Transcript Renal Cell Carcinoma

Nexavar in Patients with Renal
Cell Carcinoma
Naomi B. Haas
October 4, 2007
Historical Management
of Advanced-Stage RCC
• Nephrectomy
• Metastectomy
– Solitary lesions
• Cytokine combination
• Combined modalities
– Adjunctive nephrectomy
prior to cytokine therapy
– Cytokine therapy
followed by nephrectomy
• Clinical trials
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology:
Kidney Cancer:
Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
RCC is not one disease
*2004 WHO lists over 50 different types of kidney cancer
(Sarcomatoid variant can occur with any subtype)
Undifferentiated type and Collecting duct carcinoma
constitute the other 2 types listed in AJCC classification
Clear cell
Papillary type 1
Papillary type 2
Chromophobe
Oncocytoma
Incidence (%)
75%
5%
10%
5%
5%
Associated
mutations
VHL
c-Met
FH
BHD
BHD
Type
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.
Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.
Treatment of Advanced Disease
• Based in part on risk factors
MSKCC Risk Factor Model in
mRCC
0 risk factors (n=80 patients)
1 or 2 risk factors (n=269 patients)
3, 4, or 5 risk factors (n=88 patients)
1.0
Proportion Surviving
0.9
0.8
Risk factors associated with worse prognosis
0.7
• KPS <80
0.6
• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)
0.5
• High corrected calcium (10 mg/dL)
0.4
• High LDH (300 U/L)
0.3
• Time from Dx to IFN- <1 yr
0.2
0.1
0
0
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;20:289-296.
ADVERSE PROGNOSTIC FACTORS FOR
RENAL CELL CARCINOMA Motzer et al, JCO
17:2530-2540, 1999
Risk
# Risk Factors
• Favorable
0
• Intermediate
1-2
• Poor
3 and +
Median Survival
29 mo.
14 mo.
4 mo.
Do patients with advanced disease
do better with nephrectomy?
Performance status matters
This issue has not been addressed in
the era of targeted therapy
Advanced Disease Therapy in
2007
• Multitargeted tyrosine kinase inhibitors
• Mammalian target of rapamycin (mTor)
inhibitors
• Anti VEGF antibodies
• VEGF Trap
• Other angiogenesis inhibitorsthrombospondin inhibitors, pure PDGFR
and VEGFR inhibitors
The molecular profiles associated with the
various histologic RCC subtypes have
identified logical targets
• Pathways associated with EGFR,
AKT/mTOR, MAPK/MEK, and VEGF are
important in RCC
• Drugs available in 2007
– Multitargeted TK inhibitors:
• sunitinib, sorafenib, (FDA approved)
• GW786034, AG013736,ABT869
– Antibodies:
• Bevacizumab
– Imids: CC-5013
– mTor inhibitors: temsirilimus, RAD001, rapamycin
Target
Sunitini
b
Sorafe
nib
AG013
736
GW78
6034
ABT869
PTK- Bevacizu
787mab
Temsirolimus/
Vascular
endothelial
growth
factor
(VEGF)
N
N
N
N
N
N
Y
N
VEGFR1 (Flt-1)
Y
N
Y
Y
Y
Y
N
N
VEGFR2
N
Y
Y
Y
Y
Y
N
N
VEGFR3 (FLT-4)
Y
Y
Y
Y
N
N
Platelet derived
growth factor
receptor 
N
N
N
N
PDGFR-
Y
Y
c-kit
Y
FLT-3
Everolimus
(Flk-1/KDR)
Y
N
Y
Y
Y
N
N
N
Y
Y
Y
Y
N
N
N
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 (bFGF)
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
N
N
N
N
N
N
N
Y
Mammalian
target
rapamycin
(MTOR)
of
Common Treatment related side effects
Toxicity
Fatigue
Hand-Foot
Syndrome
Other Rash
Hypertension
Edema
Dyspnea
LVEF decline
Anorexia
Diarrhea
Stomatitis
Nausea
Bleeding
Thrombosis
Hypothyroidism
High AST/ALT
High
amylase/lipase
High Cholesterol
High
Triglycerides
Low Phosphorus
Neutropenia
Thrombocytopeni
a
GI perforation
Sunitinib
(n= 169)
Likely
Sorafenib
(n=451)
Likely
Less likely
Likely
Less likely
Less likely
Likely
Less likely
Less likely
ND
Less likely
Less likely
Rare
ND
Likely
Likely
Likely
Likely
Less likely
Rare
Less likely
Less likely
Likely
Less likely
Less likely
Less likely
Rare
ND
Less likely
Less likely
Less likely
Less likely
ND
ND
ND
ND
Less likely
Less likely
Less likely
Less likely
Less likely
Less likely
Rare
Rare
Bevacizumab Temsirolimus
(n=39)10mg/kg (n=212)
Less likely
Likely
ND
ND
Likely
Likely
ND
Likely
ND
Less likely
ND
Likely
ND
ND
ND
ND
ND
ND
Less likely
Rare
ND
Likely
Likely
Likely
Likely
Rare
ND
ND
Less likely
Less likely
ND
ND
ND
ND
Likely
Likely
ND
ND
ND
Likely
Likely
Likely
Rare
ND
Bevacizumab for mRCC:
Phase II Study Design
mRCC patients
(N=116)
ECOG PS <2
All patients have
prior therapy
(mostly IL-2)
High dose = 10 mg/kg (n=39)
Low dose = 3 mg/kg (n=37)
Placebo (n=40)
• 1° end points: TTP and ORR
• 2° end point: OS
• Study arms were balanced for demographics
Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide.
Yang JC et al. N Engl J Med. 2003;349:427-434.
Bevacizumab for mRCC:
Summary
• No significant difference in OS between treatment groups
• High dose (10 mg/kg)
– PR = 10% (95 CI, 2.9%–24.2%)
– Significantly prolonged PFS (median 4.8 months, P<.001)
– Moderate toxicity profile
– No Grade 4 AE or deaths related to therapy
• Proteinuria 64% (any grade)
• Hypertension 36% (any grade)
• Low dose (3 mg/kg)
– Not significant
Phase III study (AVOREN) of bevacizumab/interferonα2a vs placebo/interferon- α2a as first-line therapy in
metastatic RCC
641 patients
+ nephrectomy
+ clear cell RCC
IFN (9 MIU 3x weekly) +
bevacizumab(10mg/kg) IVq2w
(320)
IFN (9 MIU 3x weekly) +
placebo (321)
The addition of BEV to IFN-a2a significantly
increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001)
and objective tumor response rate (30.6% vs. 12.4%; p<0.0001).
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
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
CF3
O
CI
O
NH
O
N
H
N
H
N
CH3
1. Wilhelm SM et al. Cancer Res. 2004;10:7099-7109.
2. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA:
Onyx Pharmaceuticals, Inc.; 2005.
3. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer.
Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.
Sorafenib for mRCC: Phase II (RDT)
Progression-Free Survival
Proportion of Patients
Progression-Free
1.00
Sorafenib (n=33)
Placebo (n=32)
Censored
0.75
Median PFS from randomization
Sorafenib=24 weeks
Placebo=6 weeks
0.50
P=.0087
0.25
0
84
12-week
period
0
100
200
300
400
Time From Randomization (days)
Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.
500
Sorafenib for mRCC:
Tumor Reduction* (TARGET)
Placebo (n=452)
Sorafenib (n=451)
150
Change From Baseline (%)*
Change From Baseline (%)*
150
100
50
0
-50
100
50
0
-50
25%
-100
76%
-100
Tumor Reduction
Tumor Reduction
PD (20% increase, RECIST);
PR (30% or reduction, RECIST).
* Investigator assessment. Patients randomized at least 6 weeks before data cut-off
of May 31, 2005.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
Sorafenib for mRCC:
Progression-Free Survival* (TARGET)
1.00
Proportion of Patients
Progression Free
Sorafenib (n=451)
Placebo (n=452)
0.75
Censored observation
PFS
Sorafenib
0.50
Median (months)
5.5
Placebo
2.8
Hazard ratio (S/P)
0.51
0.25
0
0
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<.000001).
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
Sorafenib for mRCC:
Overall Survival* (TARGET)
1.00
Proportion of Patients
Overall Survival
Sorafenib (n=451)
Placebo (n=452)
0.75
Censored observation
0.50
OS
Sorafenib
0.25
Median (months)
Not reached
Placebo
Hazard ratio (S/P)
14.7
0.72
P=.018
0
0
2
4
6
8
10
12
14
16
Time From Randomization (months)
*Interim analysis.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
18
20
Conclusions
• Statistically significant improvement in
progression free survival compared to
placebo in patients with prior cytokine
therapy
• Improvement in OS may have been
affected by crossover and was not
achieved in final analysis
Sunitinib (Sutent®)
• Small-molecule receptor TKI1
• Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT31
• Formulation: 12.5 mg, 25 mg, 50 mg
• Dosing: 50 mg qd ± food
(4 wks on, 2 wks off)2
F
• FDA approved January 26, 2006
for advanced RCC
1. Pietras K, Hanahan D. J Clin Oncol. 2005;23:939-952.
2. Sutent [package insert]. New York, NY: Pfizer Inc.; 2006.
capsules2
O
H3C
N
H
N
H
N
H
O
CH3
CH3
CH3
N
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.
2.
3.
First Line:Should we combine these
agents?
Sequentially or concurrently?
Vertical inhibition or horizontal
inhibition?
Which Type of Agent should be used first?
mTKI or mTor inhibitor?
At Progression
Dose escalation of mTKI vs other
mechanism?
6. Treatment duration-are these agents purely
angiostatic?
7. Assessment of ResponseWhich is more important: RECIST or PFS?
8. Predictors of Response
Blood flow/ vascularity
histology
Imaging- PET/CT, DCE/MRI, CT
9. Role of agents-Adjuvant?, First-line? Before or
after cytokines?
10. Exposure to agent- drug levels of sunitinib
correlated with response
11. Dose escalation of agent –some patients can
tolerate dose escalation at the time of
progression
12. How to treat non clear cell and other variants
Sequential Use of
Nexavar and Sunitinib:
Retrospective Analysis in 90 Patients
MKI Sequencing: Study Design
Retrospective review of sequential therapy with MKIs in RCC
Reviewed
•
Patient demographics
N=90
•
MSKCC
4 sites in France
•
No. of metastatic sites
RCC patients in
expanded access
programs
Efficacy
• OS
• PFS
• Best response
• Safety
Nexavar → Sunitinib
n=68
Sunitinib → Nexavar
n=22
MKI=multikinase inhibitor.
Adapted from Sablin MP et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
MKI Sequencing:
Efficacy of Nexavar→Sunitinib
Sunitinib
Nexavar
PR
n (%)
SD
n (%)
PD
n (%)
NE
n (%)
PR, n
11
2 (18)
7 (64)
2 (18)
–
SD, n
45
6 (13)
24 (53)
11 (25)
4 (9)
PD, n
10
2 (20)
3 (30)
4 (40)
1 (10)
NE, n
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
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.
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
Eligibility
• Metastatic RCC,
component of
clear-cell
• ≤1 prior cytokine
therapy
• Adequate PS
• Adequate
pancreatic and
cardiac function
Nexavar
400 mg po
bid
Days 1-28
Nexavar
Nexavar
600 mg po
bid
Days 29-56
800 mg po
bid
Days 57+
After 4 weeks,
patients with no
DLT (grade 3/4)
increase dose
Treatment
continues
until PD or
intolerance
After 4 weeks,
patients with no
DLT (grade 3/4)
increase dose
Target accrual: 44 patients. Response assessed by RECIST every 8 weeks.
DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
Dose-Escalated Nexavar for RCC:
Baseline Patient Characteristics
N=44
Characteristics
Median age, years (range)
Male/female
Zubrod PS, (0/1)
Clear Cell (CC)
Other histology
CC/Sarcomatoid
CC/Focal Rhabdoid
CC/Papillary
Prior nephrectomy
Prior radiation therapy
MSKCC Risk Factors
0
1
2
3
N
50
37/7
39/5
35
9
7
1
1
42
10
%
Range 43-79
84/16
89/11
80
20
18
17
6
3
41
38
14
7
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
95
23
Dose-Escalated Nexavar for RCC:
Baseline Patient Characteristics
(cont’d)
N=44
Characteristics
N
%
Prior systemic therapy
IL-2
RAD001
Interferon
cG250
19
15
2
1
1
43
Best response to prior systemic CR/PR
3/2
16/11
Total number of metastatic sites
1
2
≥3
26
11
7
59
25
16
CR=complete response; IL-2=interleukin 2; PR=partial response.
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
Dose-Escalated Nexavar for RCC:
Intensity of Therapy
• At 800-mg dose level:
– 5 patients had dose held between Weeks 2 through 4
– 3 patients were dose reduced
• Doses were escalated to 1200 mg in 41 of 44 patients
• Doses were escalated to 1600 mg in 32 of 41 patients
– 25 patients maintained dose
– 7 patients were dose reduced
• Summary
– 41 patients were able to receive 1200 or 1600 mg per day
of Nexavar
– 3 patients were unable to be dose escalated
– Those with early toxicity have difficulty with dose escalation
Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
Dose-Escalated Nexavar for RCC:
Best Response by RECIST
Best Response
No. of Patients
(%)
Complete response
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
Image courtesy of Laura Wood, RN, MSN, OCN.
8 Weeks Post-Therapy
Management of Early-Stage RCC
•
Surgery
– Partial or radical
nephrectomy
– Open surgery
– Laparoscopic
– Cryoablation or
radiofrequency ablation
•
Adjuvant Tx
•
– No benefit from adjuvant
interleukin2 or interferon
– No benefit from radiation
therapy
– Benefit from adjuvant
targeted therapy is unknown
Neoadjuvant- investigational
National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer:
Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006.
Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
Predictors of Relapse
• Prognostic models based on postoperative
score:
–
–
–
–
UCLA Integrated Staging System (UISS)
Leibovich Model
Frank Model (SSIGN)
Kattan Model
• Prognostic Models based on preoperative
score:
– Yaycioglu
– Cindolo
Contributors to Prognosis
•
•
•
•
•
•
•
•
Pathologic stage
Histology
Fuhrman Grade
Nuclear grade
Performance status
Necrosis
Size
Clinical Presentation
The UCLA Integrated staging system (UISS)
UISS
Survival
1997 TNM
Stage (%)
I
Fuhrman
Grade
ECOG
1,2
2 Yr.
Survival
(%)
5Yr
96
94
II
I
I
II
III
III
1,2
3,4
Any
Any
I
1
Any
Any
0
1 or more
89
64
III
III
IV
2-4
1,2
1 or more
0
66
39
IV
IV
3,4
1-3
0
1 or more
42
23
V
IV
4
1 or more
9
0
A.S.S.U.R.E. (ECOG 2805)
NonMetastatic
Kidney
Cancer
That meets
radiologic
criteria to
be clinically
 T1bNany
(resectable)
M0 disease
R
E
G
I
S
T
R
A
T
I
O
N
1
R
E
S G
U I
R S
G T
E R
R A
Y T
I
O
N
2
Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk
Histologic
Subtype
Clear cell
Non-clear cell
Performance
status
Surgery
Open vs
laparoscopic
Arm A Sunitinib
R
A
N
D
O
M
I
Z
E
50 mg daily for 1
year
Arm B Sorafenib
800mg daily for 1
year
Arm C Placebo
Daily for 1 year
Objectives
Primary Question:
• Can adjuvant therapy with an oral raf
kinase inhibitor/ receptor tyrosine kinase
inhibitor (Sorafenib) or pure receptor
tyrosine kinase inhibitor (Sunitinib)
improve disease-free survival in locally
advanced RCC over placebo after surgical
resection?
• Primary endpoint is DFS
Secondary Objectives
•
•
•
Overall survival
Toxicity in the adjuvant setting
Prospective collection of tumor and biologic
specimens /Correlatives:
- Measures of angiogenesis
- Mutational analyses (oncogenes/TSG)
- Hypermethylation
- Polymorphisms
Nexavar in Adjuvant RCC:
MRC SORCE Phase III Trial
High and intermediate
risk, resected RCC
(1.5:1.5:1) Randomization
(N=1656)
Nephrectomy
• 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)
Placebo
for 3 years
(n=414)
MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients with
Resected primary renal CEll carcinoma.
Developments
• ECOG BEST Trial (4 arm) of Doublet
Targeted therapy (tem/bev vs bev vs
sorafenib/bev vs sorafenib/tem
• Temsirolimus versus sunitinib trial for
non clear cell RCC
• mTKI to mTOR vs mTor to mTKI trial
• Adjuvant trials SORCE and ASSURE
are ongoing
Conclusions
• Surgery remains the most effective therapy
for early RCC and plays a role in advanced
RCC
• New molecular targets have been identified
which are critical to the pathogenesis of
different types of RCC and new targeted
therapies are replacing traditional biologic
therapies
• The ultimate role that these agents will play in
RCC has yet to be decided
Common Treatment related side effects
Toxicity
Fatigue
Hand-Foot
Syndrome
Other Rash
Hypertension
Edema
Dyspnea
LVEF decline
Anorexia
Diarrhea
Stomatitis
Nausea
Bleeding
Thrombosis
Hypothyroidism
High AST/ALT
High
amylase/lipase
High Cholesterol
High
Triglycerides
Low Phosphorus
Neutropenia
Thrombocytopeni
a
GI perforation
Sunitinib
(n= 169)
Likely
Sorafenib
(n=451)
Likely
Less likely
Likely
Less likely
Less likely
Likely
Less likely
Less likely
ND
Less likely
Less likely
Rare
ND
Likely
Likely
Likely
Likely
Less likely
Rare
Less likely
Less likely
Likely
Less likely
Less likely
Less likely
Rare
ND
Less likely
Less likely
Less likely
Less likely
ND
ND
ND
ND
Less likely
Less likely
Less likely
Less likely
Less likely
Less likely
Rare
Rare
Bevacizumab Temsirolimus
(n=39)10mg/kg (n=212)
Less likely
Likely
ND
ND
Likely
Likely
ND
Likely
ND
Less likely
ND
Likely
ND
ND
ND
ND
ND
ND
Less likely
Rare
ND
Likely
Likely
Likely
Likely
Rare
ND
ND
Less likely
Less likely
ND
ND
ND
ND
Likely
Likely
ND
ND
ND
Likely
Likely
Likely
Rare
ND
Targeted Therapy: More Questions Than
Answers
1.
2.
3.
First Line:Should we combine these
agents?
Sequentially or concurrently?
Vertical inhibition or horizontal
inhibition?
Which Type of Agent should be used first?
mTKI or mTor inhibitor?
At Progression
Dose escalation of mTKI vs other
mechanism?
6. Treatment duration-are these agents purely
angiostatic?
7. Assessment of ResponseWhich is more important: RECIST or PFS?
8. Predictors of Response
Blood flow/ vascularity
histology
Imaging- PET/CT, DCE/MRI, CT
9. Role of agents-Adjuvant?, First-line? Before or
after cytokines?
10. Exposure to agent- drug levels of sunitinib
correlated with response
11. Dose escalation of agent –some patients can
tolerate dose escalation at the time of
progression
12. How to treat non clear cell and other variants
A.S.S.U.R.E. (ECOG 2805)
NonMetastatic
Kidney
Cancer
That meets
radiologic
criteria to
be clinically
 T1bNany
(resectable)
M0 disease
R
E
G
I
S
T
R
A
T
I
O
N
1
R
E
S G
U I
R S
G T
E R
R A
Y T
I
O
N
2
Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk
Histologic
Subtype
Clear cell
Non-clear cell
Performance
status
Surgery
Open vs
laparoscopic
Arm A Sunitinib
R
A
N
D
O
M
I
Z
E
50 mg daily for 1
year
Arm B Sorafenib
800mg daily for 1
year
Arm C Placebo
Daily for 1 year