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

1

• 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.

2
RTP TV A Live CME Webcast Series Focused on
Emerging Data Sets and Novel Therapeutic
Strategies in the Management of Common Cancers
Part III Renal Cell Carcinoma Thursday,
September 13, 2012730 PM 830 PM ET
3
Neil Love, MDResearch To PracticeMiami, Florida
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 AM 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
4
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

5
New Developments in mRCC
6
At this time, there is no known tissue or serum
predictor of response to anti-PD-1.
7
Blockade of T-Cell Signaling in Tumor
Immunotherapy
Ribas A et al. N Engl J Med 2012366(26)2517-9.
8
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 2012Abstract 4505.

9
Safety, Activity, and Immune Correlates of
Anti-PD-1 Antibody in Cancer

• Topalian SL et al.
• N Engl J Med 2012366(26)2443-54.

Safety and Activity of Anti-PD-L1 Antibody in
Patients with Advanced Cancer
Brahmer JR et al. N Engl J Med
2012366(26)2455-65.
10
Phase I Studies of Anti-PD-1/PD-L1 Agents
Advanced RCC Patient Subgroup
Clinical parameter Anti-PD-1a Anti-PD-1a Anti-PD-L1b 10 mg/kg (n 17)
Clinical parameter 1 mg/kg (n 17) 10 mg/kg (n 16) Anti-PD-L1b 10 mg/kg (n 17)
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 - gt17.5 mo 8.4 - gt22.3 mo 4 - 17 mo
PFS rate at 24 weeks 47 67 53
a Topalian SL et al. N Engl J Med
2012366(26)2443-54. b Brahmer JR et al. N Engl
J Med 2012 366(26)2455-65.
11
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
All doses of anti-PD-1 Most common Grade 3-4
AEs were respiratory system disorders (2 pts) and
hypophosphatemia (2 pts).
McDermott DF et al. Proc ASCO 2012Abstract 4505.
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(No Transcript)
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Relative Potencies of TKIs
Agent IC50 (nM) IC50 (nM) IC50 (nM)
Agent 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 2008Abstract
LB-201 Nakamura K et al. Cancer Res
2006669134-42 Chow LQ et al. J Clin Oncol
200725884-96 Lee SH et al. Clin Cancer Res
2005113633-41.
14
Tivozanib is associated with fewer side effects
and is more tolerable than sorafenib.
15
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 200725884-96.
Eskens FALM et al. Proc AACR 2008LB-201.
16
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 2012Abstract 4501.

17
TIVO-1 A Phase III Trial of First-Line Tivozanib
versus Sorafenib in Advanced RCC
Tivozanib (n 260)
Advanced RCC Clear cell histology Prior
nephrectomy No prior VEGF or mTOR therapy
Sorafenib (n 257)
Progression
Crossover to tivozanib via separate protocol

• Primary endpoint Progression-free survival
  superiority of tivozanib

Motzer RJ et al. Proc ASCO 2012Abstract 4501.
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TIVO-1 Progression-Free Survival
N Median PFS HR p-value
Tivozanib 260 11.9 mo 0.797 0.042
Sorafenib 257 9.1 mo 0.797 0.042
Probability of PFS
Time (months)
With permission from Motzer RJ et al. Proc ASCO
2012Abstract 4501.
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TIVO-1 Treatment-Emergent Adverse Events
Adverse event, Tivozanib (n 259) Tivozanib (n 259) Sorafenib (n 257) Sorafenib (n 257)
Adverse event, 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 (lt1)
Dysphonia 21 0 5 0
Fewer dose interruptions and reductions and
treatment discontinuations occurred on the
tivozanib arm.
Motzer RJ et al. Proc ASCO 2012Abstract 4501.
20
Sorafenib Reported Progression-FreeSurvival
Values Over Time
EU-ARCCS ECOG-0 (Expanded Access)
9.2
AMG 386 (PH2) and Japan CI. Exp.
9.0
Japan (PH2)
NA-ARCCS(ExpandedAccess)
RDD (PH2)
Italian Clinical Experience
8.4
8.3
7.4
6.6
EU-ARCCS Overall (Expanded Access)
6.7
5.7
5.5
6.5
AXIS/PriorCytokine(PH3)
Reported Median PFS (Months)
Sorafenib vs IFN(PH2)
Target (PH3)
Publication Year
Yellow includes treatment naïve patientsGray
prior treatment with cytokine therapy and/or
selective therapy targeting the angiogenesis
pathway
With permission from Eisen T. ASCO 2012 Discussant
21
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
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TAURUS A Phase II Crossover-Controlled Study of
First-Line Tivozanib versus Sunitinib in Advanced
RCC
Target Accrual 160 (Open)
Tivozanib
Sunitinib
Untreated, advanced RCC
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Tivozanib
Sunitinib

• 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

www.clinicaltrials.gov. Accessed September 2012.
23
BATON A Phase II Biomarker Assessment of
Tivozanib in Oncology Trial in Patients with
Advanced RCC
Trial Identifier NCT01297244 Target Accrual 105
(Closed)
Unresectable locally recurrent or metastatic
RCC Prior nephrectomy 1 prior systemic therapy
(no prior VEGF- or mTOR-targeted therapy)
Tivozanib

• 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

Hutson TE et al. Proc ASCO 2012Abstract TPS4686.
24
There is a significant association between the
development of hypertension and the antitumor
benefit with axitinib.
25
Comparative Effectiveness of Axitinib versus
Sorafenib in Advanced Renal Cell Carcinoma
(AXIS) A Randomised Phase 3 Trial

• Rini B et al.
• Lancet 2011378(9807)1931-9.

26
AXIS Progression-Free Survival in Patients with
RCC Receiving Second-Line Axitinib or Sorafenib
Axitinib Sorafenib
Median PFS 6.7 mo 4.7 mo
Stratified hazard ratio 0.665 0.665
p-value lt0.0001 lt0.0001
Rini B et al. Lancet 2011378(9807)1931-9.
27
Axitinib for First-Line Metastatic RCC Overall
Efficacy and Pharmacokinetic Analyses from a
Randomized Phase II Study

• Rini BI et al.
• Proc ASCO 2012Abstract 4503.

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Clinical Outcome According to Diastolic Blood
Pressure on Cycle 1 Day 15
Blood pressure parameter Blood pressure parameter mPFS ORR AUC12 ng.h/mLa
?dBP 10 mmHg, n 39 lt10 mmHg, n 22 16.7 mo 8.3 mo 59 45 176 63
?dBP 15 mmHg, n 20 lt15 mmHg, n 41 19.3 mo 11.1 mo 60 51 235 93
?dBP 90 mmHg, n 17 lt90 mmHg, n 46 22.5 mo 13.7 mo 65 50 195 110
a Geometric mean dBP diastolic blood pressure
(per ambulatory blood pressure monitoring) ?dBP
change in dBP from baseline
Rini BI et al. Proc ASCO 2012Abstract 4503.
29
Cabozantinib has resulted in bone scan and
symptom improvements in prostate cancer but no
other solid tumor.
30
Efficacy of Cabozantinib (XL184) in Patients with
Metastatic, Refractory Renal Cell Carcinoma

• Choueiri TK et al.
• Proc ASCO 2012Abstract 4504.

31
Partial Bone Scan Resolution and Pain Relief in a
Symptomatic Patient with Bone Metastases
Prior therapies include sorafenib, everolimus,
and sunitinib
Baseline
7-week follow-up

• 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

With permission from Choueiri TK et al. Proc ASCO
2012Abstract 4504.
32
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 2012Abstract 4504.
33
Pazopanib has about the same efficacy as
sunitinib as first-line treatment but is strongly
preferred by patients.
34
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 2012Abstract CRA4502.

35
Study Design
Period 1
Period 2
Pazopanib800 mg OD
Sunitinib 50 mg 4/2a
Patient preference for further treatment
11
N 169
Sunitinib 50 mg 4/2a
Pazopanib800 mg OD
10 weeks
2-weekwashout
End of study
10 weeks
Double-blind phase
22
12
10
0
Stratification factors ECOG PS (0 vs 1)
Metastatic sites (1 vs 2)
Time (weeks)
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 2012Abstract
CRA4502.
36
Study Design
Period 1
Period 2
Pazopanib
Sunitinib
Patient preference for further treatment
11
N 169
Sunitinib
Pazopanib
Week 0 2 4 6 8 10 12 14 16 18 20 22
Patient preference
EQ-5D
FACIT-F
SQLQ
Could occur earlier if the patient crossed over
early due to AE
Escudier BJ et al. Proc ASCO 2012Abstract
CRA4502.
37
Primary Endpoint Patient Preference Primary
Analysis Population
Difference (pazopanib vs sunitinib) 49.3
90 CI for difference 37.0 - 61.5
p-value lt0.001
70
Percent of Patients
22
8
With permission from Escudier BJ et al. Proc ASCO
2012Abstract CRA4502.
38
Which Reasons Influenced Their ChoicePrimary
Analysis Population
Patients were able to select gt1 option
Number of Patients
With permission from Escudier BJ et al. Proc ASCO
2012Abstract CRA4502.
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COMPARZ A Phase III Trial of Pazopanib versus
Sunitinib in Locally Advanced or Metastatic RCC
Trial Identifier NCT00720941 Target Accrual 927
(Closed)
Pazopanib
Untreated, advanced or metastatic RCC Clear
cell component histology
Sunitinib
11

• Primary endpoint Progression-free survival

www.clinicaltrials.gov. Accessed September 2012.
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Algorithm for Selecting Systemic Therapy
42
For patients with asymptomatic primary RCC and
symptomatic mets, do you generally recommend
nephrectomy?
43
What is your likely initial systemic treatment
for RCC in a younger (age 55), otherwise healthy
patient with low-volume asymptomatic mets?
44
What is your likely initial systemic treatment
for RCC in an elderly (age 78), otherwise healthy
patient with low-volume asymptomatic mets?
45
(No Transcript)
46
Management of Toxicities with Novel Agents
47
A patient about to receive sunitinib asks what
the chance is that the drug will need to be held
or stopped due to toxicity?
48
A patient about to receive everolimus asks what
the chance is that the drug will need to be held
or stopped due to toxicity?
49
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 201248(3)324-32.

50
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

• In the REACT study, safety findings and tumor
  responses were consistent with those observed in
  RECORD-1.

Grünwald V et al. Eur J Cancer 201248(3)324-32.
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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
Dabydeen DA et al. Eur J Cancer 2012481519-24.
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RECORD-3 A Phase II Study of Everolimus as
First- and Second-Line Treatments for Metastatic
RCC
Trial Identifier NCT00903175 Target Accrual 460
(Closed)
Everolimus
Sunitinib
Metastatic RCC
Sunitinib
Everolimus

• Primary endpoint Progression-free survival after
  first-line therapy (noninferiority)

www.clinicaltrials.gov. Accessed September 2012.
54
CALGB 90802 A Phase III Trial of Everolimus
with or without Bevacizumab for Advanced RCC
Trial Identifier NCT01198158 Target Accrual 700
(Open)
Metastatic, unresectable RCC, some clear cell
histology Treated with 1 prior VEGF
TKI, progressed/intolerant to therapy No active
brain metastases
Everolimus Bevacizumab
Everolimus Placebo

• Primary endpoint Overall survival
• Secondary endpoint Progression-free survival,
  objective response rate, toxicity

www.clinicaltrials.gov. Accessed September 2012.
55
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

56
Faculty Case Dr Hutson

• A 67-year-old man s/p sunitinib, tivozanib
  (trial)
• On Phase II trial of everolimus for 11 months

57
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

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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

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Faculty Case Dr Hutson

• A 57-year-old man with metastatic clear cell RCC
• On tivozanib for 13 months

60
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)

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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

62
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

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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)

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