Targeted Therapy in Metastatic Prostate and Renal Cell Cancers

1
Targeted Therapy in Metastatic Prostate and
Renal Cell Cancers

• Nancy A. Dawson, M.D.
• University of Maryland
• Greenebaum Cancer Center

2
Vascular Endothelial Growth Factor (VEGF)
Targeted Therapy

• VEGF expression is regulated by a number of
  factors including cytokines, growth factors,
  hormones, hypoxia and tumor suppressor genes.
• Pertinent to renal cell carcinoma, VEGF
  expression results from inactivation of the von
  Hippel-Lindau (VHL) tumor suppressor gene
  observed in the majority of RCC, thus identifying
  VEGF as a critical component of RCC tumor
  angiogenesis and a particularly relevant
  therapeutic target in RCC.

3
Biology of RCC

• VHL syndrome is characterized by a germline
  mutation of chromosome 3p and development of RCC
• Non-inherited clear cell RCC is characterized by
  VHL gene tumor suppressor gene inactivation
• VHL gene inactivation leads constitutive
  expression of an oxygen-regulated transcription
  factor (HIFa) and induction of hypoxia-inducible
  genes including VEGF
• VEGF overexpression promotes tumor angiogenesis

4
Clear cell RCC is characterized by VHL gene
inactivation

• VHL gene inactivation in clear cell renal
  carcinoma selected series

No significant VHL gene mutation (1 2/136) or
methlyation (2 3/135) observed in non-clear
cell RCC
Rini BI et al. J Clin Onc In press
5
VEGF overexpression promotes tumor angiogenesis
and RCC progression

• Cytoplasmic VEGF expression in primary clear cell
  RCC (n62) correlated with stage, grade and
  microvessel count and demonstrated independent
  prognostic significance for overall survival
  (p0.01) in a retrospective series. (Paradis et
  al. Virchows Arch 436, 2000)
• Elevated serum VEGF levels have been demonstrated
  in RCC patients versus controls and generally
  correlate with stage and grade. Assoc. w/
  survival in univariate analysis. (Jacobsen J et
  al. JUrol 163, 2000)

6
Therapeutic inhibition of VEGF in RCC

• Miscellaneous anti-VEGF agents
• Thalidomide
• AE-941 (Neovastat)
• Binding antibodies to the VEGF protein
• Bevacizumab (Avastin)
• VEGF-trap
• VEGFR inhibitors
• SU11248
• PTK787
• BAY 43-9006

7
Rini B, Small E. J Clin Onc 23(5), 2005
8
Thalidomide (Thalomid)

• Thalidomide has an anti-angiogenic mechanism
• Reduction of both bFGF- and VEGF-induced corneal
  neovascularization in animal models.
• Reduction of bFGF and VEGF expression with
  resulting inhibitory effects on endothelial cell
  proliferation.
• Other potential anti-tumor effects reduction in
  TNF-alpha production, induction of G1 cell cycle
  arrest/apoptosis and modulation of stimulated NK
  cells and T lymphocytes

9
Clinical Trials of Single Agent Thalidomide in
Metastatic RCC
10
Phase III trial of IFNA /- thalidomide
Untreated, metastatic RCC (n342)
IFNA 1 MU BID Thalidomide (200-1,000 mg/day)
IFNA 1 MU BID

• Response rate 7.6 3.1
• TTP (months) 2.8 2.8
• OS (months) 13.1 10.8

all p values n.s.
I T with worse QOL, fatigue, clots (12 vs. 4
pts.)
Gordon MS et al. ASCO 2004 (4516)
11
AE-941 (Neovastat)

• Compound prepared by homogenization and
  purification of shark cartilage.
• Inhibits several VEGF-dependent processes through
  competitive binding with VEGFR-2.
• A phase I study of AE-941 was conducted in 144
  patients with refractory solid tumors, and a
  subset of 22 metastatic RCC was reported.
  (Batist, Ann Oncol 2002)
• Two objective responses were observed (overall
  response rate 9).

12
AE-941 (Neovastat)
Cytokine-refractory, metastatic RCC (n302)
AE-941 240mL/day
placebo

• Response rate lt5
• TTP (months) 2
• OS (months) 12.3

p n.s for all values vs. placebo
Escudier B et al. ASCO 2004 (4547)
13
Therapeutic inhibition of VEGF in RCC
antibody-mediated blockade of VEGF protein

• Anti-VEGF antibody (bevacizumab, Avastin)
• Recombinant human monoclonal antibody against
  VEGF created by transferring the VEGF-binding
  regions of the murine antibody to a humanized
  IgG1 framework (93 human, 7 murine).
• Binds and neutralizes all biologically active
  isoforms of VEGF.

14
Bevacizumab in RCC
PLACEBO Q 2 WEEKS (n40)
RANDOMIZE
PD
Treatment-refractory, metastatic RCC
BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n37)
BEVACIZUMAB (10 MG/KG) Q 2
WEEKS (n39)
Yang JC et al. NEJM 349(5), 2003
15
Bevacizumab in RCC
Placebo Low-dose High-dose
Bevacizumab Bevacizumab
Response rate 0 0
10 TTP (months) 2.5 3.0
4.8 OS (months)
13.0 15.1
15.5
p0.041 vs. placebo p lt 0.001 vs.placebo
Yang JC et al. NEJM 349(5), 2003
16
Time to Progression
100
80
p
lt
0.001
p

0.041
60
of Patients Free of Progression
40
High-dose
Low-dose
Placebo
Placebo
20
0
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Months from On-Study Date
17
CALGB 90206 A Randomized Phase III Trial of
Interferon Alpha-2b or Interferon Alpha-2b Plus
Bevacizumab in Advanced Renal Carcinoma
RANDOMIZE
IFNA 9 MU TIW
STRATIFY
UNTREATED, METASTATIC CLEAR CELL RCC
IFNA 9 MU TIW Bevacizumab 10
mg/kg IV q d1 and d15

• Patients will be stratified for nephrectomy
  status and Motzer risk group (0, 1-2 or 3 risk
  factors).

18
Therapeutic inhibition of VEGF in RCC receptor
blockade (SU11248)

• Oxindole TK inhibitor
• Orally bioavailable small molecule
• Selective multitargetinhibition of
• PDGF-R
• VEGF-R
• Kit
• Flt-3
• Plasma half-life ? 40 hours

CH3
O
H3C
CH3
N
N
H
CH3
F
N
H
O
N
H
Mendel et al. Clin Cancer Res 9, 2003
19
SU11248 in cytokine-refractory RCC

• Single-arm, multi-institutional phase II of
  SU11248 in metastatic, cytokine-refractory RCC
  patients
• 50mg p.o. QD 4 weeks on / 2 weeks off
• Results (n63)
• Of 21 patients who achieved a PR, 14 remain
  progression-free (range 5.1 - 12.0 months).

Motzer R, Rini B, Michaelson D et al. Proc ASCO
2004
20
SU11248 Phase II Clinical Results
Baseline
After 4 weeks of SU11248
After 8 weeks of SU11248
21
BAY 43-9006

• BAY 43-9006 is a Raf kinase inhibitor
• Raf-MEK-ERK pathway involved in tumor growth
• VEGF and PDGFR inhibitor (Wilhelm AACR 2003)

22
BAY 43-9006 Trial Schema
gt 25 Tumorshrinkage
-25 to 25Tumor stabilization
BAY 43-9006 12 week run-in
gt 25Tumor growth
23
BAY 43-9006 in RCC

• 203 total RCC pts -gt 106 reached 12-week re-eval.
  point -gt 89 evaluable
• Results (n89)
• Median TTP in pts. continuing drug 48 weeks 23
  weeks in randomized pts.

Ratain M et al. Proc ASCO 2004
24
Drug related grade 3 and 4 adverse events (N397)
Grade 3
Grade 4
Events

• Any event 118 (34.5) 30 (8.8)
• Cardiovascular (Any) 22 (6.4) 3 (0.9)
• Hypertension 17 (5) 0 (0)
• Dermatology/Skin 40 (11.7) 1 (0.3)
• HFS 28 (8.2) 0 (0)
• Rash/desquamation 12 (3.5) 0 (0)
• Constitutional Symptoms 17 (5) 3 (0.9)
• Fatigue 15 (4.4) 2 (0.6)
• Gastrointestinal (Any) 30 (8.8) 1 (0.3)
• Hepatic 14 (4.1) 1 (0.3)
• Metabolic/Lab 10 (2.9) 5 (1.5)
• Neurology 10 (2.9) 2 (0.6)
• Pain (Any) 32 (9.4) 4 (1.2)
• Pulmonary (Any) 15 (4.4) 6 (1.8)
• Dyspnea 14 (4.1) 2 (0.6)

Includes at least 3 occurrence data
unmonitored
25
Conclusions

• VHL gene inactivation is a frequent event in
  clear cell RCC leading to VEGF overexpression
• Therapeutic inhibition of VEGF via antibody or
  receptor blockade results in anti-tumor activity
  in metastatic RCC

26
The future of anti-VEGF therapy in RCC

• Definitive phase III trials of anti-VEGF therapy
• In combination with initial cytokine therapy
  (CALGB IFN vs. IFN/Avastin)
• First-line therapy vs. cytokines (SU11248 vs.
  IFN)
• Second-line therapy vs. placebo (BAY 43-9006) or
  single-agent (SU11248)
• Adjuvant BAY 43-9006 vs.placebo adjuvant trial
  planned (ECOG)
• Combination therapy
• Bevacizumab OSI-779 (EGFR inhibitor) rPII
  completed
• CALGB planning rPII of PTK787 vs. RAD-001 (mTOR
  inhibitor) vs. PTK/RAD
• Many others . . . . .

27
EGFR-Targeted Therapy Rationale

• EGFR is constitutively expressed in normal
  kidney.
• EGFR by IHC is over-expressed in 75-90 of kidney
  neoplasms.
• Over-expression of EGFR appears to play a role in
  tumor initiation and progression in RCC.
• Mab C225, an anti-EGFR monoclonal antibody, can
  delay tumor growth in human RCC tumor xenografts.

28
Trial Design

• ZD1839 500 mg po qd.
• Dose modification to 250 mg qd based on toxicity.
  No reescalation or further reduction permitted.
• Response based on RECIST.
• Primary EP RR (CRPRSD).
• Secondary EP TTP, OS, Toxicity, EGFR status
  correlation.
• Two-stage optimal design. Study closed if lt
  11/21 responses.

29
Overall Survival - SD vs. PD
30
Prostate CancerTreatment Paradigms
Hormone refractory
Relapsed and newly diagnosed M
Clinically localized
Docetaxel-based regimens
Local treatment
Endocrine
Improves survival
31
Emerging Options in Castrate Metastatic Prostate
Cancer (CMPC)

• Newer cytotoxic combinations
• Calcitriol docetaxel, satraplatin, ixabepilone
• Antiangiogenesis inhibitors
• Gene therapy/tumor vaccines/oncolytic viruses
• Provenge (PSMA stimulated dendritic cells), GVAX
  (GM-CSF secreting tumor cells), CG787
• Monoclonal antibodies
• PSMA targeted radiopharmaceutical or toxin
  (DM-1)
• Endothelin-receptor antagonists (atrasentan)

32
Biomolecular Markers in CMPC
Multivariate model of plasma VEGF levels
predicting survival time among 197 patients
George DJ, et al. Clin Cancer Res. 2001
Jul7(7)1932-6.
33
Docetaxel Plus Thalidomide in CMPC
NCI Randomized Phase 2 Trial
Taxotere
Docetaxel/Thalidomide (n50)
R A N D O M I Z E
AIPC (n75)
Endpoint PSA Decline
Docetaxel (n25)
Dose Docetaxel 30 mg/m2 q wk x 3 of
4 Thalidomide 200 mg/day
Dahut WL, et. al. 2002 ASCO Annual Meeting
Proceedings. Abstract 730.
34
Docetaxel Plus Thalidomide Results
Dahut WL, et. al. 2002 ASCO Annual Meeting
Proceedings. Abstract 730.
35
Cancer and Leukemia Group BPhase 2 Studies
Picus J, et al. Proc Am Soc Clin Oncol. 2003 ASCO
Annual Meeting Proceedings. Abstract 1578.
36
Avastin (bevacizumab)

• Recombinant humanized monoclonal IgG1 antibody1
• Recognizes all isoforms of VEGF2
• Estimated half-life is approximately 20 days
  (range, 11-50 days)1
• Approved for the use in metastatic Colon Cancer

1. Avastin (Avastin) PI. February 2004. 2.
Presta et al. Cancer Res. 1997574593.
37
Randomized Phase 3 Trial for Castrate Metastatic
Disease
Eligibility Metastatic PC T lt50 ng/ml No prior
chemo Adequate hem, renal, and liver function
Stratification Halabi nomogram
Docetaxel q 3 wks Prednisone
Placebo Docetaxel q 3 wks bevacizumab
prednisone
RANDOMIZE
N 1020 patients CALGB, ECOG, NCIC
38
Atrasentan A Selective Endothelin-A Receptor
Antagonist

• Orally bioavailable
• Once daily dosing
• 1800 x more selective for ETA than ETB

Opgenorth TJ, et al. J Pharmacol Exp Ther. 1996
Feb276(2)473-81. Carducci MA, et al. J Clin
Oncol. 2002 Apr 1520(8)2171-80. Nelson JB,
Carducci MA. BJU Int. 2000 Apr85 Suppl
245-8. Nelson, Prostate J 19991126.
39
Atrasentan Clinical Studies Asymptomatic
Metastatic CMPC
40
Hazard Ratios Confirm Consistency of Results
Cox proportional hazards modelingtime to disease
progression
Favors Atrasentan 10 mg
Favors Placebo
1.189
P.014
1.130
P.131
1.260
P.008
1.239
P.142
1.484
P.010
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
Data on file.
41
Atrasentan Adverse Events
Common adverse events reported by gt5 of subjects
( incidence)
M00-211
M96-594
Placebo (n104)
Atrasentan 10 mg (n89)
Atrasentan 2.5 mg (n95)
Atrasentan (n404)
Placebo (n397)
Adverse event
17
34
34
40
12
Peripheral edema
15
28
25
36
14
Rhinitis
10
20
16
21
14
Headache
10
11
15
13
8
Infection
17
6
9
4
Dyspnea
4
7
8
12
5
4
Rash
3
4
3
6
2
Dry mouth
Premature discontinuation due to AE8.9 vs 5.5
for atrasentan and placebo, respectively, in
M00-211.
42
Meta-analysis Time-to-disease Progression
1.0
Intent-to-treat N1097
0.9
P.013
Log rank
HR1.19
0.8
Atrasentan n592
0.7
0.6
0.5
Probability of No Disease Progression
0.4
0.3
Placebo n505
0.2
0.1
0.0
Days Since Randomization
Data on file.
43
Atrasentan

• Delays disease progression in men with metastatic
  CMPC
• Meta-analysis of data from 1097 men in 2 large,
  randomized, controlled studies
• Reduces incidence of and delays time to onset of
  bone pain
• Provides quality of life benefit
• Maintains good health state for longer
• Has a favorable safety profile

44
PSMA Protein Structure
transmembrane region
Javelin peptides hsp antigen presentation
dendritic cell loading PSM1 and PSM2
Cross species DNA Immunization T cell and
antibody response
Internal Domain Antibodies includes CYT-356
epitope Binds dead cells
External Domain Antibodies J591, MSKCC
(Ab) Bind viable cells, Internalized
45
The Antibody J591 (MLN2704)

• Extracellular domain of PSMA
• Equivocal to weak reactivity
• Subcortical white matter brain
• Epididymis
• Internalizes following binding
• Excellent correlation with bone and/or CT

46
Tumor Localization Bone (25 mg dose)
J591 Scan
Bone Scan
47
Tumor localization Soft Tissue (25 mg dose)
48
264 mg/m2 dose level
49
Pre-Treatment Post 3 cycles MLN2704
50
SAHA selected for development as a broad
anti-cancer agent
SuberoylAnilide Hydroxamic Acid

• Small molecule, MW lt 300
• 45 nM inhibitor of HDAC activity
• Induces histone acetylation and alters gene
  expression (p21, TBP-2 and others)
• Blocks proliferation of cultured cells
• Inhibits tumor growth in animal models

51
SAHA inhibits tumor growth in CWR22 human
prostate xenografts in mice and increases histone
acetylation in tumors

• No evidence of toxicity by
• weight gain, hematological
• parameters or extensive
• necropsy at doses of
• 25 or 50 mg/kg SAHA

Start Treatment
Butler et al.
52
Emerging Therapies in CMPC
PSMA Ab Vaccine B\T cells Dendritic
Ansamycins (17-AAG) TK Inhibitors
(ZD1839,OSI774) Mono Abs (C225, Herceptin, 2c4)
Atrasentan
Src
PD173855/PD179483)
Grb2/Shc
PI3K
LY294002
PTEN
Sos
AKT
Bad
BCL-2
Antisense (G3139)
FTI (BMS 214662)
Ras
mTOR
Rapamycin, CCI-779
G2
Raf
Ansamycins
Tubulin (Epothilone B)
S
M
Flavopiridol
Cyclin D/ CDK4
PD98059
Satraplatin
MEK
G1
SERM3
ER
MAPK
NF-kB
Proteasome inhibitors (PS341)
Casodex
AR
Altered Gene Expression
HDAC inhibitors (SAHA) Vit D, Retinoids
53
Thank You