Download Metastatic Renal Cell

Updates on Renal Cell Cancer
Sandy Srinivas.M.D
Stanford University
&
David Minor.M.D
CPMC
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
Histological Classification
of Human Renal Epithelial Neoplasms
RCC
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.
American Joint Committee on Cancer (AJCC)
2002 Clinical Staging System
5-Year Survival
(%)
Stage
Description
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
Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477-2490.
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
MS:
20 mo
10 mo
4 mo
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.
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
1. Krown SE. Cancer. 1987;59:647-651.
2. Muss HB. Semin Oncol. 1988;15:30-34.
3. Rosenberg SA et al. JAMA. 1994;271:907-913.
Role of VHL in RCC Progression
Paracrine
Function
Pericyte
RAS
RAF
MEK
Autocrine
Function
ERK
Tumor cell
VHL
HIF-1
HIF-1
RAS
HIF-1
RAF
Paracrine
Function
MEK
RAS
HIF-1
ERK
RAF
MEK
EGF
EGF
PDGF PDGF
EGF
VEGFVEGF
VEGF
PDGF
ERK
Endothelial cell
Rational Targets in RCC (cont’d)
Sunitinib
Sorafenib
RAS
Sorafenib
Pericyte
Sunitinib
Sorafenib
RAF
MEK
ERK
Tumor cell
VHL
HIF-1
HIF-1
RAS
RAF
Sorafenib
HIF-1
Sunitinib
Sorafenib
MEK
RAS
Sorafenib
HIF-1
ERK
Sunitinib
RAF
MEK
EGF
EGF
PDGF PDGF
EGF
VEGFVEGF
ERK
Bevacizumab
Endothelial cell
VEGF
PDGF
Bevacizumab
Bevacizumab
Sorafenib
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:
Progression-Free Survival
Median PFS (months)
Patients Free
of Tumor Progression (%)
100
90
80
High dose, 10 mg/kg(n=39)
4.8 (P<.001)
Low dose, 3 mg/kg (n=37)
3.0 (P<.041)
70
Placebo (n=40)
60
2.5
50
40
Partial Response-10%
30
20
10
0
0
6
12
18
Time (months)
Adapted from Yang JC et al. N Engl J Med. 2003;349:427-434.
24
30
36
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)
1° end points: PFS and
ORR
Bevacizumab 10 mg/kg IV q 2 wks
+ placebo 150 mg PO qd
Results
Bevacizumab +Erlotinib
Bevacizumab + Placebo
# Patients
51
53
ORR (CR+PR)
7(14%)
7(13%)
Stable Disease
34(68%)
36(68%)
PFS (months)
9.9
8.5 P=0.58
Bukowski , Srinivas ASCO 2006
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) Study Design
≥25% tumor shrinkage  continue sorafenib
Solid tumors
(N=502)
mRCC
patients
(n=202)
Stable patients
(-25% to +25%)
randomized
Sorafenib
Placebo*
>25% tumor growth  off-study
1° end points
– PFS from day 1
– PFS 12 weeks post-randomization,
tumor response rate, safety
RDT=randomized discontinuation trial.
*May cross over to sorafenib.
Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.
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: Phase II (RDT)
Drug-Related Adverse Events
Any grade
%
Grade 3/4
%
Any event
98
48
Cardiovascular
38
25
Hypertension
35
24
90
15
Rash/desquamation
62
2
Hand-foot skin reaction
60
13
Alopecia
50
–
Other
38
–
Dry skin
21
–
Flushing
13
–
68
6
Fatigue
55
4
Weight loss
24
–
Dermatology
Constitutional symptoms
Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.
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
*Out of 905 patients randomized by February 15, 2005.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
Sorafenib for mRCC:
Response Rate* (TARGET)
Best Response by RECIST
Complete response
Partial response
Stable disease
Sorafenib
(n=451)
n (%)
1 (<1)
43 (10)
Placebo
(n=452)
n (%)
—
8 (2)
333 (74)
239 (53)
Progressive disease
56 (12)
167 (37)
Missing
18 (4)
38 (8)
* 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:
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
Median
(months)
5.5
PFS
Sorafenib
0.50
Placebo
Hazard ratio
0.25
2.8
0.51
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
Median
(months)
Not reached
OS
Sorafenib
0.25
Placebo
Hazard ratio
(S/P)
0
0
2
4
14.7
0.72
6
8
10
12
14
16
P=.018
Time From Randomization (months)
*Interim analysis.
Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
18
20
Sorafenib for mRCC:
Adverse Events Profile (TARGET)
19
Pruritus
6
Pruritus
<1
Nausea
<1
<1
Rash/Desquamation
<1
<1
Sorafenib (n=451)
Placebo (n=452)
23
19
Grade 3
Any Grade
Nausea
40
Rash/Desquamation
16
43
Diarrhea
13
37
Fatigue
7
10
20
30
3
Hand-foot skin
reaction
30
0
5
Fatigue
28
Hand-foot skin
reaction
2
Diarrhea
40
Patients (%)
50
6
0
0
10
20
30
40
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.
50
Sorafenib for mRCC:
Laboratory Toxicities (TARGET)
12
Thrombocytopenia
30
23
44
Anemia
49
18
10
41
Elevated lipase
23
45
11
0
10
20
3
2
Anemia
4
5
Neutropenia
2
12
7
13
Lymphopenia
13
Hypophosphatemia
Placebo (n=452)
Elevated lipase
30
Lymphopenia
Sorafenib (n=451)
1
Elevate amylase
Grade 3
Any Grade
Elevated amylase
Neutropenia
1
0
Thrombocytopenia
5
30
Patients (%)
40
50
7
13
Hypophosphatemia
3
0
10
20
30
Patients (%)
Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA:
Onyx Pharmaceuticals, Inc.; 2005.
40
50
TARGETs
Hand–Foot Skin Reaction
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
Response in Treatment naïve
patients(32)
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
PR
6(18.8%)
MR
8(25%)
SD
10(31.3%)
PD
3(9%)
Uneval
5(15%)
Phase II Randomized Trial- First Line
MET RCC
CLEAR CELL
NO PRIOR RX
ECOG 0/1
NO BRAIN METS
ALL MSKCC
RISK GROUPS
N=189
R
E
G
I
S
T
R
A
T
I
O
N
SORAFENIB
400MG BID
IFN-α
9 M TIW
P
R
O
G
R
E
S
S
I
O
N
SORAFENIB
600MG BID
SORAFENIB
400MG BID
Accrual completed; too few events for results
Escudier, ASCO 2006
Randomized phase III trial of Sorafenib:
Impact of Crossover o survival
OS @ Cross
over
OS@6 months
Cross over
OS@ 6 mos
Crossover with
placebo censored
Placebo
14.7
15.9
14.3
Sorafenib
NR
19.3
19.3
Hazard Ratio
0.72
0.77
0.74
P-value
0.018
0.015
0.01
O-BrienFlemming SR
0.0005
0.0094
0.0094
Eisen, ASCO 2006
Summary-PFS (months)
First Line
Second Line
Bevazizumab
8.5
4.8
Sorafenib
9
5.5
ECOG 2805: Adjuvant Trial
Stratify
TNM
Intermediate high risk
Very high risk
Histologic Subtype
Clear cell
Non-clear cell
(except collecting duct
or medullary)
ECOG Performance Status
0
1
Surgery
Laparoscopic
Open
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†
Randomization
(N=1332)
Nephrectomy
Preregister
1° end point: Disease-free survival (DFS)
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†
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†
Nexavar in Adjuvant RCC:
MRC SORCE Phase III Trial
High and intermediate
risk, resected RCC
(1.5:1.5:1) Randomization
(N=1656)
Nephrectomy
Preregister
1º end point: Disease-free survival
2º end points: RCC-specific survival time, toxicity, QOL, and biomarkers
Nexavar
for 3 years
(n=621)
Nexavar for 1 year
Placebo for 2 years
(n=621)
Placebo
for 3 years
(n=414)