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Targeted Therapy in Metastatic Prostate and Renal Cell Cancers

Targeted Therapy in Metastatic Prostate and Renal Cell Cancers. Nancy A. Dawson, M.D. University of Maryland Greenebaum Cancer Center. Vascular Endothelial Growth Factor (VEGF) Targeted Therapy.

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Targeted Therapy in Metastatic Prostate and Renal Cell Cancers

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  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 (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)

  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 (n=342) Response rate 7.6% 3.1% TTP (months) 2.8 2.8 OS (months) 13.1 10.8 IFNA 1 MU BID + Thalidomide (200-1,000 mg/day) IFNA 1 MU BID *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 (n=302) Response rate % <5%* TTP (months) 2* OS (months) 12.3* AE-941 240mL/day placebo *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 (n=40) RANDOMIZE PD Treatment-refractory, metastatic RCC BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n=37) BEVACIZUMAB (10 MG/KG) Q 2 WEEKS (n=39) 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 *p=0.041 vs. placebo; **p < 0.001 vs.placebo Yang JC et al. NEJM 349(5), 2003

  16. 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).

  17. 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

  18. 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

  19. SU11248 Phase II: Clinical Results Baseline After 4 weeks of SU11248 After 8 weeks of SU11248

  20. 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)

  21. Continue BAY 43-9006 Continue BAY 43-9006 12 weeks % SD 24 weeks Placebo* 12 weeks Off study *Placebo pts with PD may cross over to BAY 43-9006 BAY 43-9006: Trial Schema > 25% Tumorshrinkage BAY 43-9006 12 week run-in -25% to +25%Tumor stabilization > 25%Tumor growth

  22. 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

  23. 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

  24. 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 . . . . .

  25. 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.

  26. 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.

  27. Overall Survival - SD vs. PD

  28. Prostate CancerTreatment Paradigms Relapsed and newly diagnosed M+ Hormone refractory Clinically localized Docetaxel-based regimens Local treatment Endocrine Improves survival

  29. 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)

  30. Biomolecular Markers in CMPC Multivariate model of plasma VEGF levels predicting survival time among 197 patients George DJ, et al. Clin Cancer Res. 2001 Jul;7(7):1932-6.

  31. Docetaxel Plus Thalidomide in CMPC NCI Randomized Phase 2 Trial Taxotere Docetaxel/Thalidomide (n=50) R A N D O M I Z E AIPC (n=75) Endpoint: PSA Decline Docetaxel (n=25) 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.

  32. Docetaxel Plus Thalidomide: Results Dahut WL, et. al. 2002 ASCO Annual Meeting Proceedings. Abstract 730.

  33. Cancer and Leukemia Group B:Phase 2 Studies Picus J, et al. Proc Am Soc Clin Oncol. 2003 ASCO Annual Meeting Proceedings. Abstract 1578.

  34. 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.

  35. Randomized Phase 3 Trial for Castrate Metastatic Disease Eligibility Metastatic PC T <50 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

  36. Atrasentan: A Selective Endothelin-A Receptor Antagonist Orally bioavailable Once daily dosing 1800 x more selective for ETAthan ETB 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.

  37. Atrasentan Clinical Studies Asymptomatic Metastatic CMPC

  38. Meta-analysis Intent-to-treat M00-211 M96-594 M96-594 M00-211 Intent-to-treat Intent-to-treat Per-protocol Per-protocol Hazard Ratios Confirm Consistency of Results Cox proportional hazards modeling—time to disease progression Favors Placebo Favors Atrasentan 10 mg 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.

  39. Atrasentan Adverse Events* Common adverse events reported by >5% of subjects (% incidence) M00-211 M96-594 Adverse event Placebo (n=397) Atrasentan (n=404) Placebo (n=104) Atrasentan 2.5 mg (n=95) Atrasentan 10 mg (n=89) Peripheral edema 12 40 17 34 34 Rhinitis 14 36 15 25 28 Headache 14 21 10 16 20 Infection 8 13 10 15 11 Dyspnea 4 9 4 6 17 Rash 4 7 8 5 12 Dry mouth 2 6 3 3 4 *Premature discontinuation due to AE=8.9% vs 5.5% for atrasentan and placebo, respectively, in M00-211.

  40. 0 56 112 168 224 280 336 392 448 504 Meta-analysis Time-to-disease Progression 1.0 Intent-to-treat N=1097 0.9 Log rank P=.013 0.8 HR=1.19 Atrasentan n=592 0.7 0.6 0.5 Probability of No Disease Progression 0.4 0.3 0.2 Placebo n=505 0.1 0.0 Days Since Randomization Data on file.

  41. 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

  42. 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

  43. 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

  44. Tumor Localization: Bone (25 mg dose) J591 Scan Bone Scan

  45. Tumor localization: Soft Tissue (25 mg dose)

  46. 264 mg/m2 dose level

  47. Pre-Treatment Post 3 cycles MLN2704

  48. 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

  49. 6 hrs 12 hrs SAHA (mg/kg) 0 25 50 0 25 50  Ac-H3 Coomassie stain  Ac-H4 Coomassie stain 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.

  50. 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 Antisense (G3139) BCL-2 FTI (BMS 214662) Ras mTOR Rapamycin, CCI-779 G2 Raf Ansamycins Tubulin (Epothilone B) S M • Flavopiridol Cyclin D/ CDK4 Satraplatin PD98059 MEK G1 SERM3 ER MAPK NF-kB Proteasome inhibitors (PS341) Casodex AR Altered Gene Expression HDAC inhibitors (SAHA) Vit D, Retinoids

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