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Metastatic Renal Cell Carcinoma Whats Hot In The Treatment Of Renal Cell Carcinoma And Is There Hope

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Title: Metastatic Renal Cell Carcinoma Whats Hot In The Treatment Of Renal Cell Carcinoma And Is There Hope


1
Metastatic Renal Cell Carcinoma Whats 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

2
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

3
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 2005 Mancuso
and Sternberg, Can J Urol. Feb 2005
4
Von Hippel-Lindau Suppressor Gene Inactivated in
gt 75 Sporadic RCC
Critical Cofactor in the Ubiquitin Ligase Complex
Regulated by hypoxia No HIF1-a breakdown
degradation of hypoxia inducible

pVHL
HIF
b
Suppressor gene
mTOR inhib, HSP 90 inhib
Bevacizumab, VEGF TRAP
PDGF periocytes
VEGF angiogenesis
TGFa
autocrine growth factors
EGFR
KDR
PDGFR

Sunitinib, Sorafenib AG13736,Vatalanib
Sunitinib, Sorafenib CCI-779
Sunitinib, Sorafenib Imatinib
5
The VEGF Family Are Critical Tumor-Secreted
Angiogenic Factors
  • 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)

VEGF-E
VEGF-A
VEGF-D
VEGF-C
VEGF-B
Bevacizumab binds VEGF A
6
Time to Progression High-Dose Ab vs. Placebo
(RR 10)
4.8 mos
2.5 mos
Yang, NEJM 2003
7
Survival Update
Yang, NEJM 2003
8
CALGB 90206 Randomized Phase III Trial of IFNa
or IFNa Bevacizumab in Advanced RCC (n700)
RANDOMI ZE
IFNa 9MU TIW
No prior Rx Stratify Motzer Score
VS
IFNa 9MU TIW Bevacizumab 10 mg/KG D1 and D15
1 Endpoint Survival, 89 Power to Detect
Improvement in OS of 13 to 17 mos
9
Europe Randomized Phase III Trial of IFNa or
IFNa Bevacizumab in Advanced RCC (n638)
RANDOMI ZE
IFNa 9MU TIW placebo
VS
Nephrectomy Clear Cell gt 50
IFNa 9MU TIW Bevacizumab 10 mg/KG D1 and D15
1 Endpoint Survival, 80 Power to Detect
Improvement in OS of 13 to 17 mos
10
Sunitinib Mechanism of Action in RCC
Loss of VHL Protein Function
? VEGF
? PDGF
VEGF
PDGF
VEGFR
PDGFR
Pericyte/Fibroblast/ Vascular Smooth Muscle
Vascular Endothelial Cell
Sunitinib
Vascular permeability
Cell survival, proliferation, migration
Vascular formation, maturation
Inhibition of RCC pathogenesis and progression
11
Best Response By RECIST


Motzer R ,J Clin Oncol. 2006 Jan 124(1)16-24
Motzer R, JAMA. 2006 Jun 7295(21)2516-24
12
Two Types of Response Observed
2-Central Necrosis
1-Shrinkage
Week0
Week12
Week32
13
Phase 3 Randomized Trial of Sunitinib malate
(SU11248) versus Interferon-alfa as First-line
Systemic Therapy for Patients with Metastatic
Renal Cell Carcinoma
Pre-planned analysis of primary endpoint PFS
R A N D O M I Z A T I O N
Sunitinib (N375)
  • N750
  • Stratification Factors
  • LDH ?1.5 vs gt1.5xULN
  • ECOG PS 0 vs 1
  • Presence vs Absence of Nephrectomy

IFN-? (N375)
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)
Motzer R, ASCO 2006
14
Outcome Summary

Sunitinib vs IFN-? P lt0.000001
15
Progression-Free Survival
(Independent Central Review)
1.0
Sunitinib
0.9
Median 11 months
(95 CI 1012)
0.8
IFN-?
0.7
Median 5 months
(95 CI 46)
0.6
Progression Free Survival Probability
0.5
0.4
0.3
0.2
Hazard Ratio 0.415
(95 CI 0.3200.539)
0.1
P lt0.000001
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time (Months)
No. at Risk Sunitinib 235 90 32 2 No. at Risk
IFN-? 152 42 18 0
16
Overall Survival
No. at Risk Sunitinib 341 190 84 15 1 No. at
Risk IFN-? 296 162 66 10 0
The observed p-value did not meet the
pre-specified level of significance for this
interim analysis
17
Laboratory Abnormalities
Greater frequency, P lt0.05
18
Treatment-Related Adverse Events
Greater frequency, P lt0.05
19
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

Motzer R, ASCO 2006
20
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 OToole, S
Kong, and L Moore 2006 ASCO Presentation
21
Temsirolimus Mechanism of Action
Growth Factors
extracellular membrane
PI-3 Kinase
PTEN
PI-3K/AKT Activation
PTEN Loss
Akt
mTOR
Temsirolimus
S6K
4EBP1
Translation
cMyc overexpression
HIF-1?, HIF-2? overexpression
Cyclin D1 overexpression
22
Phase 3 Study of TEMSR and IFN in Advanced RCC
  • 626 patients with advanced metastatic RCC with
    poor-risk features
  • 209 sites (26 countries)
  • Geographic Regions
  • WEU AU CA (22)
  • US (30)
  • EEU Other (48)
  • Nephrectomy
  • Yes (67)
  • No (33)

23
Overall Survival by Treatment Arm
Arm 2 Temsirolimus
Probability of Survival
Arm 1 IFN
Arm 3 IFN Temsirolimus
Time from Randomization, Months
24
Overall Survival by Treatment Arm
OBrien-Fleming boundary for significance
0.0155
25
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

26
Sorafenib (BAY 43-9006)
Inhibits survival of tumor cells Targets
proliferation angiogenesis
GF
P
P
P
P
Potent inhib c-RAF
Other targets - VEGFR-2 -
VEGFR-3 - FLT-3 - PDGFR
- c-kit
BAY 43-9006
ERK
Nucleus
27
Sorafenib (BAY 43-9006)Randomized
Discontinuation Trial Schema (n202)

gt 25 Shrinkage Continue BAY 43-9006Open Label
BAY 43-9006

gt-25 to lt25 Randomized
Tumor Assessment
12 Week Induction
Placebo

gt 25 Growth Off study
Baseline
12 weeks
24 weeks
Ratain, ASCO 2005 Eisen T, Br J Cancer. 2006 Sep
495(5)581-6
May cross over to BAY 43-9006
28
TARGETs Pretreated Patients Study Design
  • 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

Sorafenib400 mg bid
  • Major endpoints
  • Survival (alpha0.04)
  • PFS (alpha0.01)

Placebo
Treatment Approaches in RCC Global Evaluation
Trial
Escudier, ASCO and ECCO 2005
29
Maximum Percent Reduction in Tumor Measurement
Placebo
Sorafenib
100
80
60
Maximum Percent Reduction in Tumor Measurement
40
20
250
100
150
200
250
0
50
100
150
200
50
-20
Patient number
Patient number
-40
-60
-80
-100
74
20
Independently assessed measurements available
for 574 patients
30
TARGETsProgression-Free Survival Benefit
Median PFS Sorafenib 5.5 months Placebo 2.8
months Hazard ratio (S/P) 0.51
Sorafenib
5.5 mos
2.8 mos
Placebo
Censored observation
Based on investigator assessment
Escudier, ECCO, October 2005
31
Overall Survival Analysis 6 Months
Post-crossover
1.00
0.75
Survival distribution function
0.50
Median OS Placebo 15.9 months Sorafenib 19.3
months Hazard ratio 0.77 (95 CI 0.63,
0.95) p-value 0.015
0.25
0
0
5
10
25
15
20
Time from randomization ( months)
Of 367 events, a total of 122 deaths were
reported in the low-risk and 245 in the
intermediate-risk groups
At 367 events, Nov. 30, 2005OBrien-Fleming
stopping boundary for significance was plt0.0094
Eisen T, ASCO 2006
32
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)

33
Pazopanib Phase III Trial (VEG105192) Design
(n350)
R A N D O M I Z E
Eligibility Prior cytokines Stratification ECOG
PS 0 vs 1 Prior nephrectomy
Pazopanib 800mg qd
Matching Placebo
21
1 Endpoint PFS, 2 survival and RR
34
Adjuvant Therapy
  • ASSURE trial (n1,332) 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.

35
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?

36
Whats 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

37
Whats Hot in the Treatment of Renal Cell
Carcinoma and is there Hope?
  • Strong rationale for targeting multiple pathways
    particularly angiogenesis in patients with
    advanced RCC
  • Novel signal transduction inhibitors have
    demonstrated an increase in PFS in 1st and 2nd
    line and an increase in survival in poor risk
    therapy naive patients
  • Some of these agents have been recently approved
    and others are still awaiting trial results
  • They are defining a new standard of care
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