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Part III – Renal Cell CarcinomaThursday, September 13, 20127:30 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, PharmDDirector, GU Oncology ProgramCo-Director, GU Center of Excellence, Texas Oncology, PACharles A Sammons Cancer Center and Baylor University Medical CenterProfessor of Medicine, Texas A&M Health Science Center College of MedicineCo-Chair of GU Research, US OncologyDallas, Texas

Robert J Motzer, MD Medical Oncologist Memorial Sloan-Kettering Cancer Center New York, New York

Neil Love, MDResearch To PracticeMiami, 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):2517-9.

Clinical activity and safety of anti-PD-1 (BMS-936558, 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):2443-54.

Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer

Brahmer JR et al. N Engl J Med 2012;366(26):2455-65.

Phase I Studies of Anti-PD-1/PD-L1 Agents: Advanced RCC Patient Subgroup

Clinical parameter

Anti-PD-1a

Anti-PD-L1b

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)

5.6 - >17.5 mo 8.4 - >22.3 mo 4 - 17 mo

PFS rate at 24 weeks 47% 67% 53%

a Topalian SL et al. N Engl J Med 2012;366(26):2443-54. b Brahmer JR et al. N Engl J Med 2012; 366(26):2455-65.

Anti-PD-1 Treatment-Related Adverse Events: Advanced RCC Patient Subgroup (n = 34)

Adverse event (AE)* All grades Grades 3-4†

Any adverse event 82% 18%

Fatigue 38% 0%

Rash 24% 0%

Pruritis 18% 3%

Diarrhea 15% 0%

Decreased appetite 9% 0%

Nausea 6% 0%

McDermott DF et al. Proc ASCO 2012;Abstract 4505.

* All doses of anti-PD-1† Most common Grade 3-4 AEs were respiratory system disorders (2 pts) and hypophosphatemia (2 pts).

AgentIC50 (nM)

VEGFR-1 VEGFR-2 VEGFR-3

Tivozanib 0.21 0.16 0.24

Axitinib 1.2 0.25 0.29

Sunitinib 2 10 17

Pazopanib 10 47 30

Dovitinib 10 13 8

Sorafenib Not reported 90 20

Eskens FALM et al. Proc AACR 2008;Abstract LB-201; Nakamura K et al. Cancer Res 2006;66:9134-42; Chow LQ et al. J Clin Oncol 2007;25:884-96; Lee SH et al. Clin Cancer Res 2005;11:3633-41.

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;25:884-96. 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 RCCClear cell histologyPrior nephrectomyNo 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 4501.

Time (months)

Pro

bab

ility

of

PF

S

N Median PFS HR p-value

Tivozanib 260 11.9 mo0.797 0.042

Sorafenib 257 9.1 mo

TIVO-1: Treatment-Emergent Adverse Events

Adverse event, %

Tivozanib

(n = 259)

Sorafenib

(n = 257)

All grade Grade 3 (4) All grade Grade 3 (4)

Diarrhea 22 2 32 6

Hand-foot syndrome 13 2 54 17

Alopecia 2 0 21 0

Hypertension 44 24 (2) 34 17 (<1)

Dysphonia 21 0 5 0

Motzer RJ et al. Proc ASCO 2012;Abstract 4501.

Fewer dose interruptions and reductions and treatment discontinuations occurred on the tivozanib arm.

Sorafenib: Reported Progression-FreeSurvival Values Over Time

With permission from Eisen T. ASCO 2012 Discussant

Japan (PH2)RDD (PH2)

Target (PH3)

6.7

7.4

5.5 5.7

8.3

6.5

6.6

8.4

9.0

9.2

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 patientsGray = prior treatment with cytokine therapy and/or selective therapy targeting the angiogenesis pathway

Publication Year

Rep

ort

ed

Med

ian

PFS

(M

on

ths)

Sorafenib Studies Safety

TARGET Ph III AMG 386 TIVO-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 DR21 DI

35 DR61 DI

43 DR35 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

TivozanibTivozanib SunitinibSunitinib

RUntreated, advanced RCC

Target Accrual: 160 (Open)

1:1TivozanibTivozanibSunitinibSunitinib

www.clinicaltrials.gov. 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

TivozanibTivozanib

Unresectable locally recurrent or metastatic RCC

Prior nephrectomy

≤1 prior systemic therapy (no prior VEGF- or mTOR-targeted therapy)

Trial Identifier: NCT01297244 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 TrialRini B et al. Lancet 2011;378(9807):1931-9.

AXIS: Progression-Free Survival in Patients with RCC Receiving Second-Line Axitinib or Sorafenib

Rini B et al. Lancet 2011;378(9807):1931-9.

Axitinib Sorafenib

Median PFS 6.7 mo 4.7 mo

Stratified hazard ratio 0.665

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 4503.

Blood pressure parameter mPFS ORR

AUC12

ng.h/mLa

ΔdBP≥10 mmHg, n = 39

<10 mmHg, n = 22

16.7 mo

8.3 mo

59%

45%

176

63

ΔdBP≥15 mmHg, n = 20

<15 mmHg, n = 41

19.3 mo

11.1 mo

60%

51%

235

93

ΔdBP≥90 mmHg, n = 17

<90 mmHg, n = 46

22.5 mo

13.7 mo

65%

50%

195

110

a Geometric meandBP = 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 4504.

• 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

Baseline 7-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 weeks 18 (72%)

Median duration of response Not yet estimable

Median PFS 14.7 mo

Median OS Not 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 01064310

Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.

Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.

Study Design

Pazopanib800 mg OD Pazopanib

800 mg OD

Sunitinib50 mg 4/2a

Sunitinib50 mg 4/2a

Sunitinib50 mg 4/2a

Sunitinib50 mg 4/2a

Patient preference for further treatment

Patient preference for further treatment

10 weeks 2-weekwashout

End of study

Time (weeks)Stratification factors:• ECOG PS (0 vs 1)• Metastatic sites (1 vs ≥2)

R

10 weeks

Period 1 Period 2

Pazopanib800 mg OD Pazopanib

800 mg OD

Double-blind phase

1:1

N = 169

2212100

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 Pazopanib

SunitinibSunitinib

SunitinibSunitinib

Patient preference for further treatment

Patient preference for further treatment

R

Period 1 Period 2

PazopanibPazopanib

1:1

N = 169

Week 0 2 4 6 8 10 12 14 16 18 20 22

Patient preference

EQ-5D

FACIT-F

SQLQ

CT CT* CT

* Could occur earlier if the patient crossed over early due to AE

Primary Endpoint: Patient PreferencePrimary Analysis Population

With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.

70%

22%8%

Pe

rce

nt o

f Pa

tien

ts

Difference (pazopanib vs sunitinib) 49.3%

90% CI for difference 37.0% - 61.5%

p-value <0.001

With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.

Which Reasons Influenced Their ChoicePrimary 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

PazopanibPazopanib

R

Untreated, advanced or metastatic RCC

Clear cell component histology

SunitinibSunitinib

Trial Identifier: NCT00720941 Target Accrual: 927 (Closed)

1:1

www.clinicaltrials.gov. 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 TherapyGrünwald V et al. REACT Study Group.Eur J Cancer 2012;48(3):324-32.

REACT: Efficacy and Safety of Everolimus

Everolimus

(n = 1,367)

Partial response 1.7%

Stable disease 51.6%

Grade 3 or 4 adverse event

Anemia 13.4%

Fatigue 6.7%

Dyspnea 6.5%

Hyperglycemia 5.5%

Stomatitis 5.4%

Pneumonia 4.2%

Pneumonitis 2.7%

Grünwald V et al. Eur J Cancer 2012;48(3):324-32.

• 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;48:1519-24.

Best Response with Everolimus/Temsirolimus in Relation to Pneumonitis

No. of patients

Stable Disease

Progressive Disease

Pneumonitis 14 85.7% 14.3%

No Pneumonitis

32 43.8% 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

EverolimusEverolimus

RMetastatic RCC

SunitinibSunitinib

Trial Identifier: NCT00903175 Target Accrual: 460 (Closed)

www.clinicaltrials.gov. Accessed September 2012.

SunitinibSunitinib

EverolimusEverolimus

• 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 +BevacizumabEverolimus +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: NCT01198158Target Accrual: 700 (Open)

R

www.clinicaltrials.gov. 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 11Advanced Prostate CancerChristopher J Logothetis, MD A Oliver Sartor, MD