Nexavar in Patients with Renal

Cell Carcinoma
Naomi B. Haas
October 4, 2007

Historical Management
of Advanced-Stage RCC

Nephrectomy

Metastectomy
Solitary lesions

Cytokine combination

Combined modalities
Adjunctive nephrectomy
prior to cytokine therapy
Cytokine therapy
followed by nephrectomy

Clinical trials
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology:
Kidney Cancer:
Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.

RCC is not one disease

*2004 WHO lists over 50 different types of kidney
cancer
(Sarcomatoid variant can occur with any subtype)
Undifferentiated type and Collecting duct carcinoma
constitute the other 2 types listed in AJCC
classification

Clear cell

Papillary type 1

Papillary type 2

Chromophobe

Oncocytoma

Incidence (%)

75%

5%

10%

5%

5%

Associated
mutations

VHL

c-Met

FH

BHD

BHD

Type

BHD=Birt-Hogg-Dub; FH=fumarate hydratase; VHL=von Hippel-Lindau.

Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

Treatment of Advanced Disease

Based in part on risk factors

MSKCC Risk Factor Model in

mRCC
0 risk factors (n=80 patients)
1 or 2 risk factors (n=269 patients)
3, 4, or 5 risk factors (n=88 patients)

1.0

Proportion Surviving

0.9
0.8

Risk factors associated with worse prognosis

0.7

KPS <80

0.6

Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)

0.5

High corrected calcium (10 mg/dL)

0.4

High LDH (300 U/L)

0.3

Time from Dx to IFN- <1 yr

0.2
0.1
0
0

10 11 12 13 14 15 16

Time From Start of IFN- (years)

Motzer RJ et al. J Clin Oncol. 2002;20:289-296.

ADVERSE PROGNOSTIC FACTORS FOR

RENAL CELL CARCINOMA Motzer et al, JCO
17:2530-2540, 1999
Risk
# Risk Factors
Favorable
0
Intermediate
1-2
Poor
3 and +

Median Survival
29 mo.
14 mo.
4 mo.

Do patients with advanced disease

do better with nephrectomy?
Performance status matters
This issue has not been addressed in
the era of targeted therapy

Advanced Disease Therapy in

2007
Multitargeted tyrosine kinase inhibitors
Mammalian target of rapamycin (mTor)
inhibitors
Anti VEGF antibodies
VEGF Trap
Other angiogenesis inhibitorsthrombospondin inhibitors, pure PDGFR
and VEGFR inhibitors

The molecular profiles associated with the

various histologic RCC subtypes have
identified logical targets
Pathways associated with EGFR, AKT/mTOR,
MAPK/MEK, and VEGF are important in RCC
Drugs available in 2007
Multitargeted TK inhibitors:
sunitinib, sorafenib, (FDA approved)
GW786034, AG013736,ABT869

Antibodies:
Bevacizumab

Imids: CC-5013
mTor inhibitors: temsirilimus, RAD001, rapamycin

Target

Sunitini
b

Sorafe
nib

AG013
736

GW78
6034

ABT869

PTK- Bevacizu
787mab

Temsirolimus/

Vascular
endothelial
growth
factor
(VEGF)

VEGFR1 (Flt-1)

VEGFR2

VEGFR3 (FLT-4)

Platelet derived
growth factor
receptor

PDGFR-

c-kit

FLT-3

Everolimus

(Flk-1/KDR)

Receptor
Stem
cell factor (SCF)

RET

FAK
(focal
adhesion kinase)

Basic fibroblast
growth factor (bFGF)

B-raf kinase

c-raf kinase

Mammalian
target
rapamycin
(MTOR)

of

Common Treatment related side effects

Toxicity
Fatigue
Hand-Foot
Syndrome
Other Rash
Hypertension
Edema
Dyspnea
LVEF decline
Anorexia
Diarrhea
Stomatitis
Nausea
Bleeding
Thrombosis
Hypothyroidism
High AST/ALT
High
amylase/lipase
High Cholesterol
High
Triglycerides
Low Phosphorus
Neutropenia
Thrombocytopeni
a
GI perforation

Sunitinib
(n= 169)
Likely

Sorafenib
(n=451)
Likely

Less likely

Likely

Less likely
Less likely

Likely
Less likely

Less likely

ND

Less likely

Less likely

Rare

ND

Likely
Likely
Likely
Likely
Less likely
Rare
Less likely

Less likely
Likely
Less likely
Less likely
Less likely
Rare
ND

Less likely

Less likely

Less likely

Less likely

ND

ND

ND

ND

Less likely
Less likely

Less likely
Less likely

Less likely

Less likely

Rare

Rare

Bevacizumab Temsirolimus
(n=39)10mg/kg (n=212)
Less likely
Likely
ND
ND
Likely
Likely
ND

Likely
ND
Less likely

ND

Likely

ND

ND

ND
ND
ND
ND
Less likely
Rare
ND

Likely
Likely
Likely
Likely
Rare
ND
ND

Less likely

Less likely

ND

ND

ND
ND

Likely
Likely

ND
ND
ND

Likely
Likely
Likely

Rare

ND

Bevacizumab for mRCC:

Phase II Study Design
mRCC patients
(N=116)
ECOG PS <2
All patients have
prior therapy
(mostly IL-2)

High dose = 10 mg/kg (n=39)

Low dose = 3 mg/kg (n=37)

Placebo (n=40)

1 end points: TTP and ORR

2 end point: OS
Study arms were balanced for demographics
Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide.
Yang JC et al. N Engl J Med. 2003;349:427-434.

Bevacizumab for mRCC:

Summary
No significant difference in OS between treatment groups
High dose (10 mg/kg)
PR = 10% (95 CI, 2.9%24.2%)
Significantly prolonged PFS (median 4.8 months, P<.001)
Moderate toxicity profile
No Grade 4 AE or deaths related to therapy
Proteinuria 64% (any grade)
Hypertension 36% (any grade)
Low dose (3 mg/kg)
Not significant

Phase III study (AVOREN) of

bevacizumab/interferon-2a vs
placebo/interferon- 2a as first-line therapy
in metastatic RCC
641 patients
+ nephrectomy
+ clear cell RCC

IFN (9 MIU 3x weekly) +

bevacizumab(10mg/kg)
IVq2w (320)
IFN (9 MIU 3x
weekly) + placebo
(321)

The addition of BEV to IFN-a2a significantly

increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001)
and objective tumor response rate (30.6% vs. 12.4%; p<0.000
A trend toward improved OS
was observed with the addition of BEV to IFN-a2a (p=0.0670)
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings
Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3

Sorafenib (Nexavar)
Small-molecule receptor TKI1
Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf
kinases1
Formulation: 200 mg tablets2
Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)2
FDA approved December 20, 2005 for advanced RCC3
CI

CF3

O
N
H

N
H

NH
N

CH3

1. Wilhelm SM et al. Cancer Res. 2004;10:7099-7109.

2. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA:
Onyx Pharmaceuticals, Inc.; 2005.
3. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer.
Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.

Sorafenib for mRCC: Phase II (RDT)

Progression-Free Survival
Proportion of Patients
Progression-Free

1.00
Sorafenib (n=33)
Placebo (n=32)
Censored

0.75
Median PFS from randomization
Sorafenib=24 weeks
Placebo=6 weeks

0.50

P=.0087

0.25

0
84
12-week
period

100

200

300

400

Time From Randomization (days)

Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.

500

Sorafenib for mRCC:

Tumor Reduction* (TARGET)
Placebo (n=452)

Sorafenib (n=451)
150

Change From Baseline (%)*

Change From Baseline (%)*

150

100

50

-50

100

50

-50

25%
-100

76%
-100

Tumor Reduction

Tumor Reduction

PD (20% increase, RECIST);

PR (30% or reduction, RECIST).
* Investigator assessment. Patients randomized at least 6 weeks before data cut-off
of May 31, 2005.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC:

Progression-Free Survival* (TARGET)
Proportion of Patients
Progression Free

1.00
Sorafenib (n=451)
Placebo (n=452)

0.75

Censored observation
PFS

0.50

0.25

Median (months)

Sorafenib

5.5

Placebo

2.8

Hazard ratio (S/P)

0.51

0
0

10

12

14

16

18

20

Time From Randomization (months)

* Investigator assessment. Independent assessment at planned interim analysis (ASCO 2005)
demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P<.000001).
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC:

Overall Survival* (TARGET)
1.00

Proportion of Patients
Overall Survival

Sorafenib (n=451)
Placebo (n=452)

0.75

Censored observation

0.50

OS

Median (months)

Sorafenib

0.25

Not reached

Placebo

14.7

Hazard ratio (S/P)

0.72
P=.018

0
0

10

12

14

16

Time From Randomization (months)

*Interim analysis.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

18

20

Conclusions
Statistically significant improvement in
progression free survival compared to
placebo in patients with prior cytokine
therapy
Improvement in OS may have been
affected by crossover and was not
achieved in final analysis

Sunitinib (Sutent )

Small-molecule receptor TKI1

Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT31
Formulation: 12.5 mg, 25 mg, 50 mg capsules2
O

Dosing: 50 mg qd food
(4 wks on, 2 wks off)2
F
FDA approved January 26, 2006
for advanced RCC

1. Pietras K, Hanahan D. J Clin Oncol. 2005;23:939-952.

2. Sutent [package insert]. New York, NY: Pfizer Inc.; 2006.

H 3C

N
H
N
H

N
H

CH3

CH3
CH3
N

Results
Median PFS 11 months for sunitinib vs. 5
months for IFN- (p<0.000001)].
The objective response rate by third-party
independent review was 31% for sunitinib
vs. 6% for IFN- (p<0.000001).
8% withdrew from the study due to
adverse event on sunitinib arm vs. 13% on
IFN- arm.

Conclusion
Statistically significant improvement
in PFS and objective response rate
for sunitinib over IFN- in first-line
treatment of patients with metastatic
RCC

Targeted Therapy: More Questions Than

Answers
1.

2.
3.

First Line:Should we combine these

agents?
Sequentially or concurrently?
Vertical inhibition or horizontal
inhibition?
Which Type of Agent should be used first?
mTKI or mTor inhibitor?
At Progression
Dose escalation of mTKI vs other
mechanism?

6. Treatment duration-are these agents purely

angiostatic?
7. Assessment of ResponseWhich is more important: RECIST or PFS?
8. Predictors of Response
Blood flow/ vascularity
histology
Imaging- PET/CT, DCE/MRI, CT
9. Role of agents-Adjuvant?, First-line? Before or after
cytokines?
10. Exposure to agent- drug levels of sunitinib correlated
with response
11. Dose escalation of agent some patients can tolerate
dose escalation at the time of progression
12. How to treat non clear cell and other variants

Sequential Use of
Nexavar and Sunitinib:
Retrospective Analysis in 90 Patients

MKI Sequencing: Study Design

Retrospective review of sequential therapy with MKIs in RCC
Reviewed

Patient demographics

N=90

MSKCC

4 sites in France

No. of metastatic sites

RCC patients in
expanded access
programs

Efficacy
OS
PFS
Best response
Safety

Nexavar Sunitinib
n=68

Sunitinib Nexavar
n=22

MKI=multikinase inhibitor.
Adapted from Sablin MP et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

MKI Sequencing:
Efficacy of NexavarSunitinib
Sunitinib

Nexavar

PR
n (%)

SD
n (%)

PD
n (%)

NE
n (%)

PR, n

11

2 (18)

7 (64)

2 (18)

SD, n

45

6 (13)

24 (53)

11 (25)

4 (9)

PD, n

10

2 (20)

3 (30)

4 (40)

1 (10)

NE, n

Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

MKI Sequencing:
Efficacy of SunitinibNexavar
Nexavar

Sunitinib

PR
n (%)

SD
n (%)

PD
n (%)

PR, n

1 (20)

2 (40)

2 (40)

SD, n

12

1 (8)

7 (58)

4 (34)

PD, n

3 (60)

2 (40)

Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Phase II Trial of Intrapatient

Dose-Escalated-Nexavar in Patients
With Metastatic Renal Cell Cancer

Dose-Escalated Nexavar for RCC:

Study Design
1 endpoints: Safety and toxicity
2 endpoints: RR, PFS, and OS
Eligibility
Metastatic RCC,
component of
clear-cell
1 prior cytokine
therapy
Adequate PS
Adequate
pancreatic and
cardiac function

Nexavar
400 mg po
bid
Days 1-28

Nexavar

Nexavar

600 mg po
bid
Days 29-56

800 mg po
bid
Days 57+

After 4 weeks,
patients with no
DLT (grade 3/4)
increase dose

Treatment
continues
until PD or
intolerance

After 4 weeks,
patients with no
DLT (grade 3/4)
increase dose

Target accrual: 44 patients. Response assessed by RECIST every 8 weeks.

DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Dose-Escalated Nexavar for RCC:

Baseline Patient Characteristics
N=44
Characteristics
Median age, years (range)
Male/female
Zubrod PS, (0/1)
Clear Cell (CC)
Other histology
CC/Sarcomatoid
CC/Focal Rhabdoid
CC/Papillary
Prior nephrectomy
Prior radiation therapy
MSKCC Risk Factors
0
1
2
3

N
50
37/7
39/5
35
9
7
1
1
42
10

%
Range 43-79
84/16
89/11
80
20

18
17
6
3

41
38
14
7

Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

95
23

Dose-Escalated Nexavar for RCC:

Baseline Patient Characteristics
Characteristics

(contd)

N=44
N

Prior systemic therapy

IL-2
RAD001
Interferon
cG250

19
15
2
1
1

43

Best response to prior systemic CR/PR

3/2

16/11

Total number of metastatic sites

1
2
3

26
11
7

59
25
16

CR=complete response; IL-2=interleukin 2; PR=partial response.

Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Dose-Escalated Nexavar for RCC:

Intensity of Therapy
At 800-mg dose level:
5 patients had dose held between Weeks 2 through 4
3 patients were dose reduced

Doses were escalated to 1200 mg in 41 of 44 patients

Doses were escalated to 1600 mg in 32 of 41 patients
25 patients maintained dose
7 patients were dose reduced

Summary
41 patients were able to receive 1200 or 1600 mg per day
of Nexavar
3 patients were unable to be dose escalated
Those with early toxicity have difficulty with dose escalation
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Dose-Escalated Nexavar for RCC:

Best Response by RECIST
Best Response

No. of Patients

(%)

Complete response

16

Partial response

17

39

Stable disease 6 months

20

Progression defined as 4 months

11

25

Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Dose-Escalated Nexavar for RCC:

Incidence of Treatment-Related AEs
Cycle 1
Days 1-28 (n=44)

Cycle 2
Days 29-56 (n=41)

Cycle 3
Days 57+ (n=32)

Adverse Events

G1

G2

G3

G1

G2

G3

G4

G1

G2

G3

Hand-foot syndrome

13

18

21

Diarrhea

11

13

16

Fatigue

11

13

Nausea

Rash

Hypertension

Stomatitis

18

Alopecia

10

17

Anorexia

Dry skin

Stomatitis

Anemia

16

16

14

ALT/AST

Amylase/lipase
5

3
3

6
AEs=adverse
events; ALT=alanine
AST=aspartate
aminotransferase.
Hypophosphatemia
aminotransferase;
12
6
10
3

Adapted from Amato RJ et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Dose-Escalated Nexavar for

RCC: Conclusions
Dose-escalated Nexavar was well tolerated when
given twice daily by oral administration
93% of patients were able to be dose escalated
to either 1200 or 1600 mg per day
A high level of antitumor activity was demonstrated
by a 55% complete and partial response rate in
patients with metastatic RCC
Follow-up trials are in progress to verify these data
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Sorafenib for mRCC:

Tumor Response (TARGET)
Pre-Therapy

Image courtesy of Laura Wood, RN, MSN, OCN.

8 Weeks Post-Therapy

Management of Early-Stage RCC

Surgery
Partial or radical
nephrectomy
Open surgery
Laparoscopic
Cryoablation or
radiofrequency ablation

Adjuvant Tx

No benefit from adjuvant

interleukin2 or interferon
No benefit from radiation
therapy
Benefit from adjuvant
targeted therapy is unknown
Neoadjuvant- investigational

National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer:
Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.

Predictors of Relapse
Prognostic models based on postoperative
score:

UCLA Integrated Staging System (UISS)

Leibovich Model
Frank Model (SSIGN)
Kattan Model

Prognostic Models based on preoperative

score:
Yaycioglu
Cindolo

Contributors to Prognosis

Pathologic stage
Histology
Fuhrman Grade
Nuclear grade
Performance status
Necrosis
Size
Clinical Presentation

The UCLA Integrated staging system (UISS)

UISS
Survival

1997 TNM
Stage (%)

Fuhrman
Grade

ECOG

1,2

2 Yr.
Survival
(%)

5Yr

96

94

II

I
I
II
III
III

1,2
3,4
Any
Any
I

1
Any
Any
0
1 or more

89

64

III

III
IV

2-4
1,2

1 or more
0

66

39

IV

IV

3,4
1-3

0
1 or more

42

23

IV

1 or more

A.S.S.U.R.E. (ECOG 2805)

NonMetastatic
Kidney
Cancer
That meets
radiologic
criteria to be
clinically
T1bNany
(resectable)
M0 disease

R
E
G
I
S
T
R
A
T
I
O
N
1

R
E
S G
U I
R S
G T
E R
R A
Y T
I
O
N
2

Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk

Histologic
Subtype
Clear cell
Non-clear cell

Performance
status
Surgery
Open vs
laparoscopic

Arm A Sunitinib

R
A
N
D
O
M
I
Z
E

50 mg daily for 1
year

Arm B Sorafenib
800mg daily for 1
year

Arm C Placebo
Daily for 1 year

Objectives
Primary Question:
Can adjuvant therapy with an oral raf
kinase inhibitor/ receptor tyrosine kinase
inhibitor (Sorafenib) or pure receptor
tyrosine kinase inhibitor (Sunitinib)
improve disease-free survival in locally
advanced RCC over placebo after surgical
resection?
Primary endpoint is DFS

Secondary Objectives

Overall survival
Toxicity in the adjuvant setting
Prospective collection of tumor and biologic
specimens /Correlatives:
- Measures of angiogenesis
- Mutational analyses (oncogenes/TSG)
- Hypermethylation
- Polymorphisms

Nexavar in Adjuvant RCC:

MRC SORCE Phase III Trial

High and intermediate

risk, resected RCC

(1.5:1.5:1) Randomization
(N=1656)

1 endpoint: Metastasis-free survival

2 endpoints: RCC-specific survival time, toxicity, QoL, and
biomarkers
Nexavar

Nephrectomy

for 3 years
(n=621)

Nexavar for 1 year, then

placebo for 2 years
(n=621)

Placebo
for 3 years
(n=414)

MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients with
Resected primary renal CEll carcinoma.

Developments
ECOG BEST Trial (4 arm) of Doublet
Targeted therapy (tem/bev vs bev vs
sorafenib/bev vs sorafenib/tem
Temsirolimus versus sunitinib trial for
non clear cell RCC
mTKI to mTOR vs mTor to mTKI trial
Adjuvant trials SORCE and ASSURE
are ongoing

Conclusions

Surgery remains the most effective therapy

for early RCC and plays a role in advanced
RCC
New molecular targets have been identified
which are critical to the pathogenesis of
different types of RCC and new targeted
therapies are replacing traditional biologic
therapies
The ultimate role that these agents will play in
RCC has yet to be decided

Common Treatment related side effects

Toxicity
Fatigue
Hand-Foot
Syndrome
Other Rash
Hypertension
Edema
Dyspnea
LVEF decline
Anorexia
Diarrhea
Stomatitis
Nausea
Bleeding
Thrombosis
Hypothyroidism
High AST/ALT
High
amylase/lipase
High Cholesterol
High
Triglycerides
Low Phosphorus
Neutropenia
Thrombocytopeni
a
GI perforation

Sunitinib
(n= 169)
Likely

Sorafenib
(n=451)
Likely

Less likely

Likely

Less likely
Less likely

Likely
Less likely

Less likely

ND

Less likely

Less likely

Rare

ND

Likely
Likely
Likely
Likely
Less likely
Rare
Less likely

Less likely
Likely
Less likely
Less likely
Less likely
Rare
ND

Less likely

Less likely

Less likely

Less likely

ND

ND

ND

ND

Less likely
Less likely

Less likely
Less likely

Less likely

Less likely

Rare

Rare

Bevacizumab Temsirolimus
(n=39)10mg/kg (n=212)
Less likely
Likely
ND
ND
Likely
Likely
ND

Likely
ND
Less likely

ND

Likely

ND

ND

ND
ND
ND
ND
Less likely
Rare
ND

Likely
Likely
Likely
Likely
Rare
ND
ND

Less likely

Less likely

ND

ND

ND
ND

Likely
Likely

ND
ND
ND

Likely
Likely
Likely

Rare

ND

Targeted Therapy: More Questions Than

Answers
1.

2.
3.

First Line:Should we combine these

agents?
Sequentially or concurrently?
Vertical inhibition or horizontal
inhibition?
Which Type of Agent should be used first?
mTKI or mTor inhibitor?
At Progression
Dose escalation of mTKI vs other
mechanism?

6. Treatment duration-are these agents purely

angiostatic?
7. Assessment of ResponseWhich is more important: RECIST or PFS?
8. Predictors of Response
Blood flow/ vascularity
histology
Imaging- PET/CT, DCE/MRI, CT
9. Role of agents-Adjuvant?, First-line? Before or after
cytokines?
10. Exposure to agent- drug levels of sunitinib correlated
with response
11. Dose escalation of agent some patients can tolerate
dose escalation at the time of progression
12. How to treat non clear cell and other variants

A.S.S.U.R.E. (ECOG 2805)

NonMetastatic
Kidney
Cancer
That meets
radiologic
criteria to be
clinically
T1bNany
(resectable)
M0 disease

R
E
G
I
S
T
R
A
T
I
O
N
1

R
E
S G
U I
R S
G T
E R
R A
Y T
I
O
N
2

Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk

Histologic
Subtype
Clear cell
Non-clear cell

Performance
status
Surgery
Open vs
laparoscopic

Arm A Sunitinib

R
A
N
D
O
M
I
Z
E

50 mg daily for 1
year

Arm B Sorafenib
800mg daily for 1
year

Arm C Placebo
Daily for 1 year