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
Historical management of advanced-stage RCC offer little overall
improvement in patient outcomes
Common historical therapies for RCC include:1
Nephrectomy, either before or after cytokine therapy
Metastectomy of solitary lesions
Combination or solitary cytokine therapy
Interleukin (IL-2) or interferon- (IFN-) or the combination of IL-2 plus IFN- are the most widely used treatment options for patients with advanced RCC.
Combined modality such as nephrectomy prior to cytokine treatment is effective in improving patient’s clinical outcome based on two independent phase 3 trials.2,3
Clinical trials offer an alternative approach.
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version  Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:
References
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alpha-2b compared with interferon alpha-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:
Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alpha-based immunotherapy compared with interferon alpha alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:

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
Clear cell
75%
Type
Incidence (%)
Associated mutations
VHL
Papillary type 1 5%
c-Met
Papillary type 2
10% FH
Chromophobe
BHD
Oncocytoma
Common epithelial neoplasms of the kidney can be either familial
or sporadic
Mutations in the gene for VHL, c-Met, FH, or BHD are common in both the familial and sporadic forms of kidney neoplasms.1,2
Cases of familial neoplasm arise from inherited germline mutations earlier than cases of sporadic neoplasm.
Familial neoplasm requires only one additional mutation to inactivate the gene while sporadic neoplasm requires multiple subsequent mutations in order to inactivate the gene.1
Clear-cell RCC is the predominant histological type (75%).1,2
There are two types of papillary renal cell cancer: Type II is very aggressive; Type I less so.
Oncocytoma is no longer considered to be malignant tumor, it is a benign neoplasm.3
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.
Modified from Linehan WM et al. J Urol. 2003;170:
References
1. Linehan WM et al. The genetic basis of cancer of the kidney. J Urol. 2003;170: Kim WY. J Clin Oncol. Role of VHL gene mutation in human cancer. 2004;22: Kidney Cancer Association. Kidney cancer subtypes. Available at: Accessed March 21, 2006.

5. Treatment of Advanced Disease
Based in part on risk factors

6. 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)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
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
Proportion Surviving
The Memorial Sloan-Kettering risk-factor model is predictive of patient
long-term prognosis
This retrospective study was performed on 670 patients with mRCC treated at Memorial Sloan-Kettering Cancer Center.
The subsequent model that was developed, identifies prognostic factors that predicted survival for patients with mRCC.
Risk factors associated with shorter survival (no prior nephrectomy) were:
KPS <80
Low serum hemoglobin (13 g/dL in males,11.5 g/dL in females)
High corrected calcium (10 mg/dL)
High lactate dehydrogenase (300 U/L)
The model predicts that patient prognosis declines as the number of risk factors increases. 6 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time From Start of IFN- (years)
Motzer RJ et al. J Clin Oncol. 2002;20:
Reference
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M, et al. Interferon-alfa as a comparitive treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:

7. ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Motzer et al, JCO 17:2530-2540, 1999
Risk # Risk Factors Median Survival
Favorable mo.
Intermediate mo.
Poor 3 and 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

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

12. There are over 15 different angiogenic targets identified and at least 14 drugs under development for them

13. Common Treatment related side effects

14. Bevacizumab for mRCC: Phase II Study Design
High dose = 10 mg/kg (n=39)
mRCC patients
(N=116)
ECOG PS <2
All patients have prior therapy (mostly IL-2)
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
Phase 2 study of efficacy and safety of bevacizumab in mRCC
This was a randomized, double-blind phase 2 trial.
116 patients received either 3 mg/kg or 10 mg/kg of bevacizumab, or placebo, every 2 weeks.
Patients initially receiving placebo were permitted to cross over to treatment with bevacizumab.
Primary end points in this study were TTP and ORR.
Overall survival was a secondary end point in this study.
Patients were well-matched for all groups.
116 previously treated, metastatic RCC patients were randomized to three groups: high dose (10 mg/kg), low dose (3 mg/kg), and placebo.
ECOG PS were ≤2, which is a relatively fit patient population.
Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide.
Yang JC et al. N Engl J Med. 2003;349:
Reference
Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:

16. 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
Bevacizumab, an angiogenesis inhibitor, is an effective treatment option
for patients diagnosed with mRCC
High-dose bevacizumab significantly prolonged patient’s PFS (P<.001).
High-dose bevacizumab (10 mg/kg) is well-tolerated in patients with an objective response rate of 10%.
No life-threatening toxic events were observed.
Low-dose bevacizumab (3 mg/kg) did not produce any significant difference between in time to progression of disease vs the placebo group (P=0.041).

17. Phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a 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) (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).
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
N H O N CI
CF3 NH
CH3
Sorafenib targets multiple pathways involved in RCC tumorigenesis
Sorafenib is an orally administered, small-molecule receptor TKI that targets VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, and Raf kinases.1
Although sorafenib is a potent inhibitor of Raf, there is little or no evidence to suggest that Raf plays a role in the oncogenesis of RCC.2
FDA approved December 20, 2005 for treatment of advanced RCC.3
Wilhelm SM et al. Cancer Res. 2004;10:
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.
Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: Accessed January 24, 2006.
References
Wilhelm SM, Carter C, Tang L, et al. BAY exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:
Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:
Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: Accessed January 24, 2006.

19. Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival
1.00
Sorafenib (n=33)
Placebo (n=32)
Censored
0.75
Median PFS from randomization
Sorafenib=24 weeks Placebo=6 weeks
P=.0087
Proportion of Patients Progression-Free
0.50
Patients receiving sorafenib had a median PFS of 24 weeks
Twelve weeks after patient randomization, 50% of the patients receiving sorafenib remained progression free, while 18% of patients in the placebo group were progression free.
During the initial 12 weeks of sorafenib treatment, 71% of patients experienced tumor shrinkage or stabilization of disease.
There were no deaths attributed to treatment toxicity in this trial; however, 5% of patients experienced a serious drug-related AE.
AEs were similar between the randomized treatment groups.
0.25 84
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.
Reference
Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a phase 2, placebo-controlled, randomized discontinuation trial of sorafenib (BAY ) in patients with advanced renal cell carcinoma. Presented at: ASCO; May 13-17, 2005; Orlando, FL.

21. Sorafenib for mRCC: Tumor Reduction* (TARGET)
Placebo (n=452)
Sorafenib (n=451) 50
100
150
-50
-100 50
100
150
-50
-100
Change From Baseline (%)*
Change From Baseline (%)*
Patients treated with sorafenib had a more significant increase in clinical
benefit vs patients treated with placebo
Sorafenib was significantly more effective in reducing tumor size than placebo.
Clinical benefit referrers to changes in the tumor.
Volume vs character changes
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.
Reference
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY ) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

22. Sorafenib for mRCC: Progression-Free Survival* (TARGET)
1.00
Censored observation
Placebo (n=452)
Sorafenib (n=451)
0.75
PFS
Median (months)
Sorafenib
Placebo
5.5
2.8
Hazard ratio (S/P)
0.51
Proportion of Patients Progression Free
0.50
0.25
Sorafenib increases the progression-free survival of patients with
unresectable refractory mRCC
The hazard ratio for disease progression was reduced by almost half in patients with mRCC who were treated with sorafenib.
A significant reduction in the hazard ratio for progression was found in all patient subgroups.
Sorafenib extended median patient PFS to 5.5 months.
Independent assessment at planned interim analysis (ASCO) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P< ). 2 4 6 8 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< ).
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
Reference
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY ) in patients with advanced RCC. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

23. Sorafenib for mRCC: Overall Survival* (TARGET)
1.00
Censored observation
Placebo (n=452)
Sorafenib (n=451)
0.75
Proportion of Patients Overall Survival
0.50 OS
Median (months)
Sorafenib
Placebo
Not reached
14.7
Hazard ratio (S/P)
0.72
P=.018
Sorafenib increases the overall survival of patients with unresectable
refractory mRCC
The hazard ratio for OS was significantly reduced to 0.72 (P=.018) in patients with mRCC who were treated with sorafenib.
To date, the median OS has not yet been reached in patients treated with sorafenib.
Following interim analysis, patients who have been on placebo were allowed to crossover to sorafenib even in absence of disease progression.
0.25 2 4 6 8 10 12 14 16 18 20
Time From Randomization (months)
*Interim analysis.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
Reference
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY ) in patients with advanced RCC. 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 RCC—Study 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
Nexavar 400 mg bid
N=97
Nexavar 600 mg bid
N=44
Eligibility Criteria
Clear-cell histology
No prior systemic therapy
ECOG Performance Status 0 or 1
All MSKCC risk groups
PROGRESSION
Open-label randomization 1:1
Stratification MSKCC N=189
This phase II study compared the activity of Nexavar versus IFN in 189 patients with unresectable and/or metastatic RCC.
The study had two phases:
Period 1: patients received Nexavar 400mg twice daily (arm 1) or IFN 9MU three times weekly (arm 2) until progression.
Period 2: following progression, patients receiving Nexavar were dose-escalated to Nexavar 600mg twice daily and patients receiving IFN switched to second-line Nexavar 400mg twice daily.
Period 1
Period 2
IFN
9 MIU tiw
N=92
Nexavar 400 mg bid
N=50
PROGRESSION
IFN=interferon.
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 RCC—Results
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: )
TARGET=Treatment 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, for advanced RCC
H3C
CH3 F O
N H N
Sunitinib inhibits multiple signaling pathways involved
in tumorgenesis of RCC
Once-daily, orally administered small-molecule receptor tyrosine kinase inhibitor (TKI) selectively targets VEGFR, PDGFR-a, PDGFR­b, c-KIT, and FLT-3 receptor tyrosine kinases.1
Sunitinib IC50 values indicate that it is a potent TKI of VEGFR and PDGFR.1
FDA approved January 26, 2006 for treatment of advanced RCC.
Pietras K, Hanahan D. J Clin Oncol. 2005;23:
Sutent [package insert]. New York, NY: Pfizer Inc.; 2006.
References
Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23:

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

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

33. Targeted Therapy: More Questions Than Answers
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?

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 → Sunitinib n=68
N=90
4 sites in France
RCC patients in expanded access programs
Sunitinib → Nexavar n=22
MKI=multikinase 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
Su→NEX
Median Overall Survival, weeks NR 70
Nexavar
Sunitinib
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 (%)
17 (25)
8 (36)
Not evaluated (NE), n (%)
2 (3)
6 (9) –
Average duration, weeks 33 28 27
NR=not 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
PR n (%)
SD n (%)
PD n (%)
NE n (%)
PR, n 11
2 (18)
7 (64) –
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
Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

40. MKI Sequencing: Efficacy of Sunitinib→Nexavar
PR n (%)
SD n (%)
PD n (%)
PR, n 5
1 (20)
2 (40)
SD, n 12
1 (8)
7 (58)
4 (34)
PD, n
3 (60)
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-Nexavar 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
Nexavar 400 mg po bid
Days 1-28
Nexavar 600 mg po bid
Days 29-56
Nexavar 800 mg po bid
Days 57+
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. DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

44. Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics%
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
Prior nephrectomy 42 95
Prior radiation therapy 10 23
MSKCC Risk Factors 18 41 17 38 2 6 14 3
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

45. Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics (cont’d)%
Prior systemic therapy 19 43
IL-2 15
RAD001 2
Interferon 1
cG250
Best response to prior systemic CR/PR
3/2
16/11
Total number of metastatic sites 26 59 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.

46. 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.

47. Dose-Escalated Nexavar for RCC: Best Response by RECIST
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 (n=44)
Cycle 2 Days (n=41)
Cycle 3 Days 57+ (n=32)
Adverse Events G1 G2 G3 G4
Hand-foot syndrome 13 2 18 4 — 21 1
Diarrhea 11 16
Fatigue 9
Nausea 6
Rash 7
Hypertension 5 3
Stomatitis 8
Alopecia 10 17
Anorexia
Dry skin
Anemia 14
ALT/AST
Amylase/lipase
Hypophosphatemia 12
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.

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
Management of early-stage RCC
Surgery is the primary approach for early-stage, localized RCC.1
Surgical approaches for early-stage RCC include:
Partial or radical nephrectomy
Open surgery
Laprascopic
Cryoablation or radiofrequency
There are no proven adjuvant therapies.2
Clinical trials offer an alternative approach.1,2
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version  Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:
References
1. National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version Jenkintown, PA: National Comprehensive Cancer Network; 2006.
2. Urban BA, Fishman EK. Renal lymphoma: CT patterns with emphasis on helical CT. Radiographics. 2000;20:

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
Locally advanced renal cell carcinoma has a high risk of recurrence.Based on stage alone, five year relapse free survival rates of 65-80%, 40-60% and 0-20% have been reported for stages II, III and IVA respectively. The use of preoperative and postoperative prognostic models, including these listed, has further refined predicted clinical course.

53. Contributors to Prognosis
Pathologic stage
Histology
Fuhrman Grade
Nuclear grade
Performance status
Necrosis
Size
Clinical Presentation
These models have confirmed that pathologic stage, histology, fuhrman grade, performance status and other features such as necrosis, size and clinical presentation can be powerful prognostic indicators. Newer molecular features,which require prospective validation may ultimately further refine prognosis.

54. The UCLA Integrated staging system (UISS)
UISS Survival
1997 TNM Stage (%)
Fuhrman Grade
ECOG
2 Yr. Survival (%)
5Yr I
1,2 96 94 II
III
3,4
Any 1
1 or more 89 64 IV
2-4 66
 39
1-3 42 23 V 4 9

55. A.S.S.U.R.E. (ECOG 2805) REGISTRATION2 REGISTRATION1 S U R G E Y
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 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
(n=621)
Nexavar for 1 year, then
placebo for 2 years
(n=621)
Nephrectomy
High and intermediate risk, resected RCC
(1.5:1.5:1) Randomization
(N=1656)
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.

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 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?

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) REGISTRATION2 REGISTRATION1 S U R G E Y
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 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