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Targeted Therapy in Metastatic Prostate and Renal Cell Cancers Nancy A. Dawson, M.D.
University of Maryland
Greenebaum Cancer Center 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. Vascular Endothelial Growth Factor (VEGF) Targeted Therapy 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 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 VEGF overexpression promotes tumor angiogenesis and RCC progression Cytoplasmic VEGF expression in primary clear cell RCC (n=62) correlated with stage, grade and microvessel count and demonstrated independent prognostic significance for overall survival (p=0.01) 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)
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 Rini B, Small E. J Clin Onc 23(5), 2005 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 Clinical Trials of Single Agent Thalidomide in Metastatic RCC Phase III trial of IFNA +/- thalidomide Untreated, metastatic RCC (n=342) 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. Gordon MS et al. ASCO 2004 (#4516) I + T with worse QOL, fatigue, clots (12 vs. 4 pts.) 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%).
AE-941 (Neovastat®) Cytokine-refractory, metastatic RCC (n=302) placebo Response rate % <5%*
TTP (months) 2*
OS (months) 12.3*
*p = n.s for all values vs. placebo Escudier B et al. ASCO 2004 (#4547) AE-941 240mL/day 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.
Bevacizumab in RCC Yang JC et al. NEJM 349(5), 2003 RANDOMIZE BEVACIZUMAB (3 MG/KG) Q 2 WEEKS
(n=37) PLACEBO Q 2 WEEKS
(n=40) BEVACIZUMAB (10 MG/KG) Q 2 WEEKS
(n=39) PD Treatment-refractory, metastatic RCC Bevacizumab in RCC Yang JC et al. NEJM 349(5), 2003 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 *p=0.041 vs. placebo; **p < 0.001 vs.placebo % of Patients Free of Progression Time to Progression 100 80 60 40 20 0 0 6 12 18 24 Months from On-Study Date 30 36 0 6 12 18 24 30 36 Low-dose Placebo High-dose Placebo p < 0.001 p = 0.041 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 IFNA 9 MU TIW +
Bevacizumab 10 mg/kg IV q d1 and d15 STRATIFY UNTREATED, METASTATIC CLEAR CELL RCC Patients will be stratified for nephrectomy status and Motzer risk group (0, 1-2 or 3+ risk factors). Therapeutic inhibition of VEGF in RCC: receptor blockade (SU11248) Oxindole TK inhibitor
Orally bioavailable small molecule
Selective multitarget inhibition of:
PDGF-R
VEGF-R
Kit
Flt-3
Plasma half-life 40 hours
N H O N H F H3C CH3 N H O N CH3 CH3 Mendel et al. Clin Cancer Res 9, 2003 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 (n=63):
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 Baseline After 4 weeks of SU11248 After 8 weeks of SU11248 SU11248 Phase II: Clinical Results BAY 43-9006 is a Raf kinase inhibitor
Raf-MEK-ERK pathway involved in tumor growth
VEGF and PDGFR inhibitor (Wilhelm AACR 2003) BAY 43-9006 BAY 43-9006: Trial Schema > 25%
Tumor shrinkage -25% to +25% Tumor
stabilization > 25% Tumor
growth BAY 43-9006
12 week
run-in BAY 43-9006 in RCC 203 total RCC pts -> 106 reached 12-week re-eval. point -> 89 evaluable
Results (n=89):
Median TTP in pts. continuing drug = 48 weeks; 23 weeks in randomized pts.
Ratain M et al. Proc ASCO 2004 Drug related grade 3 and 4 adverse events (N=397) Events*
Grade 3 Grade 4 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 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 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 . . . . . 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. 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 (CR+PR+SD).
Secondary EP = TTP, OS, Toxicity, EGFR status correlation.
Two-stage optimal design. Study closed if < 11/21 responses. Overall Survival - SD vs. PD Clinically
localized
Hormone
refractory
Local treatment Endocrine Docetaxel-based
regimens Relapsed
and
newly diagnosed M+ Improves survival Prostate Cancer Treatment Paradigms 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)
Biomolecular Markers in CMPC George DJ, et al. Clin Cancer Res. 2001 Jul;7(7):1932-6. Multivariate model of plasma VEGF levels predicting survival time among 197 patients Docetaxel Plus Thalidomide in CMPC NCI Randomized Phase 2 Trial
AIPC
(n=75)
R
A
N
D
O
M
I
Z
E Taxotere Docetaxel/Thalidomide
(n=50) Docetaxel
(n=25) Endpoint: PSA Decline 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. Docetaxel Plus Thalidomide: Results Dahut WL, et. al. 2002 ASCO Annual Meeting Proceedings. Abstract 730. Cancer and Leukemia Group B: Phase 2 Studies Picus J, et al. Proc Am Soc Clin Oncol. 2003 ASCO Annual Meeting Proceedings. Abstract 1578.
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. 1997;57:4593. Randomized Phase 3 Trial for Castrate Metastatic Disease RANDOMIZE Docetaxel q 3 wks +
Prednisone + Placebo
Docetaxel q 3 wks +
bevacizumab +
prednisone Eligibility
Metastatic PC
T <50 ng/ml
No prior chemo
Adequate hem, renal,
and liver function Stratification
Halabi
nomogram
N = 1020 patients
CALGB, ECOG, NCIC
Opgenorth TJ, et al. J Pharmacol Exp Ther. 1996 Feb;276(2):473-81.
Carducci MA, et al. J Clin Oncol. 2002 Apr 15;20(8):2171-80.
Nelson JB, Carducci MA. BJU Int. 2000 Apr;85 Suppl 2:45-8.
Nelson, Prostate J 1999;1:126. Orally bioavailable
Once daily dosing
1800 x more selective for ETA than ETB
Atrasentan: A Selective Endothelin-A Receptor Antagonist Atrasentan Clinical Studies Asymptomatic Metastatic CMPC 1.239 1.189 1.130 1.260 1.484 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 Cox proportional hazards modeling—time to disease progression P=.131 P=.142 P=.010 P=.008 Intent-to-treat M00-211 Intent-to-treat Meta-analysis P=.014 Per-protocol M00-211 Intent-to-treat M96-594 Per-protocol M96-594 Favors Atrasentan 10 mg Favors Placebo Data on file. Hazard Ratios Confirm Consistency of Results 10 7 8 12 5 4 Rash 17 6 9 4 Dyspnea 3 4 10 15 17 4 3 6 2 Dry mouth 11 15 13 8 Infection 20 16 21 14 Headache 28 25 36 14 Rhinitis 34 34 40 12 Peripheral edema Placebo
(n=104) Atrasentan
10 mg
(n=89) Atrasentan
2.5 mg
(n=95) Atrasentan
(n=404) Placebo
(n=397) Adverse event M96-594 M00-211 *Premature discontinuation due to AE=8.9% vs 5.5% for atrasentan and placebo, respectively, in M00-211. Common adverse events reported by >5% of subjects
(% incidence) Atrasentan Adverse Events* Days Since Randomization Probability of No Disease Progression HR=1.19 P=.013 Log rank Intent-to-treat
N=1097 Atrasentan
n=592 Placebo
n=505 0.8 1.0 0.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 56 112 168 224 280 336 392 448 504 0 Data on file. Meta-analysis Time-to-disease Progression 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 PSMA Protein Structure Internal Domain Antibodies:
includes CYT-356 epitope
Binds “dead” cells transmembrane
region External Domain Antibodies:
J591, MSKCC (Ab)
Bind viable cells, Internalized Javelin peptides:
hsp antigen presentation
dendritic cell loading
PSM1 and PSM2 Cross species
DNA Immunization:
T cell and antibody
response 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 Tumor Localization: Bone (25 mg dose) J591 Scan Bone Scan Tumor localization: Soft Tissue (25 mg dose) 264 mg/m2 dose level Pre-Treatment Post 3 cycles MLN2704 SAHA selected for development as a broad anti-cancer agent Small molecule, MW < 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
SuberoylAnilide Hydroxamic Acid Start
Treatment No evidence of toxicity by:
weight gain, hematological
parameters or extensive
necropsy at doses of
25 or 50 mg/kg SAHA Ac-H3 Coomassie
stain 0 6 hrs 12 hrs 25 50 0 25 50 SAHA
(mg/kg) Ac-H4 Coomassie
stain SAHA inhibits tumor growth in CWR22 human prostate xenografts in mice and increases histone acetylation in tumors Butler et al. FTI
(BMS 214662) AKT PI3K NF-kB Bad BCL-2 ER Altered Gene
Expression Ansamycins (17-AAG)
TK Inhibitors (ZD1839,OSI774)
Mono Abs (C225, Herceptin, 2c4) PTEN Antisense (G3139) Grb2/Shc Sos Ras Raf MEK MAPK Src PD98059 PD173855/PD179483) mTOR Rapamycin, CCI-779 Cyclin D/
CDK4 LY294002 SERM3 Emerging Therapies in CMPC Proteasome inhibitors (PS341) Ansamycins AR Casodex Flavopiridol HDAC inhibitors (SAHA)
Vit D, Retinoids Tubulin
(Epothilone B) PSMA Ab
Vaccine B\T cells
Dendritic M G1 S G2 Atrasentan Satraplatin
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