1. Updates on Renal Cell Cancer
Sandy Srinivas.M.D
Stanford University
&
David Minor.M.D
CPMC

2. Educational Objectives
Describe the intracellular signaling cascades associated with VEGFR, PDGFR, and Ras/Raf kinases in tumor cells and tumor vasculature
Discuss Clinical trials and data on Sorafenib
Discuss the national clinical trial on adjuvant and metastatic disease
Discuss Clinical trials and data on Sutent
Role of High dose IL-2
Describe mTor Inhibitors
FR=platelet-derived growth factor; RCC=renal cell carcinoma; VEGFR=vascular endothelial growth factor

3. Histological Classification of Human Renal Epithelial Neoplasms
RCC
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.

4. American Joint Committee on Cancer (AJCC) 2002 Clinical Staging System
Stage
Description
5-Year Survival (%)
Stage I
T1, N0, M0 95
Stage II
T2, N0, M0 88
Stage III
T1-2, N1 or T3, N0-1 59
Stage IV
T4 (any N or M) or N2 (any T or M) or M1 20
5-year survival rates by clinical stage of RCC.
Revisions of the AJCC-TNM Staging System
The AJCC system was revised in The most significant change was an increase in size cutoff between T1 and T2 tumors from 2.5 cm to 7 cm. This modification also induced a corresponding change in 5-year survival rate for tumors at stage II between 1987 and 1997 staging systems (from 94% to 88%).
Both the 1987 and 1997 staging systems are similar in predicting patient outcome, but the revised system permits better stratification of cases based on survival.
Advanced stages of RCC are associated with worsening prognosis.
Cohen HT, McGovern FJ. N Engl J Med. 2005;353:
Reference
Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:

5. 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:

6. Historical Management Strategies for RCC: Summary
Chemotherapy
RCC is highly resistant, <10% ORR1
IFN-
15% ORR, but responses rarely complete or durable2
HD IL-2
15% ORR in stage IV patients, only 5% were CR3
Urgent need for additional options in late-stage RCC
Historical management strategies for RCC: summary
RCC is highly resistant to current chemotherapeutic agents, which have yielded a disappointing response rate of less than 10%.1
Treatment with IFN- yields an objective response rate of 15% in advanced patients, but the responses are rarely complete or durable.2
High-dose IL-2 has elicited a 15% objective response rate in stage IV patients, but only 5% were complete responses. In this small group of patients achieving a complete response with high-dose IL-2, responses appear to be durable, with a median duration in excess of 80 months.3
1. Krown SE. Cancer. 1987;59: Muss HB. Semin Oncol. 1988;15: Rosenberg SA et al. JAMA. 1994;271:
References
1. Krown SE. Interferon treatment of renal cell carcinoma. Cancer. 1987;59: Muss HB. The role of biological response modifiers in renal cell carcinoma. Semin Oncol. 1988;15: Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:

7. Role of VHL in RCC Progression
Paracrine
Function
Pericyte
RAS
RAF
MEK
ERK
Autocrine
Function
Tumor cell
VHL
HIF-1
HIF-1
RAS
RAF
MEK
ERK
Scene 1
RCC is a highly vascularized tumor
Scene 2
Three cell types play a role in the progression of RCC
The 1° effector is the tumor cell itself
Mutation or inactivation of VHL in the tumor cell allows for accumulation of HIF-1 protein.
Increased levels of HIF-1 result in an overexpression of angiogenic and cellular growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF).
Scene 3
Through a paracrine function, VEGF travels to regional endothelial cells where it binds to the VEGF-receptor, initiating a signal for the stabilization of blood vessels and the further proliferation of tumor cells.
Scene 4
Through a paracrine function, PDGF travels to regional pericytes where it binds to the PDGF-receptor, initiating a signal for the growth of blood vessels and the further proliferation of tumor cells.
Scene 5
Through an autocrine function, EGF travels back to the tumor cell where it binds to the EGF-receptor, initiating a signal for the growth of the tumor.
Paracrine
Function
HIF-1
RAS
RAF
MEK
ERK
Endothelial cell
HIF-1
VEGF
VEGF
EGF
EGF
PDGF
PDGF
EGF
VEGF
PDGF
Reference
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:

8. Rational Targets in RCC (cont’d)
EGF
PDGF
VEGF
Pericyte
Endothelial cell
Tumor cell
HIF-1
VHL
HIF-1
RAS
RAF
MEK
ERK
Sorafenib
Sunitinib
Approved and investigational kinase inhibitors have multiple molecular
targets in RCC
Bevacizumab binds to the VEGF, inhibiting its ability to bind to its receptor.
Sorafenib binds to the kinase domain of the VEGF and PDGF, inhibiting their ability to initiate cell-signaling cascades. Sorafenib also inhibits RAF kinase.
Sunitinib binds to the kinase domain of the VEGF and PDGF, inhibiting their ability to initiate cell-signaling cascades.
Bevacizumab

9. 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:

10. Bevacizumab for mRCC: Progression-Free Survival
Median PFS (months)
High dose, 10 mg/kg(n=39)
4.8 (P<.001)
Low dose, 3 mg/kg (n=37)
3.0 (P<.041)
Placebo (n=40)
2.5
100 90 80 70 60
Patients Free of Tumor Progression (%) 50 40
Bevacizumab increased PFS in patients with mRCC to a median
of 4.8 months
Significant increases in the PFS were observed in patients treated with both dosages of bevacizumab.
High-dose median PFS was almost twice that of patients receiving placebo, 4.8 months vs 2.5 months (P<.001).
Partial responses were seen in 10% (4 patients) of patients treated with high­dose bevacizumab.
No responses were reported in patients receiving low­dose bevacizumab or placebo.
No complete responses were observed.
This study was terminated early, at the second interim by the National Cancer Institute (NCI) Data Safety and Monitoring Board because of the significant difference in the TTP between patients treated with high-dose bevacizumab (10 mg/kg) and patients in the placebo group. 30
Partial Response-10% 20 10 6 12 18 24 30 36
Time (months)
Adapted from 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:

11. Bevacizumab + Erlotinib for mRCC: Phase II Study Design
Bevacizumab 10 mg/kg IV q 2 wks + erlotinib 150 mg PO qd
mRCC patients, no prior therapy
(N=104)
Bevacizumab 10 mg/kg IV q 2 wks + placebo 150 mg PO qd
1° end points: PFS and ORR
Results
Bevacizumab +Erlotinib Bevacizumab + Placebo
# Patients
ORR (CR+PR) 7(14%) 7(13%)
Stable Disease 34(68%) 36(68%)
PFS (months) P=0.58
Preliminary data from a bevacizumab in combination with erlotinib phase 2
trial suggest no significant improvement over erlotinib alone
104 mRCC patients with no prior therapy were enrolled in a multicenter, randomized, placebo-controlled, double-blind phase 2 trial.
Patients were treated with either bevacizumab at 10 mg/kg IV q 2 weeks plus erlotinib at 150 mg PO qd or bevacizumab 10 mg/kg IV q 2 weeks plus 150 mg PO qd.
The primary end points were PFS and ORR.
Based on the preliminary data, there were no significant differences in PFS between the 2 arms.
Bukowski , Srinivas ASCO 2006
Reference
Genentech press release, Tuesday, October 18, Available at: press-releases/display.do?method=detail&id=8967. Accessed March 20, 2006.

12. Sorafenib (Nexavar®) CF3 CI NH O N CH3 N H
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.

13. Sorafenib for mRCC: Phase II (RDT) Study Design
≥25% tumor shrinkage  continue sorafenib
Solid tumors (N=502) mRCC patients
(n=202)
Sorafenib
Stable patients (-25% to +25%)
randomized
Placebo*
>25% tumor growth  off-study
1° end points
PFS from day 1
PFS 12 weeks post-randomization, tumor response rate, safety
All patients treated with sorafenib 400 mg bid during the open-label
run in phase
Patients evaluated at 12 weeks:
Responding patients (≥25% tumor shrinkage) continue sorafenib
Stable patients (-25% to +25%) randomized in double-blind fashion to sorafenib vs placebo
Progressing patients (>25% tumor growth) off-study
69 patients had tumor stabilization and were randomized either to continue treatment with sorafenib or to placebo.
Of the patients randomized to sorafenib, 50% had stable disease at 24 weeks vs 18% of patients receiving placebo. The difference was statistically significant (P=.0077).
RDT=randomized discontinuation trial. *May cross over to sorafenib. 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.

14. 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.

15. Sorafenib for mRCC: Phase II (RDT) Drug-Related Adverse Events
Any grade %
Grade 3/4
Any event 98 48
Cardiovascular 38 25
Hypertension 35 24
Dermatology 90 15
Rash/desquamation 62 2
Hand-foot skin reaction 60 13
Alopecia 50 –
Other
Dry skin 21
Flushing
Constitutional symptoms 68 6
Fatigue 55 4
Weight loss
Sorafenib for mRCC: Phase 2 (RDT) Drug-Related Adverse Events
The major drug-related adverse events seen in the sorafenib RDT were hypertension, rash, hand-foot syndrome, fatigue, and alopecia.
The incidence of adverse experiences was similar between treatment groups post-randomization.
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.

16. Sorafenib for mRCC: Phase III Study Design (TARGET)
Unresectable and/or mRCC,
1 prior systemic Tx in last 8 months, ECOG PS 0/1
(N=903*)
Sorafenib, 400 mg bid (n=451)
Placebo (n=452)
1° end point: OS
2° end points: ORR, PFS, safety, HR-QoL
Demographics
MSKCC good or intermediate risk patients
Clear-cell carcinoma
The efficacy of sorafenib in patients with unresectable, refractory
or mRCC was assessed in the TARGET phase 3 trial
TARGET is the largest phase 3 randomized, placebo-controlled trial to date in patients with advanced RCC.
A total of 905 patients with unresectable or metastatic RCC who had already failed at least one systemic therapy were enrolled.
The primary end point of this trial was OS.
The secondary end points were overall response rate, PFS, safety, and patient quality of life.
Patients who had failed while on placebo were permitted to cross over to sorafenib treatment after interim analysis was completed.
*Out of 905 patients randomized by February 15, 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.

17. Sorafenib for mRCC: Response Rate* (TARGET)
Best Response by RECIST
Sorafenib (n=451) n (%)
Placebo (n=452) n (%)
Complete response
1 (<1) —
Partial response
43 (10)
8 (2)
Stable disease
333 (74)
239 (53)
Progressive disease
56 (12)
167 (37)
Missing
18 (4)
38 (8)
A significant percentage of patients treated with sorafenib displayed
some level of tumor response
Sorafenib has significantly higher PR and SD rates than placebo (10% vs 2%, 74% vs 53%, respectively).
* 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.

18. 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.

19. 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
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.

20. 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.

21. Sorafenib for mRCC: Adverse Events Profile (TARGET)
Placebo (n=452)
Sorafenib (n=451)
<1
<1
<1
Any Grade
Grade 3
Sorafenib treatment was well tolerated with limited adverse events
The most common AEs observed were:
Diarrhea (43%)
Rash/desquamation (40%)
Fatigue (37%)
Hand-foot skin reaction (30%)
Hand-foot skin reaction (6%) and fatigue (5%) were the most frequent grade 3 AEs.
Patients (%)
Patients (%)
7% grade 4 toxicities in sorafenib-treated patients vs 6% grade 4 toxicities in placebo-treated patients.
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.
Reference
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.

22. Sorafenib for mRCC: Laboratory Toxicities (TARGET)
Placebo (n=452)
Sorafenib (n=451)
Any Grade
Grade 3
Sorafenib treatment was well tolerated with limited
laboratory abnormalitites
The most frequent laboratory abnormalities associated with sorafenib treatment were hypophosphatemia (45%), anemia (44%), elevated lipase (41%).
Hypophosphatemia (13%), lymphopenia (13%), and elevated lipase (12%) were the most frequent grade 3 laboratory abnormalities associated with sorafenib treatment.
Patients (%)
Patients (%)
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.
Reference
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.

23. TARGETs Hand–Foot Skin Reaction
Early in treatment and reversible. hypersensitivity of foot, soreness

24. Sorafenib for mRCC: Conclusion
First MKI approved for treatment of advanced RCC
December 20, 2005
More than doubles PFS compared to placebo
Therapeutic response
Radiographic response vs disease stabilization
OS survival trend at planned interim analysis (P<.018)
Mild to moderate toxicity profile
Sorafenib is a valuable therapeutic option in mRCC
Sorafenib is the first in class approved multikinase inhibitor (MKI) for the management of advanced RCC.
FDA approval on December 20, 2005.
Treatment with sorafenib more than doubled the PFS in patients vs placebo.
Adverse event toxicities observed with sorafenib were mild to moderate.
Front-line data forthcoming for sorafenib vs IFN-.

25. Response in Treatment naïve patients(32)PR
6(18.8%) MR
8(25%) SD
10(31.3%) PD
3(9%)
Uneval
5(15%)
32 of the 202 patients in the RDT had no prior therapy
PFS in this group was 40 weeks -10 months
Overall response of 75%
Escudier ASCO 2006

26. Phase II Randomized Trial- First LineG I S T A O N P R O G E S I N
SORAFENIB
400MG BID
SORAFENIB
600MG BID
MET RCC
CLEAR CELL
NO PRIOR RX
ECOG 0/1
NO BRAIN METS
ALL MSKCC
RISK GROUPS
N=189
IFN-α
9 M TIW
SORAFENIB
400MG BID
Accrual completed; too few events for results
Escudier, ASCO 2006

27. Randomized phase III trial of Sorafenib: Impact of Crossover o survival
Cross
over
months Cross over
6 mos
Crossover with placebo censored
Placebo
14.7
15.9
14.3
Sorafenib NR
19.3
Hazard Ratio
0.72
0.77
0.74
P-value
0.018
0.015
0.01
O-Brien-Flemming SR
0.0005
0.0094
357 events as of 11/05; Mature data when 540 events
Eisen, ASCO 2006

28. Summary-PFS (months) First Line Second Line Bevazizumab 8.5 4.8
Sorafenib 9
5.5

29. ECOG 2805: Adjuvant Trial 1° end point: Disease-free survival (DFS)
Group A: (sunitinib)
Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles†
Stratify TNM
Intermediate high risk
Very high risk
Histologic Subtype
Clear cell
Non-clear cell (except collecting duct or medullary) ECOG Performance Status
1 Surgery
Laparoscopic
Open
Nephrectomy
Group B: (Nexavar)
Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and placebo for sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles†
Preregister
Randomization
(N=1332)
Group C: (placebo)
Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; and placebo for sunitinib 50 mg (4 capsules) po qd 4 wks followed by rest 2 wks for 9 cycles†

30. Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial
1º end point: Disease-free survival
2º end points: RCC-specific survival time, toxicity, QOL, and biomarkers
(1.5:1.5:1) Randomization
(N=1656)
High and intermediate risk, resected RCC
Nephrectomy
Preregister
Placebo
for 3 years
(n=414)
Nexavar for 1 year
Placebo for 2 years
(n=621)
Nexavar