targeted approach to renal cell carcinoma therapy robert j. … · 2006. 6. 7. · targeted...
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Targeted Approach to Renal Cell Carcinoma Therapy
Robert J. Motzer MD,
Memorial Sloan-Kettering Cancer Center
Targeted Approach to RCC Therapy
Background • 38,000 cases/year in U.S.• High proportion develop
metastases• Lack of effective systemic
therapy• Low proportion of long term
survivors for advanced RCC• Drug discovery is of the
highest priority
JCO:18,1928,2000
Metastatic Renal Cell Carcinoma
Survival by Systemic Treatment at MSKCC
Renal Cell Carcinoma Approved Drugs
rIL-2 High-dose Bolus in U.S.Number
Patients 255
Partial response 11%
Complete response 4%
Median response duration 23 mo
(1-50) JCO 14: 2410
NCI: High Dose vs Low Dose vs Subcutaneous IL-2No Improvement in Median Survival for High-dose
Interleukin-2 vs Interferon-alpha vs Combination
*p=0.55, NEJM 338:1272
Category IL2 IFN-α IL2 + IFN-αPatients 138 147 140
Response 8% 8% 21%
Med Survival 12 mo 13 mo 17 mo*
Toxic Deaths 9% 1% 6%
Months from randomization
% S
urv
ival
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 6 12 18 24 30 36 42 48
MPA
IFN
IL2
IFN + IL2
Median 14.9 months [11.7 - 19.2]
Median 15.2 months [12.8 - 19.9]
Median 15.3 months [13.3 - 20.0]
Median 16.8 months [14.0 - 18.9]
Phase III Immunotherapy Trial for RCC by Negrier et al
Randomized Trial Showing Role of Cytoreductive Nephrectomy Before Interferon-α
Median Survival (mos)No Nephrectomy Nephrectomy
(n=123) (n=123)
All Patients 8.1 12.5
Performance Status1 12.8 17.4
>1 4.8 6.9
MetastasesLung only 10.3 14.3Other 6.3 10.2
NEJM 345:1655
Survival by MSKCC Risk Group (JCO 17:2530)
Unmet Need: Assessing New Therapies for RCCProgression-Free Survival for 2nd-line Therapy
Response to Cytokines by Histology
Cell Type Responsive
Clear Cell (>85% of cases) Yes
Sarcomatoid variant Yes (Less)
Papillary No
Collecting duct No
Medullary No
Chromophobe No
Origin, Classification, GeneticsRenal Cell Carcinoma
VHL Gene In Renal Cell CarcinomaMutations in Sporadic Clear Cell
Nat Genet 7:85-90,1994
Role Of Vhl In Ubiquitination Of Hif-1αααα
VHL GeneMutation VHL Complex
Disrupted
VHL Protein
HIF1-α,α,α,α, HIF2-ααααAccumulation
VEGF TGF-α,
Angiogenesis Endothelial stabilization Autocrine GrowthStimulation
PDGF
Targeted Approach to RCC TherapyDrugs and Targets
ββββ pVHL HIF=αααα
VEGF TGFααααPDGF
VEGF-receptor EGFRPDGF-receptor
Sunitinib, Sorafenib Sunitinib, Sorafenib
Bevacizumab
Temsirolimus(CCI-779)
Target Approach to RCC TherapyBevacizumab in RCC : Phase II Trial
Yang JC et al. NEJM 349(5), 2003
RANDOMIZE
BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n=37)
PR 0/37, TTP 3.0 m¹, OS 15.1 m
PLACEBO Q 2 WEEKS (n=40)
PR 0/40, TTP 2.5 m, OS 13.0 m
BEVACIZUMAB (10 MG/KG) Q 2 WEEKS (n=39)
PR 4/39, TTP 4.8 m², OS 15.5 m
PDTreatment-refractory, metastatic RCC - clear cell Ca
¹vs placebo p=0.041²vs placebo p=0.001
Randomized Phase 2 Trial of Randomized Phase 2 Trial of BevacizumabBevacizumab vs. vs. Placebo :Major Responses Placebo :Major Responses (NEJM 349:427)(NEJM 349:427)
NN CRCR PRPR RRRR
PlaceboPlacebo 40 0 0 0%40 0 0 0%
HighHigh--Dose Ab 39 0 4* 10%Dose Ab 39 0 4* 10%
LowLow--Dose Ab 37 0 0 0%Dose Ab 37 0 0 0%
*Durations 39+, 15, 9, 6 months*Durations 39+, 15, 9, 6 months
High-Dose Bevacizumab vs. PlaceboProgression-free Survival (NEJM 349:427)(NEJM 349:427)
Phase II Trial of Bevacizumab + Erlotinib in Metastatic RCC: Response Rates
36 (61)SD/minor response†
13 (22)PR
8 (14)PD
2 (3)CR
No. of Patients (%)Response (N=59*)
*59/63 evaluable patients were included in the response analysis.†13 patients (22%) had minor responses.
Spigel et al. ASCO, 2005. Abstract 4540 and poster presentation.
Subjects withuntreated
metastatic renal cell carcinoma;
first-line(n = 100)
Arm 1: Bevacizumab + Elotinib x 12 months
Arm 2: Bevacizumab + placebo x 12 months
Phase II Randomized Trial : Bevacizumab +Erlotinib in RCC
� Primary endpoints: PFS and RR� Bevacizumab dose = 10 mg / kg IV q 2 wks� Erlotinib dose = 150 mg p.o. q d� Study closed 11/04 - 104 patients randomized� Genentech press release (10/18/05) - “preliminary results from the randomized
phase II trial … in renal cell carcinoma.” PFS similar in both arms.No additional trials of the combination in RCC are planned.
Bevacizumab + IFNαααα : Phase 3 Trials in Renal Cell Carcinoma
Patient Population : Metastatic Clear Cell Ca
CALGB 90206
N = 700 patients
BO17705 (Roche)
N = 638
IFNαααα 9.0 MU TIW
IFNαααα 9.0 MU TIW
+
Bevacizumab10 mg/kg d1,15
IFNαααα 9.0 MU TIW
+Placebo
d 1, 15, etc
Randomize Randomize
Studies powered to detect ↑ median survival : 13.0 → 17.0 mos
– Designed as a C-RAF-targeted agent� Also inhibits wild-type and mutant B-RAF
– Recently demonstrated to inhibit other targets
� VEGFR-2, PDGFR-b, FLT-3 and c-KIT
N
CF3
Cl
NH
NH
OO
NH
O
CH 3
BAY 43-9006 (Sorafenib)
BAY 43-9006 (sorafenib) Study 100391 Trial Schema for Patients with Advanced
Refractory Solid Tumors
* May cross over to BAY 43-9006
12 Week Induction
>-25% to <25%Randomized
≥≥≥≥ 25% Shrinkage Continue BAY 43-9006
Open Label
≥≥≥≥ 25% GrowthOff study
BAY 43-9006
Placebo*
Tumor Assessment
Baseline 12 weeks 24 weeks
Ratain MJ et al. ASCO 2004: Presentation 4501.
BAY 43-9006 (sorafenib) Study 100391 RCC Bidimensional Tumor Measurements* at Week 12:
Change from Baseline in Target Lesions (n=89)
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
% C
han
ge
in T
um
or
Mea
sure
men
t
Number of Patients
> 25% Growth
< 25% to >-25% Change
>-25% to -49% Shrinkage
> -50% Shrinkage
7
45** 24 13
* Investigator assessed
* * 7 of 45 patients not randomized
Ratain MJ et al. ASCO 2004: Presentation 4501.
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n o
f p
atie
nts
pro
gre
ssio
n f
ree
0 100 200 300 400 500
Days from randomization
Sorafenib (n=32)Placebo (n=33)Censored
Median progression-free survival from randomization:Placebo = 6 weeksSorafenib = 24 weeksp = 0.0087
12-weekrun-in period
-84
Rationale for Study: Clinical
Ratain MJ et al. ASCO 2005, Orlando, FL Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005
Sorafenib: TARGETsStudy Design
Sorafenib400 mg bid
Placebo
Major endpoints• Survival (alpha=0.04) • PFS (alpha=0.01)
(1:1) Randomization
n~905
Stratification
• Motzer criteria
• Country
Eligibility criteria• Histologically/cytologically
confirmed, unresectable and/or metastatic disease
• Clear-cell histology
• Measurable disease
• Failed one prior systemic therapy in last 8 months
• ECOG PS 0 or 1
• Good organ function• No brain metastasis
• Poor risk Motzer group excluded
Complete Response 1 (<1%) 0 (0%)
Partial Response 43 (10%) 8 (2%)
Stable Disease 333 (74%) 239 (53%)
Progressive Disease 56 (12%) 167 (37%)
Missing 18 (4%) 38 (8%)
TARGETsObjective Responses by Investigator Assessment
*Patients randomized at least 6 weeks before data cut-off of May 31, 2005
Sorafenib (n=451)* Placebo (n=452)*
Best Response (RECIST)
TARGETsMaximum Percent Reduction in Tumor Measurement*
*Independently assessed measurements available for 574 patients (January 28, 2005 data cut-off)
0
50
100
150
-50
-100
-150
Per
cen
tag
e ch
ang
e fr
om
bas
elin
e
Placebo
25%
*Investigator assessed measurements
Sorafenib
76%
Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005
Pro
po
rtio
n o
f p
atie
nts
pro
gre
ssio
n f
ree
0
0.25
0.50
0.75
1.00
Time from randomization (months)0 4 10 202 6 8 12 14 16 18
Censored observation
Placebo
Sorafenib
Median PFS
Sorafenib = 5.5 months
Placebo = 2.8 months
Hazard ratio (S/P) = 0.51
TARGETsProgression-Free Survival Benefit*
*Based on investigator assessment
TARGETsPlanned Interim Analysis of Overall Survival*
*Results are from a planned interim analysis as per protocol (220 events) and are considered preliminary**Threshold for significance of interim analysis was p<0.0005
Time from randomization (months)0 4 10 202 6 8 12 14 16 18
0
0.25
0.50
0.75
1.00
Ove
rall
surv
ival
Censored observation
Placebo
Sorafenib
Median OSPlacebo = 14.7 months
Sorafenib = Not reached
Hazard ratio (S/P) = 0.72
p-value = 0.018**
TARGETsIncidence of Grade 3/4 Treatment-Emergent Adverse
Events* in ≥2% patientsSorafenib (n=451) Placebo (n=451)
Any grade Grades 3/4 Grades 3/4Any grade
Diarrhea 195 (43%) 11 (2%) 58 (13%) 3 (1%)
Hypertension 76 (17%) 16 (4%) 8 (2%) 2 (<1%)
Fatigue 165 (37%) 22 (5%) 125 (28%) 16 (4%)
Hand–foot skin reaction 134 (30%) 25 (6%) 30 (7%) –
Decreased hemoglobin 34 (8%) 12 (3%) 33 (7%) 20 (4%)
Tumor pain 29 (6%) 13 (3%) 24 (5%) 8 (2%)Bone pain 34 (8%) 3 (1%) 35 (8%) 15 (3%)
Dyspnea 65 (14%) 16 (4%) 52 (12%) 11 (2%)
*NCI-CTC Version 3.0 Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005
TARGETsHand–Foot Skin Reaction
Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005
Sorafenib : Phase 2 Trial in Untreated RCC Patients
Study schema :
Sorafenib
400 mg bid
INFαααα2a9 MIU TIW
Randomize*
DiseaseProgression
Sorafenib600 mg bid
Sorafenib400 mg bid
Primary
Endpoint :
PFS
Secondary
Endpoints:
DCR, RR, PK,
Resp. Duration,
PRO’s* Stratification - MSK criteria
Integration of Novel Agents in Therapy of Metastatic RCC
Sorafenib
Monotherapy :
Untreated Pts.
StandardCytokineRegimen (s) :IL-2, IFNα
Targeted Agents :1) TKI’s2) VEGF inhibitors3) EGFR inhibitors4) mTOR inhibitors5) Others
Chemotherapy:1) 5-FU2) Capecitabine3) Gemzar4) Others
Unique Settings:1) CNS mets2) Renal/hepatic
dysfunction3) Others
Adjuvant Therapy Neoadjuvant Setting
SU11248- Multi-targeted T-K Inhibitor from Pfizer,
Inc.
• Oxindole TK inhibitor• Orally bioavailable small
molecule• Selective multi-target
inhibition of:– PDGFR– VEGFR– KIT– FLT3
• Antitumor and antiangiogenicactivity
• Long plasma half-life ≈ 40 hours
• Active metabolite
NH
O
NH
F
H3C
CH3
NH
O
N
CH3
CH3
Phase II Evaluation of Sunitinib in mRCC
Sunitinib
Two independent, single-arm, multicenter, phase II trials (trial 014: N=63; trial 1006: N=106)
Patients with advanced disease and failure of prior cytokine therapy
Continuesunitinibtreatment unless progression or intolerability
4 weeks on, 2 week off (4/2)
50 mg/day*
SunitinibDosing schedule Sunitinib
*Dose reduction permitted (to 37.5 mg/day and then to 25 mg/day)
Objective Response to Sunitinib in Patients with mRCC
35 (33)
24 (23)
46 (44)1 (1)
45 (43)
Study 1006*(N=105)
56 (33)21 (33)PD, SD <3 months or not evaluable
41 (24)17 (27)SD ≥3 months
71 (42)1 (1)
70 (42)
25 (40)0
25 (40)
Overall responseCRPR
Pooled analysis(N=168)
Study 014(N=63)Response, n (%)
*Study ongoing
-100
-80
-60
-40
-20
0
20
40
Trial 1: Maximum % Reduction of Target Lesions According to RECIST Criteria by Patient
Subcarinal LN Resolved Subcarinal LN Lung Nodule
Renal Mass
Trial 2: Tumor Assessment Over Time Target Lesions for Patients with PR or
CR
-100
-80
-60
-40
-20
0
20
40
60
80
100
1 2 3 4 5 6 7 8
Cycle
Per
cent
Cha
nge
from
Bas
elin
e (%
)
Progression-free Survival Trials 1 and 2 Combined
Pro
po
rtio
n o
f p
atie
nts
p
rog
ress
ion
fre
e
Sunitinib therapy (months)
0 5 10 15 20 25 30
1.00.90.80.70.60.50.40.30.20.1
0
Median PFSTrial 1: 8.7 monthsTrial 2: 8.1 months
Combined: 8.2 months(95% CI: 7.8, 10.4)
Treatment-Related Adverse Events
16562103Hypertension
Trial 2Trial 2Trial 2Grade 3 Total
Incidence (%)
4
7
5
0
3
11
2
2
2
3
3
11Trial 1
3
8
9
13
17
17
9
6
17
16
21
27Trial 1
Grade 2
7
15
14
13
20
28
11
8
19
19
24
38Trial 1
LVEF decline
Dermatitis
Stomatitis
Nausea
Diarrhea
FatigueEvent
SU11248 Hand-foot Syndrome
SU11248: Change in Color of Hair on Treatment
Phase 3 Trial of SU11248 versus Interferon-α in First-Line Treatment for Metastatic RCC
• Randomized, Open-Label, Multicenter Trial (100 Sites: US, Canada, Europe, Australia, and Brazil)
• Endpoints: progression-free survival, overall survival, and response rate
1:1Randomization
N=690
SU11248: orally administered daily (Schedule 4/2)
IFN-αααα: administered TIW
Additional Trials with SU11248 for RCC
• SU11248 in bevacizumab-refractory RCC
• “ with gefitinib in RCC
• “ in continuous dosing schedule for RCC
• “ plus interferon in RCC (planned)
• “ plus bevacizumab in RCC (planned)
• “ as adjuvant therapy (under discussion)
• “ with gemcitabine (phase I)
• “ with capecitabine (phase I)
Renal EFFECT Study• Randomized, Open-Label, Multicenter Trial
(60 Sites: US)
• Primary endpoint: time to progression
• Secondary endpoints: response rate, overall survival, QOL by FACT-renal (MSKCC)
• Stratified by MSKCC prognostic criteria
1:1:1Randomization
N=474Sunitinib 4/2 Schedule
Sutent 4/2 Schedule + Interferon-αααα
Sunitinib continuous dose schedule
Growth factors promote angiogenesis by mTOR dependent upregulation of HIF-1αααα
RTK
PIP3
PI3KpY
Membrane
AKT
mTOR CCI-779
Tumor Angiogenesis
Amino acid
Translation & Stability of HIF-1αααα transcript
VEGF gene expression
Targeted Approach to RCC TherapyCCI-779 in Heavily Pretreated RCCn Heavily Pretreated RCC
Number
Patients 111
Partial Response 7%
PR, MR, Stable>24wks 51%
Median Time to Progression 5.8 mo
Median Survival 15 mo
J Clin Oncol 22:909-918; 2004
Targeted Approach to RCC Therapy Phase III Trial Design for CCI-779 304-WW:
CCI-779 25 mg IV q Wk
CCI-779 15 mg IV q Wk+ IFNαααα 6 MU s.c. TIWk
IFNαααα escalating as tolerated to 18 MU s.c. TIWk
RANDOMIZE
Advanced RCC First-line Rx High-risk PtsN = 600Sites ~165
Event-driven analyses with one interim analysisNumber of subjects: 600 (200 per arm)
Primary endpoint: Survival
Vertical Combinations-Targeting of VEGF at multiple levels
HIF
VEGF
KDR
CCI-779, 17-AAG, RAD001
Bevacizumab
BAY 43-9006,SU11248
Targeted Therapy for Renal Cell Carcinoma
Conclusions• Sorafinib, Sunitinib, Bevacizumab and CCI-779 show
activity in second-line therapy.
• Randomized phase 3 pivotal trials are comparing targeted therapy to interferon in first-line therapy.
• Future trials are dependent on the outcome of these pivotal trials, and will include new combinations and comparisons of targeted agents.
• Studies of tumor biology to identify markers of response are a priority.
Trials To Watch
In developmentECOGE2804 - 6 arm combination trial
PlannedPfizerPhase III SU11248 +/- IFN
AccruingMSKCCSU11248 plus Iressa
Just openedVand/PennDF/HCC
Bevacizumab + BAY 43-9006
In DevelopmentNCISU11248 vs BAY 43-9006 vs Placebo as Adjuvant
AccruingBayerPhase II BAY 43-9006 vs IFN
completedWyethPhase III CCI-779 + IFN vs IFN vs CCI
Completed/accruing
US/EuropePhase III bevacizumab + IFN vs IFN
CompletedPfizerPhase III SU 11248 vs IFN
StatusGroupRegimen
Q&A