metastatic renal cell carcinoma what’s hot in the treatment of renal cell carcinoma and is there...
Post on 12-Jan-2016
217 Views
Preview:
TRANSCRIPT
Metastatic Renal Cell Carcinoma What’s Hot In The Treatment Of Renal Cell Carcinoma And Is There Hope?
Cora N. Sternberg, MD, FACP
Chairman, Department of Medical OncologySan Camillo and Forlanini Hospitals
Rome, Italy
Metastatic Kidney Cancer: Options
• Interferon- for good risk patients until recently
• HD-IL-2 for intermediate and good risk patients.
–Limited availability
–Intensive treatment
–Of value (long lasting CR) for a small group of patients
–Patient selection required
• Poor risk patients: no proven therapeutic options until recently
• Second line: no proven therapeutic options until recently
Treatment of Metastatic Kidney Cancer
• Has our perception of RCC been changed with the advent of new drugs?
• Can we commute a death sentence to a chronic disease that patients can learn to live with?
• How have traditional criteria to measure response with cytotoxics led us astray?
• Can we afford these expensive promising new treatments?
Mancuso and Sternberg, BJU Int. Jun 2005Mancuso and Sternberg, Can J Urol. Feb 2005
Von Hippel-Lindau Suppressor Gene Inactivated in > 75% Sporadic RCC
pVHL HIF=
VEGFangiogenesis
TGFaPDGF
periocytes
KDR EGFRPDGFR
degradation of hypoxia inducibleSuppressor gene
Sunitinib, SorafenibAG13736,Vatalanib
Sunitinib, SorafenibImatinib
Sunitinib, SorafenibCCI-779
Bevacizumab,VEGF TRAP
Regulated by hypoxia; NoHIF1-breakdown
autocrine growth factors
mTOR inhib, HSP 90 inhib
Critical Cofactor in the Ubiquitin Ligase Complex
VEGF-B
VEGF-A
VEGF-E
VEGF-C
VEGF-D
Bevacizumab binds VEGF A
• The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis
• There are five members of the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E)
The VEGF Family Are Critical Tumor-Secreted Angiogenic Factors
Time to ProgressionHigh-Dose Ab vs. Placebo
Yang, NEJM 2003
4.8 mos
2.5 mos
(RR= 10%)
Survival Update
Yang, NEJM 2003
CALGB 90206: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=700)
IFNα 9MU TIW
IFNα 9MU TIW + Bevacizumab 10 mg/KG
D1 and D15
VS
RANDOMI ZE
1° Endpoint: Survival, 89% Power to Detect Improvement in OS of 13 to 17 mos
No prior Rx
Stratify Motzer Score
Europe: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=638)
IFNα 9MU TIW + placebo
IFNα 9MU TIW + Bevacizumab 10 mg/KG D1 and D15
VS
RANDOMI
ZE
1° Endpoint: Survival, 80% Power to Detect Improvement in OS of 13 to 17 mos
NephrectomyClear Cell
> 50%
Sunitinib Mechanism of Action in RCC
Inhibition of RCC pathogenesis and progression
↑ VEGF ↑ PDGF
Vascularpermeability
Cell survival, proliferation, migration
Vascularformation, maturation
Loss of VHL Protein Function
VEGFR PDGFRVEGF PDGFPDGF
Vascular Endothelial CellPericyte/Fibroblast/
Vascular Smooth Muscle
Sunitinib
Best Response By RECIST
ResponseTrial 1n (%)
Trial 2n (%)
Patients 63 106
Overall response Complete response Partial response
25 (40) 0
25 (40)
44 (42) 1 (1)
43 (41)
Stable disease (SD) 3 months 18 (28) 22 (21)
Progression, SD <3 months 16 (25) 33 (31)
Not evaluable 4 (6) 7 (7)
Motzer R ,J Clin Oncol. 2006 Jan 1;24(1):16-24 Motzer R, JAMA. 2006 Jun 7;295(21):2516-24
Two Types of Response Observed
Week32
1-Shrinkage 2-Central Necrosis
Week0
Week12
Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for
Patients with Metastatic Renal Cell Carcinoma
N=750
Stratification Factors
● LDH 1.5 vs >1.5xULN
● ECOG PS 0 vs 1
● Presence vs Absence of Nephrectomy
RANDOMIZATION
Sunitinib(N=375)
IFN-(N=375)
90% power to detect a 35% improvement in median PFS from 20 weeks to 27 weeks (4.6 months to 6.2 months; 2-sided unstratified log-rank test; significance level 0.05)
Pre-planned analysis of primary endpoint PFS
Motzer R, ASCO 2006
Outcome Summary
Sunitinib IFN-
Median Progression-freeSurvival*, mos (95% CI) Independent Review Investigator
11 (10-12)11 (8-14)
5 (4-6)4 (4-5)
Objective response*, % (95% CI) Independent Review Investigator
31 (26-36)37 (32-42)
6 (4-9)9 (6-12)
Safety Acceptable —
Patient-reported Outcomes Superior —
*Sunitinib vs IFN-: P <0.000001
No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-: 152 42 18 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Time (Months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
gre
ssio
n F
ree
Su
rviv
al P
rob
ab
ilit
y
SunitinibMedian: 11 months(95% CI: 10–12)
IFN- Median: 5 months(95% CI: 4–6)
Hazard Ratio = 0.415(95% CI: 0.320–0.539)P <0.000001
(Independent Central Review)
Progression-Free Survival
No. at Risk Sunitinib: 341 190 84 15 1No. at Risk IFN-: 296 162 66 10 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time (Months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Su
rviv
al P
rob
abil
ity
Sunitinib (n=375)Median not reached
IFN- (N=375)Median not reached
Hazard Ratio = 0.65(95% CI: 0.449–0.942)P = 0.0219*
*The observed p-value did not meet the pre-specified level of significance for this interim analysis
Overall Survival
Laboratory Abnormalities
Sunitinib (%) IFN- (%)
Event All grade Grade 3/4 All grade Grade 3/4
Neutropenia 72 11/1* 46 7
Anemia 71 3/<1 64 4/<1
Thrombocytopenia 65 8* 21 0
Lymphopenia 59 12 63 22*
Hypophosphatemia 36 4/<1 32 6
Hyperamylasemia 31 4/1* 28 2/<1
* Greater frequency, P <0.05
Treatment-Related Adverse Events
Event
Sunitinib (%) IFN- (%)
All grade Grade 3/4 All grade Grade 3/4
Fatigue 51 7 51 11/<1*
Diarrhea 53 5* 13 0
Nausea 44 3 33 1
Stomatitis 25 1 2 <1
Hypertension 24 8* 1 <1
Hand-foot syndrome 20 5* 1 0
Ejection fraction decline 10 2 3 1
Pyrexia 7 1 34 0
Chills 6 1 29 0
Myalgia 5 <1 16 <1
Flu-like symptoms 1 0 8 <1* Greater frequency, P <0.05
Motzer R, ASCO 2006
Conclusions
•Sunitinib is a new reference standard for the first-line treatment of RCC
•Mechanism-directed RCC therapy based on tumor-specific molecular features is validated
•Sunitinib is a new treatment option providing hope for patients with RCC
Global ARCC Trial
A Phase 3, Randomized, 3-Arm Study of Temsirolimus (TEMSR) or Interferon-Alpha (IFN) or the Combination of TEMSR + IFN in the Treatment
of First-Line, Poor-Risk Patients With Advanced Renal Cell Carcinoma
G Hudes, M Carducci, P Tomczak, J Dutcher, R Figlin, A Kapoor, E Staroslawska, T O’Toole,
S Kong, and L Moore
2006 ASCO Presentation
Temsirolimus: Mechanism of Action
PI-3 KinasePI-3 Kinase
AAktkt
mTOR
PTENPTEN
S6KS6K 4EBP14EBP1
HIF-1, HIF-2overexpression
PTENLoss
TranslationTranslation
PI-3K/AKTActivation
cMycoverexpression
extracellularmembrane
Cyclin D1Cyclin D1overexpressionoverexpression
TemsirolimusTemsirolimus
GrowthGrowth FFactorsactors
• 626 patients with advanced metastatic RCC with poor-risk features
• 209 sites (26 countries)
Stratificationby:
Geographic Regions:• WEU + AU + CA (22%)• US (30%)• EEU + Other (48%)
Nephrectomy:• Yes (67%)• No (33%)
Global ARCC Trial
RANDOMIZE
IFN: escalating to 18 MU SC TIW
TEMSR: 25 mg IV QW
TEMSR: 15 mg IV QW
+ IFN: 6 MU TIW
n = 207
n = 209
n = 210
Phase 3 Study of TEMSR and IFN in Advanced RCC
Overall Survival by Treatment Arm
Arm 3: IFN + Temsirolimus
Arm 2: Temsirolimus
Arm 1: IFN
Time from Randomization, Months
Pro
bab
ilit
y o
f S
urv
ival
Parameter IFN Arm 1
TEMSR Arm 2
TEMSR + IFN Arm 3
n 207 209 210
Comparisons Arm 2:Arm 1 Arm 3:Arm 1
Stratified Log-Rank p 0.0069 0.6912
IFNArm 1n=207
TEMSRArm 2n=209
TEMSR + IFNArm 3n=210
Deaths, n 149 141 152
Median Survival, months(95% CI)
7.3(6.1 - 8.9)
10.9(8.6 - 12.7)
8.4(6.6 - 10.2)
Arm 2: Arm 1 Arm 3: Arm 1
Increase inMedian Survival 49% 15%
Hazard Ratio
(95% CI)
0.73
(0.57 - 0.92)
0.95
(0.76 - 1.2)
Stratified Log-Rank p 0.0069* 0.6912
Overall Survival by Treatment Arm
*O’Brien-Fleming boundary for significance = 0.0155
Global ARCC Trial
•This is the first study to demonstrate a
statistically significant improvement in
survival in advanced poor-risk RCC patients
•The results of this global phase 3 trial
demonstrate that mTOR is an important
therapeutic target in RCC
Global ARCC Trial
Ras
P P
P P
GF
Raf kinase
MEKP
ERKP
NucleusNucleus
BAY 43-9006
Sorafenib (BAY 43-9006)
Potent inhib c-RAF Other targets: - VEGFR-2 - VEGFR-3- FLT-3- PDGFR - c-kit
Inhibits survival of tumor cells Targets proliferation + angiogenesis
* 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, ASCO 2005
Eisen T, Br J Cancer. 2006 Sep 4;95(5):581-6
Sorafenib (BAY 43-9006)Randomized Discontinuation Trial Schema (n=202)
Sorafenib400 mg bidSorafenib
400 mg bid
PlaceboPlacebo
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
Escudier, ASCO and ECCO 2005
Treatment Approaches in RCC Global Evaluation Trial
TARGETs: Pretreated Patients Study Design
*Independently assessed measurements available for 574 patients
Placebo Sorafenib
74%20%
Max
imum
Per
cent
Red
uctio
n in
Tum
or M
easu
rem
ent
-100
-80
-60
-40
-20
0
20
40
60
80
100
Patient number
50 100 150 200
250
Patient number
50
100 150 200 250
Maximum Percent Reduction in Tumor Measurement*
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
*Based on investigator assessment Escudier, ECCO, October 2005
5.5 mos2.8 mos
TARGETsProgression-Free Survival Benefit
*At 367 events, Nov. 30, 2005**O’Brien-Fleming stopping boundary for significance was p<0.0094
Time from randomization ( months)0 5 10 2515 20
0
0.25
0.50
0.75
1.00
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
Median OS
Placebo = 15.9 months
Sorafenib = 19.3 months
Hazard ratio = 0.77 (95% CI: 0.63, 0.95)
p-value = 0.015**
Of 367 events, a total of 122 deaths were reported
in the low-risk and 245 in the intermediate-risk groups
Eisen T, ASCO 2006
Overall Survival Analysis 6 Months Post-crossover*
Pazopanib Preclinical Summary
•Potent Multi-target tyrosine kinase inhibitor
•Selectively inhibits
•VEGFR-1, 2 and 3
•PDGFR- and -
•c-kit
•IC50 of 10, 30, 47, 71, 84 and 74 nM
respectively (high affinity for all receptors)
Pazopanib 800mg qd
Matching Placebo
RANDOMIZE
1° Endpoint PFS, 2° survival and RR
2:12:1
Pazopanib Phase III Trial (VEG105192) Design (n=350)
EligibilityPrior cytokines*
StratificationECOG PS 0 vs 1Prior nephrectomy
Adjuvant Therapy
• ASSURE trial (n=1,332) Intergroup ECOG. After nephrectomy patients are stratified by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) among 3 arms to 1 year of adjuvant sunitinib, sorafenib or placebo. The primary endpoint is disease free survival.
• SOURCE trial (n = 1,420), MRC. After nephrectomy, patients with high- and intermediate-risk RCC will be randomized to 3 years of sorafenib, 1 year of sorafenib and 2 years of placebo, or 3 years of placebo. The primary endpoint is metastases free survival.
Unaddressed Questions
•Is any one agent better than the other?–Are they cross-resistant?–Are the studied doses/schedules optimal?
•Can combination therapy improve outcome?•Can novel imaging modalities identify
“benefiting” patients?•What is the role of these agents in the
adjuvant setting?
•What is the role of these agents in non-clear cell RCC?
What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope?
•Oral VEGFR/PDGFR and mTOR inhibitors are extremely active in clear cell RCC
•They are much better tolerated than IFN or IL2 but there is toxicity associated with these agents
•These agents have changes how we treat this disease
•Complete responses are extremely rare and
the vast majority of patients eventually progress
• Strong rationale for targeting multiple pathways Strong rationale for targeting multiple pathways
particularly angiogenesis in patients with particularly angiogenesis in patients with
advanced RCCadvanced RCC
• Novel signal transduction inhibitors have Novel signal transduction inhibitors have
demonstrated an increase in PFS in 1demonstrated an increase in PFS in 1stst and 2 and 2ndnd line line
and an increase in survival in poor risk therapy and an increase in survival in poor risk therapy
naive patients naive patients
• Some of these agents have been recently Some of these agents have been recently
approved and others are still awaiting trial results approved and others are still awaiting trial results
• They are defining a new standard of care They are defining a new standard of care
What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope?
top related