Nexavar in Patients with Renal Cell Carcinoma

Naomi B. Haas

October 4, 2007

• Nephrectomy

• Metastectomy

– Solitary lesions

• Cytokine combination

• Combined modalities

– Adjunctive nephrectomy prior to cytokine therapy

– Cytokine therapy followed by nephrectomy

• Clinical trials

Historical Management of Advanced-Stage RCC

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.

BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

RCC is not one disease

Clear cell

75%

Type

Incidence (%)

Associated mutations VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

*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

Treatment of Advanced Disease

• Based in part on risk factors

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

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)

Risk factors associated with worse prognosis

• KPS <80

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

• High corrected calcium (10 mg/dL)

• High LDH (300 U/L)

• Time from Dx to IFN- <1 yr

Time From Start of IFN- (years)

Pro

po

rtio

n S

urv

ivin

g

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 1614131195436 151210876

ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Motzer et al, JCO

17:2530-2540, 1999

Risk # Risk Factors Median Survival• Favorable 0 29 mo.• Intermediate1-2 14 mo.• Poor 3 and + 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 inhibitors-

thrombospondin 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 Sunitinib

Sorafenib

AG013736

GW786034

ABT-869

PTK-787

Bevacizumab

Temsirolimus/

Everolimus

Vascular endothelial growth factor (VEGF)

N N N N N N Y N

VEGFR1 (Flt-1) Y N Y Y Y Y N N

VEGFR2

(Flk-1/KDR)

N Y Y Y Y Y N N

VEGFR3 (FLT-4) Y Y Y Y N N

Platelet derived growth factor receptor

N N Y N N N

PDGFR- Y Y Y Y Y N N N

c-kit Y Y Y Y Y N N N

FLT-3 Y Y Y U Y N N N

Receptor Stem cell factor (SCF)

Y N U U N N N

RET Y N Y N U N N N

FAK (focal adhesion kinase)

N N N N U N N N

Basic fibroblast growth factor (b-FGF)

Y Y Y Y Y N N N

B-raf kinase N Y N N N N N N

c-raf kinase N Y N N N N N N

Mammalian target of rapamycin (MTOR)

N N N N N N N Y

Common Treatment related side effects Toxicity

Sunitinib (n= 169)

Sorafenib (n=451)

Bevacizumab (n=39)10mg/kg

Temsirolimus (n=212)

Fatigue Likely Likely Less likely Likely Hand-Foot Syndrome

Less likely Likely ND ND

Other Rash Less likely Likely Likely Likely Hypertension Less likely Less likely Likely ND Edema

Less likely ND ND Less likely

Dyspnea

Less likely Less likely ND Likely

LVEF decline

Rare ND ND ND

Anorexia Likely Less likely ND Likely Diarrhea Likely Likely ND Likely Stomatitis Likely Less likely ND Likely Nausea Likely Less likely ND Likely Bleeding Less likely Less likely Less likely Rare Thrombosis Rare Rare Rare ND

Hypothyroidism Less likely ND ND ND

High AST/ALT

Less likely Less likely Less likely Less likely

High amylase/lipase

Less likely Less likely ND ND

High Cholesterol ND ND ND Likely High Triglycerides

ND ND ND Likely

Low Phosphorus Less likely Less likely ND Likely Neutropenia Less likely Less likely ND Likely Thrombocytopenia

Less likely Less likely ND Likely

GI perforation Rare Rare Rare ND

Bevacizumab for mRCC: Phase II Study Design

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

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

Placebo (n=40)

Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide.Yang JC et al. N Engl J Med. 2003;349:427-434.

• 1° end points: TTP and ORR• 2° end point: OS• Study arms were balanced for demographics

mRCC patients (N=116)

ECOG PS <2All patients have

prior therapy (mostly IL-2)

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-α2a vs

placebo/interferon- α2a as first-line therapy in metastatic RCC

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3

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<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670).

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

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.

NH

NH

OO

O

N

CICF3

NH

CH3

Median PFS from randomization

Sorafenib=24 weeksPlacebo=6 weeks

P=.0087

Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival

Time From Randomization (days)

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

-Fre

e1.00

0.75

0.50

0.25

0

12-week period

84 0 100 200 300 400 500

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

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

Sorafenib for mRCC: Tumor Reduction* (TARGET)

* 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 (n=451)Placebo (n=452)

Tumor Reduction Tumor Reduction

PR (30% or reduction, RECIST).

Ch

an

ge

Fro

m B

as

eli

ne

(%

)*

25% 76%

Ch

an

ge

Fro

m B

as

eli

ne

(%

)*

0

50

100

150

-50

-100

0

50

100

150

-50

-100

PD (20% increase, RECIST);

PFS Median (months)

Sorafenib

Placebo

5.5

2.8

Hazard ratio (S/P) 0.51

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n F

ree

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

Sorafenib for mRCC: Progression-Free Survival* (TARGET)

* 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.

Censored observation

Placebo (n=452)

Sorafenib (n=451)

Sorafenib for mRCC:Overall Survival* (TARGET)

OS Median (months)Sorafenib

Placebo

Not reached

14.7Hazard ratio (S/P) 0.72

P=.018

Censored observation

Placebo (n=452)

Sorafenib (n=451)

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Ove

rall

Su

rviv

al

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

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

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 FLT-31

• Formulation: 12.5 mg, 25 mg, 50 mg capsules2

• Dosing: 50 mg qd ± food (4 wks on, 2 wks off)2

• 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.

H3C

CH3

F

O

O

CH3

CH3

NH

NH

N

NH

Results

• Median PFS 11 months for sunitinib vs. 5 months for IFN-α (p<0.000001)].

• The objective response rate by third-party independent review was 31% for sunitinib vs. 6% for IFN-α (p<0.000001).

• 8% withdrew from the study due to adverse event on sunitinib arm vs. 13% on IFN-α arm.

Conclusion

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

Targeted Therapy: More Questions Than Answers

1. First Line:Should we combine these agents?

Sequentially or concurrently?

Vertical inhibition or horizontal inhibition?

2. Which Type of Agent should be used first? mTKI or mTor inhibitor?

3. At Progression

Dose escalation of mTKI vs other mechanism?

6. Treatment duration-are these agents purely angiostatic?

7. Assessment of Response-Which is more important: RECIST or PFS?

8. Predictors of ResponseBlood flow/ vascularityhistologyImaging- 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

N=90

4 sites in France

RCC patients in expanded access programs

Reviewed

• Patient demographics

• MSKCC

• No. of metastatic sites

Efficacy• OS• PFS• Best response• Safety

Retrospective review of sequential therapy with MKIs in RCC

Nexavar → Sunitinibn=68

Sunitinib → Nexavarn=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 Nexavar→Sunitinib

Sunitinib

NexavarPR

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 2 – 1 – 1

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

MKI Sequencing: Efficacy of Sunitinib→Nexavar

Nexavar

SunitinibPR

n (%)SD

n (%)PD

n (%)

PR, n 5 1 (20) 2 (40) 2 (40)

SD, n 12 1 (8) 7 (58) 4 (34)

PD, n 5 0 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

• 1º endpoints: Safety and toxicity

• 2º endpoints: RR, PFS, and OS

Treatment continues until PD or intolerance

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.

Eligibility• Metastatic RCC,

component of clear-cell

• ≤1 prior cytokine therapy

• Adequate PS• Adequate

pancreatic and cardiac function After 4 weeks,

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

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

Nexavar800 mg po

bidDays 57+

Nexavar400 mg po

bidDays 1-28

Nexavar600 mg po

bidDays 29-56

Dose-Escalated Nexavar for RCC:Baseline Patient Characteristics

N=44Characteristics N %Median age, years (range) 50 Range 43-79Male/female 37/7 84/16Zubrod PS, (0/1) 39/5 89/11Clear Cell (CC) 35 80Other histology 9 20

CC/Sarcomatoid 7CC/Focal Rhabdoid 1CC/Papillary 1

Prior nephrectomy 42 95Prior radiation therapy 10 23MSKCC Risk Factors

0 18 411 17 382 6 143 3 7

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

(cont’d) N=44Characteristics N %

Prior systemic therapy 19 43IL-2 15RAD001 2Interferon 1cG250 1

Best response to prior systemic CR/PR 3/2 16/11

Total number of metastatic sites1 26 592 11 25≥3 7 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 7 16

Partial response 17 39

Stable disease ≥6 months 9 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 2 2 18 4 2 — 21 2 1

Diarrhea 11 — 1 13 2 — — 16 4 —

Fatigue 9 1 — 11 — — — 13 1 1

Nausea 9 — 1 4 — — — 6 2 —

Rash 7 2 1 7 — — — 7 — —

Hypertension 5 3 — 7 2 — — 6 3 —

Stomatitis 5 — — 8 — — — 18 — —

Alopecia 4 — — 10 — — — 17 — —

Anorexia 4 — — 8 — — — 6 — —

Dry skin 2 — — 4 1 — — 4 1 —

Stomatitis 1 — — — — — — — — —

Anemia 16 — — 16 — — — 14 — 1

ALT/AST 6 — — 7 1 1 1 9 3 1

Amylase/lipase 5 — 3 3 — 1 — 6 1 1

Hypophosphatemia — 12 6 10 3 — — 2 8 9

AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase.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 8 Weeks Post-Therapy

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

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 (%)

FuhrmanGrade

ECOG 2 Yr. Survival(%)

5Yr

I 1,2 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

V IV 4 1 or more 9 0

StratifyRisk by TNM

Stage/GradeIntermediate RiskHigh Risk

Histologic SubtypeClear cellNon-clear cell

Performance status

SurgeryOpen vs laparoscopic

 

Arm B Sorafenib800mg daily for 1 year

Arm C Placebo Daily for 1 year

RANDOMIZE

Non-Metastatic Kidney CancerThat meets radiologic criteria to be clinically T1bNany (resectable) M0 disease

SURGERY

Arm A Sunitinib

50 mg daily for 1 year

REGISTRATION1

REGISTRATION2

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

ObjectivesPrimary 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 for 1 year, then

placebo for 2 years

(n=621)

Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial

• 1º endpoint: Metastasis-free survival

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

(1.5

:1.5

:1)

Ran

do

miz

atio

n(N

=16

56)

High and intermediate

risk, resected RCC

Nep

hre

cto

my

Placebo

for 3 years

(n=414)

Nexavar

for 3 years

(n=621)

MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients withResected 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

Sunitinib (n= 169)

Sorafenib (n=451)

Bevacizumab (n=39)10mg/kg

Temsirolimus (n=212)

Fatigue Likely Likely Less likely Likely Hand-Foot Syndrome

Less likely Likely ND ND

Other Rash Less likely Likely Likely Likely Hypertension Less likely Less likely Likely ND Edema

Less likely ND ND Less likely

Dyspnea

Less likely Less likely ND Likely

LVEF decline

Rare ND ND ND

Anorexia Likely Less likely ND Likely Diarrhea Likely Likely ND Likely Stomatitis Likely Less likely ND Likely Nausea Likely Less likely ND Likely Bleeding Less likely Less likely Less likely Rare Thrombosis Rare Rare Rare ND

Hypothyroidism Less likely ND ND ND

High AST/ALT

Less likely Less likely Less likely Less likely

High amylase/lipase

Less likely Less likely ND ND

High Cholesterol ND ND ND Likely High Triglycerides

ND ND ND Likely

Low Phosphorus Less likely Less likely ND Likely Neutropenia Less likely Less likely ND Likely Thrombocytopenia

Less likely Less likely ND Likely

GI perforation Rare Rare Rare ND

Targeted Therapy: More Questions Than Answers

1. First Line:Should we combine these agents?

Sequentially or concurrently?

Vertical inhibition or horizontal inhibition?

2. Which Type of Agent should be used first? mTKI or mTor inhibitor?

3. At Progression

Dose escalation of mTKI vs other mechanism?

6. Treatment duration-are these agents purely angiostatic?

7. Assessment of Response-Which is more important: RECIST or PFS?

8. Predictors of ResponseBlood flow/ vascularityhistologyImaging- 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

StratifyRisk by TNM

Stage/GradeIntermediate RiskHigh Risk

Histologic SubtypeClear cellNon-clear cell

Performance status

SurgeryOpen vs laparoscopic

 

Arm B Sorafenib800mg daily for 1 year

Arm C Placebo Daily for 1 year

RANDOMIZE

Non-Metastatic Kidney CancerThat meets radiologic criteria to be clinically T1bNany (resectable) M0 disease

SURGERY

Arm A Sunitinib

50 mg daily for 1 year

REGISTRATION1

REGISTRATION2

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