Nexavar%20in%20Patients%20with%20Renal%20Cell%20Carcinoma

1
Nexavar in Patients with Renal Cell Carcinoma

• Naomi B. Haas
• October 4, 2007

2
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.
200020197-212.
3
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
BHDBirt-Hogg-Dubé FHfumarate hydratase
VHLvon Hippel-Lindau. Modified from Linehan WM
et al. J Urol. 20031702163-2172.
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5
Treatment of Advanced Disease

• Based in part on risk factors

6
MSKCC Risk Factor Model in mRCC

• Risk factors associated with worse prognosis
• KPS lt80
• 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-? lt1 yr

Proportion Surviving
4
0
2
16
13
11
9
5
3
6
15
12
10
8
7
6
14
Time From Start of IFN-? (years)
Motzer RJ et al. J Clin Oncol. 200220289-296.
7
ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL
CARCINOMA Motzer et al, JCO 172530-2540, 1999

• Risk Risk Factors Median Survival
• Favorable 0 29 mo.
• Intermediate 1-2 14 mo.
• Poor 3 and 4 mo.

8
Do patients with advanced disease do better with
nephrectomy?

• Performance status matters
• This issue has not been addressed in the era of
  targeted therapy

9
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

10
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11
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

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Common Treatment related side effects
14
Bevacizumab for mRCC Phase II Study Design
High dose 10 mg/kg (n39)
mRCC patients (N116) ECOG PS lt2 All patients
have prior therapy (mostly IL-2)
Low dose 3 mg/kg (n37)
Placebo (n40)

• 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. 2003349427-434.
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Bevacizumab for mRCCSummary

• No significant difference in OS between treatment
  groups
• High dose (10 mg/kg)
• PR 10 (95 CI, 2.924.2)
• Significantly prolonged PFS (median 4.8 months,
  Plt.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

17
Phase III study (AVOREN) of bevacizumab/interferon
-a2a vs placebo/interferon- a2a as first-line
therapy in metastatic RCC
IFN (9 MIU 3x weekly) bevacizumab(10mg/kg)
IVq2w (320)
641 patients nephrectomy clear cell RCC
IFN (9 MIU 3x weekly) placebo (321)
The addition of BEV to IFN-a2a significantly
increased PFS (10.2 vs. 5.4 mo) (HR0.63
plt0.0001) and objective tumor response rate
(30.6 vs. 12.4 plt0.0001). A trend toward
improved OS was observed with the addition of
BEV to IFN-a2a (p0.0670).
Journal of Clinical Oncology, 2007 ASCO Annual
Meeting Proceedings Part I. Vol 25, No. 18S
(June 20 Supplement), 2007 3
18
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. 2004107099-7109.
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.

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Sorafenib for mRCC Phase II (RDT)
Progression-Free Survival
1.00
0.75
Median PFS from randomization Sorafenib24
weeksPlacebo6 weeks P.0087
Proportion of Patients Progression-Free
0.50
0.25
0
84
0
100
200
300
400
500
12-week period
Time From Randomization (days)
Ratain MJ et al. Presented at ASCO May 13-17,
2005 Orlando FL.
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Sorafenib for mRCC Tumor Reduction (TARGET)
Change From Baseline ()
Change From Baseline ()
25
76
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.
22
Sorafenib for mRCC Progression-Free Survival
(TARGET)
1.00
0.75
PFS Median (months)
Sorafenib Placebo 5.5 2.8
Hazard ratio (S/P) 0.51
Proportion of PatientsProgression Free
0.50
0.25
0
0
4
10
20
2
6
8
12
14
16
18
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, Plt.000001).
• Escudier B et al. Presented at ECCO October
  30-November 3, 2005 Paris, France.

23
Sorafenib for mRCCOverall Survival (TARGET)
1.00
0.75
Proportion of PatientsOverall Survival
0.50
OS Median (months)
Sorafenib Placebo Not reached 14.7
Hazard ratio (S/P) 0.72
P.018
0.25
0
0
4
10
20
2
6
8
12
14
16
18
Time From Randomization (months)

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

24
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

25
Randomized Phase II Trial of First-line
Treatment With Nexavar vs Interferon in
Patients With Advanced Renal Cell Carcinoma
Final Results
Adapted from Szczylik C et al. Presented at ASCO
Annual Meeting June 1-5, 2007 Chicago, IL.
26
First-line Nexavar vs IFN in Advanced RCCStudy
Design

• 1º endpoints
• Period 1 PFS (Nexavar vs IFN) database cutoff
  29 Sep 06 121 PFS events
• Period 2 PFS and clinical benefit database
  cutoff 31 Dec 06 52 PFS events
• 2º endpoints
• Quality of life

Period 1
Period 2
Nexavar400 mg bid N97
Nexavar600 mg bid N44

• Eligibility Criteria
• Clear-cell histology
• No prior systemic therapy
• ECOG Performance Status 0 or 1
• All MSKCC risk groups

PROGRESSION
Open-label randomization11 Stratification
MSKCCN189
Period 1
Period 2
IFN 9 MIU tiw N92
Nexavar400 mg bid N50
PROGRESSION
IFNinterferon. Adapted from Szczylik C et al.
Presented at ASCO Annual Meeting June 1-5,
2007 Chicago, IL.
27
First-line Nexavar vs IFN in Advanced RCCResults

• Period 1 Nexavar vs IFN
• Median PFS comparable between IFN (5.6 mo) and
  Nexavar (5.7 mo)
• Clinical benefit and tumor shrinkage greater with
  Nexavar than IFN
• Quality of life was markedly better with Nexavar
  vs IFN
• Adverse events as expected with Nexavar and IFN
• Period 2 crossover, dose escalation
• IFN to Nexavar crossover mirrored results of
  TARGET study
• Nexavar 400 ? 600 mg bid
• Well tolerated
• Additional benefit following dose escalation
• Delay of progression for 4.1 months
• Improvement of clinical outcome for 46 of
  patients
• Quality of life benefit was maintained

Hazard ratio (IFN/NEX)0.883 (95 CI
0.613-1.272.) TARGETTreatment Approaches in
Renal Cancer Global Evaluation Trial. Adapted
from Szczylik C et al. Presented at ASCO Annual
Meeting June 1-5, 2007 Chicago, IL.
28
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.
   200523939-952.
2. Sutent package insert. New York, NY Pfizer
   Inc. 2006.

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Results

• Median PFS 11 months for sunitinib vs. 5 months
  for IFN-a (plt0.000001).
• The objective response rate by third-party
  independent review was 31 for sunitinib vs. 6
  for IFN-a (plt0.000001).
• 8 withdrew from the study due to adverse event
  on sunitinib arm vs. 13 on IFN-a arm.

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32
Conclusion

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

33
Targeted Therapy More Questions Than Answers

• First LineShould 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?

34

• Treatment duration-are these agents purely
  angiostatic?
• Assessment of Response-
• Which is more important RECIST or PFS?
• Predictors of Response
• Blood flow/ vascularity
• histology
• Imaging- PET/CT, DCE/MRI, CT
• Role of agents-Adjuvant?, First-line? Before or
  after cytokines?
• Exposure to agent- drug levels of sunitinib
  correlated with response
• Dose escalation of agent some patients can
  tolerate dose escalation at the time of
  progression
• How to treat non clear cell and other variants

35
Sequential Use of Nexavar and Sunitinib
Retrospective Analysis in 90 Patients
36
MKI Sequencing Study Design
Retrospective review of sequential therapy with
MKIs in RCC

• Reviewed
• Patient demographics
• MSKCC
• No. of metastatic sites
• Efficacy
• OS
• PFS
• Best response
• Safety

Nexavar ? Sunitinibn68
N90 4 sites in France RCC patients in expanded
access programs
Sunitinib ? Nexavarn22
MKImultikinase inhibitor. Adapted from Sablin MP
et al. Presented at ASCO Annual Meeting June
1-5, 2007 Chicago, IL.
37
MKI Sequencing Results

• 68 patients received Nexavar first, while 22
  received sunitinib first
• The 2 groups are comparable in terms of ECOG PS
  and MSKCC groups
• 38 of the patients in the Nexavar?sunitinib
  group are still on treatment vs 19 in the
  sunitinib?Nexavar group
• 50 of the patients have died in the
  sunitinib?Nexavar group compared to 32 in the
  Nexavar?sunitinib

Adapted from Sablin MP et al. Presented at ASCO
Annual Meeting June 1-5, 2007 Chicago, IL.
38
MKI Sequencing Efficacy of Treatment
NEX?Su NEX?Su Su?NEX Su?NEX
Median Overall Survival, weeks NR NR 70 70
Nexavar Sunitinib Sunitinib Nexavar
Median PFS, weeks 26 25 22 17
Partial response, n () 11 (16) 10 (15) 5 (23) 2 (9)
Stable disease, n () 45 (66) 35 (51) 12 (54) 12 (55)
Progressive disease, n () 10 (15) 17 (25) 5 (23) 8 (36)
Not evaluated (NE), n () 2 (3) 6 (9)
Average duration, weeks 33 28 27 22
NRnot reached. Adapted from Sablin MP et al.
Presented at ASCO Annual Meeting June 1-5, 2007
Chicago, IL.
39
MKI Sequencing Efficacy of Nexavar?Sunitinib
Sunitinib Sunitinib Sunitinib Sunitinib
Nexavar 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 2 1 1
Adapted from Sablin MP et al. Presented at ASCO
Annual Meeting June 1-5, 2007 Chicago, IL.
40
MKI Sequencing Efficacy of Sunitinib?Nexavar
Nexavar Nexavar Nexavar
Sunitinib Sunitinib PR 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.
41
MKI Sequencing Conclusions

• This study supports the sequential administration
  of Nexavar and sunitinib even though these 2
  drugs share the same targets
• In our study, using Nexavar first appears to be
  superior with
• A better PFS for each arm
• The achievement of PR after PD with sunitinib
  after Nexavar (20)
• A longer duration on therapy (61 vs 49 weeks)
• A trend toward better survival (to be confirmed)
• These data will have to be confirmed in
  prospective studies

Adapted from Sablin MP et al. Presented at ASCO
Annual Meeting June 1-5, 2007 Chicago, IL.
42
Phase II Trial of Intrapatient Dose-Escalated-Nex
avar in Patients With Metastatic Renal Cell
Cancer
43
Dose-Escalated Nexavar for RCC Study Design

• 1º endpoints Safety and toxicity
• 2º endpoints RR, PFS, and OS

• Eligibility
• Metastatic RCC, component of clear-cell
• 1 prior cytokine therapy
• Adequate PS
• Adequate pancreatic and cardiac function

Treatment continues until PD or intolerance
Nexavar800 mg po bid Days 57
Nexavar400 mg po bid Days 1-28
Nexavar600 mg po bid Days 29-56
After 4 weeks, patients with no DLT (grade
3/4) increase dose
After 4 weeks, patients with no DLT (grade
3/4) increase dose
Target accrual 44 patients. Response assessed by
RECIST every 8 weeks.DLTdose-limiting
toxicities Adapted from Amato R et al. Presented
at ASCO Annual Meeting June 1-5, 2007 Chicago,
IL.
44
Dose-Escalated Nexavar for RCCBaseline Patient
Characteristics
N44 N44
Characteristics N
Median age, years (range) 50 Range 43-79
Male/female 37/7 84/16
Zubrod PS, (0/1) 39/5 89/11
Clear Cell (CC) 35 80
Other histology 9 20
CC/Sarcomatoid 7
CC/Focal Rhabdoid 1
CC/Papillary 1
Prior nephrectomy 42 95
Prior radiation therapy 10 23
MSKCC Risk Factors
0 18 41
1 17 38
2 6 14
3 3 7
Adapted from Amato R et al. Presented at ASCO
Annual Meeting June 1-5, 2007 Chicago, IL.
45
Dose-Escalated Nexavar for RCCBaseline Patient
Characteristics (contd)
N44 N44
Characteristics N
Prior systemic therapy 19 43
IL-2 15
RAD001 2
Interferon 1
cG250 1
Best response to prior systemic CR/PR 3/2 16/11
Total number of metastatic sites
1 26 59
2 11 25
3 7 16
CRcomplete response IL-2interleukin 2
PRpartial response. Adapted from Amato R et al.
Presented at ASCO Annual Meeting June 1-5,
2007 Chicago, IL.
46
Dose-Escalated Nexavar for RCCIntensity 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.
47
Dose-Escalated Nexavar for RCCBest 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.
48
Dose-Escalated Nexavar for RCC Incidence of
Treatment-Related AEs
Cycle 1 Days 1-28 (n44) Cycle 1 Days 1-28 (n44) Cycle 1 Days 1-28 (n44) Cycle 2 Days 29-56 (n41) Cycle 2 Days 29-56 (n41) Cycle 2 Days 29-56 (n41) Cycle 2 Days 29-56 (n41) Cycle 3 Days 57 (n32) Cycle 3 Days 57 (n32) Cycle 3 Days 57 (n32)
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
AEsadverse events ALTalanine aminotransferase
ASTaspartate aminotransferase. Adapted from
Amato RJ et al. Presented at ASCO Annual
Meeting June 1-5, 2007 Chicago, IL.
49
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.
50
Sorafenib for mRCC Tumor Response (TARGET)
Pre-Therapy
8 Weeks Post-Therapy
Image courtesy of Laura Wood, RN, MSN, OCN.
51
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.
200020197-212.
52
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

53
Contributors to Prognosis

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

54
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
55
A.S.S.U.R.E. (ECOG 2805)
Stratify Risk by TNM Stage/Grade Intermediate
Risk High Risk Histologic Subtype Clear
cell Non-clear cell Performance
status Surgery Open vs laparoscopic  
REGISTRATION2
Arm A Sunitinib 50 mg daily for 1 year
REGISTRATION1
RANDOMIZE
S U R G E R Y
Non-Metastatic Kidney Cancer That meets
radiologic criteria to be clinically ? T1bNany
(resectable) M0 disease
Arm B Sorafenib 800mg daily for 1 year
Arm C Placebo Daily for 1 year
56
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

57
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

58
Nexavar in Adjuvant RCC MRC SORCE Phase III
Trial

• 1º endpoint Metastasis-free survival
• 2º endpoints RCC-specific survival time,
  toxicity, QoL, and biomarkers

Nexavar for 3 years (n621)
Nexavar for 1 year, then placebo for 2
years (n621)
Nephrectomy
High and intermediate risk, resected RCC
(1.51.51) Randomization (N1656)
Placebo for 3 years (n414)
MRCMedical Research Council QoLquality of
life SORCESOrafenib versus placebo in patients
with Resected primary renal CEll carcinoma.
59
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

60
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

61
Common Treatment related side effects
62
Targeted Therapy More Questions Than Answers

• First LineShould 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?

63

• Treatment duration-are these agents purely
  angiostatic?
• Assessment of Response-
• Which is more important RECIST or PFS?
• Predictors of Response
• Blood flow/ vascularity
• histology
• Imaging- PET/CT, DCE/MRI, CT
• Role of agents-Adjuvant?, First-line? Before or
  after cytokines?
• Exposure to agent- drug levels of sunitinib
  correlated with response
• Dose escalation of agent some patients can
  tolerate dose escalation at the time of
  progression
• How to treat non clear cell and other variants

64
A.S.S.U.R.E. (ECOG 2805)
Stratify Risk by TNM Stage/Grade Intermediate
Risk High Risk Histologic Subtype Clear
cell Non-clear cell Performance
status Surgery Open vs laparoscopic  
REGISTRATION2
Arm A Sunitinib 50 mg daily for 1 year
REGISTRATION1
RANDOMIZE
S U R G E R Y
Non-Metastatic Kidney Cancer That meets
radiologic criteria to be clinically ? T1bNany
(resectable) M0 disease
Arm B Sorafenib 800mg daily for 1 year
Arm C Placebo Daily for 1 year