic radical nephrectomy with lymph node dissection –Type II papillary RCC 2009: Subphrenic, peritoneal and hepatic nodules –Biopsy: RCC –Rx: Sunitinib 50 mg (4 weeks on/2 weeks off) Progression after 2 cycles Temsirolimus for 2 years – stable disease –Grade 1 nausea, fatigue, headache, cough, mucositis, hypercholesterolemia, epistaxis, bilateral pedal edema and skin rash

Faculty Cases: TKIs Dr Hutson: 57-year-old man treated with tivozanib Dr Motzer: 70-year-old man treated with tivozanib Dr Hutson: 65-year-old man treated with axitinib Dr Motzer: 64-year-old man treated with axitinib Dr Hutson: 65-year-old woman treated with sunitinib

Faculty Case: Dr Hutson A 57-year-old man with metastatic clear cell RCC –On tivozanib for 13 months

Faculty Case: Dr Motzer A 70-year-old man 2004: Right radical nephrectomy for clear cell RCC CT/MRI: Bilateral adrenal metastases RCC confirmed by needle biopsy Tivozanib (trial): PR for 30 months then progressed –Tolerated tivozanib well (mild abdominal pain and myalgia)

Faculty Case: Dr Hutson A 65-year-old man with mRCC On front-line Phase III trial: –Axitinib 2 mg po BID (dose reduced due to toxicity) –Near CR at 20 months on therapy

Faculty Case: Dr Motzer A 64-year-old man 2007: Left nephrectomy clear cell RCC –Mets to lung –Hypertension; on 1 antihypertensive –Sunitinib for 2 years: Dose reduction because of hand-foot syndrome –Progression in lung and bone Axitinib (trial) –PR: 23 four-week cycles –Hypertension worse –Required dose reduction for Grade 3 diarrhea

Faculty Case: Dr Hutson A 65-year-old woman with hematuria –10-cm renal mass with renal vein involvement –Pulmonary metastases too numerous to count –Retroperitoneal nodes, liver metastases Sunitinib: Cytopenias, hospitalizations (neutropenia, thrombocytopenia)

Schedule of Events Thursday, October 11 Advanced Prostate Cancer Christopher J Logothetis, MD A Oliver Sartor, MD