CLINICAL STUDIES WITH ANTIANGIOGENIC STRATEGIES FOR MALIGNANT GLIOMA C. Schichor, J.-C. Tonn Klinik für Neurochirurgie Ludwig-Maximilians Universität München - Großhadern University Hospital Munich Großhadern Department of Neurosurgery, Germany
Integrin structure and signalling Harburger DS & Calderwood DA, J Cell Sci 2009;122:159 163 Askari JA, et al. J Cell Sci 2009;122:165 170
Integrin α v β 3 expression in glioblastomas * 100 µm 100 µm 100 µm Integrin α v β 3 CD31 (endothelial cells) Integrin α v β 3 /CD31 fluorescent overlay Schnell O, et al. Brain Pathol 2008;18:378 386
Statistical analysis of α v β 3 expression Positive detected tissue Mean staining intensity Overall tumor tissue * mild * moderate strong * 100 90 80 70 60 50 40 Positive tissue in analyzed area (%) 100 90 80 70 60 50 40 30 Staining intensity in relation to M21 (%) 30 20 10 0 20 10 0 GBM LGG Non-CNS GBM LGG Positive detected glial tissue Mean staining intensity in glial cells Glial tissue only Positive glial tissue in analyzed area (%) * 100 mild * 100 90 90 80 moderate strong * 80 70 70 60 60 50 40 30 20 10 0 50 40 30 Staining intensity in relation to M21 (%) 20 10 0 GBM LGG GBM LGG *p<0.05; Student's t test Schnell O, et al. Brain Pathol 2008;18:378 386
[ 18 F]-galacto Arg-Gly-Asp (RGD) positronemission tomography for glioblastoma A B E L L C D L Schnell O, et al. Neuro Oncol 2009 Apr. 28
Summary of preclinical data Key interpretations Cilengitide: Blocks binding of α V integrins to ECM Anti-angiogenic Key experiments Receptor and cell-based inhibition. Co-crystal cilengitide and α V β 3 1 3 Rabbit cornea, mouse retina model, CAM: blocks growth factor-induced angiogenesis 1,4,5 Blocks endothelial cell proliferation HUVECs in vitro; CAM 1,4,6 Blocks adhesion, migration, and differentiation HUVECs, HBMECs, tumor cell lines. Differentiation of endothelia 2,6,7 Induces apoptosis Additive activity in combination with a wide variety of classical and molecular-targeted therapeutics HUVECs and tumor cells in vitro. Growth factor-stimulated endothelia, glioblastoma in vivo 2,7,8 Significantly enhances anti-tumor and anti-angiogenic efficacy in preclinical combination models 9,10 CAM=chorioallantoic membrane; ECM=extracellular matrix; HBMECs=human brain microvascular endothelial cells; HUVECs=human umbilical vein endothelial cells 1. Dechantsreiter MA, et al. J Med Chem 1999;42:3033 3040; 2. Nisato RE, et al. Angiogenesis 2003;6:105 119; 3. Xiong JP, et al. Science 2002;296:151 155; 4. Friedlander M, et al. Science 1995;270:1500 1502; 5. Hammes HP, et al. Nat Med 1996;2:529 533; 6. Loges S, et al. Biochem Biophys Res Commun 2007;357:1016 1020; 7. Albert JM, et al. Int J Radiat Oncol Biol Phys 2006;65:1536 1543; 8. Taga T, et al. Int J Cancer 2002;98:690 697; 9. Tentori L, et al. Oncol Rep 2008;19:1039 1043; 10. Lode HN, et al. Proc Natl Acad Sci USA 1999;96:1591 1596
Cilengitide: Mechanism of action Results from early clinical trials support the hypothesis that cilengitide: Blocks integrins α V β 3 and α V β 5 Those integrins are expressed on tumor cells and endothelial cells Cilengitide, therefore, has a dual mode of action Direct anti-tumor activity Anti-angiogenic activity
Cilengitide: Mechanism of action Results from early clinical trials support the hypothesis that cilengitide: Blocks integrins α V β 3 and α V β 5 Those integrins are expressed on tumor cells and endothelial cells Cilengitide, therefore, has a dual mode of action Direct anti-tumor activity Anti-angiogenic activity
Single agent: Partial response lasting >18 months August 2005 April 2007 Reardon D, et al. J Clin Oncol 2008;26:5610 5617
EMD 121974 010 Phase I/IIa trial of cilengitide and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy, in patients with newly diagnosed glioblastoma
Study design Concomitant phase Adjuvant phase (6 months) + C i l e n g i t i d e (twice weekly IV) Temozolomide (TMZ) daily x 6 weeks RT (30 x 2 Gy) TMZ 75 mg/m 2 daily (7/7) during RT Maintenance 150 200 mg/m 2 x 5 days for 6 cycles RT 60 Gy (30 x 2 Gy), to start 3 5 weeks post-surgery Cilengitide 500 mg flat dose twice weekly IV to start 1 week before TMZ/RT, continue throughout chemoradiotherapy, optional single-agent maintenance after completion of 6 cycles of TMZ Primary endpoint: PFS rate after 6 months of treatment Stupp R, et al. Society for Neuro-Oncology, 12th Annual Meeting, Dallas, TX, USA, November 2007, Abstract No. MA-10; Stupp R, et al. J Clin Oncol 2007;25(Suppl. 18):Abstract No. 2000 (updated information presented)
Cilengitide vs historical controls: Overall survival 1.00 Survival 0.75 0.50 0.25 X X X Lausanne pilot X EORTC Cilengitide X 0.00 0 5 10 15 20 25 Time (months) Stupp R, et al. Society for Neuro-Oncology, 12th Annual Meeting, Dallas, TX, USA, November 2007, Abstract No. MA-10 Stupp R, et al. N Engl J Med 2005;352:987 96
Cilengitide vs historical controls: Overall survival and MGMT MGMT gene-promoter status: Unmethylated Methylated X EORTC Lausanne pilot Cilengitide 1.00 0.75 X 1.00 0.75 X X Survival 0.50 0.25 X X Survival 0.50 0.25 X X 0.00 0.00 0.0 5 10 15 20 25 0.0 5 10 15 20 25 Time (months) Time (months) Stupp R, et al. Society for Neuro-Oncology, 12th Annual Meeting, Dallas, TX, USA, November 2007, Abstract No. MA-10; Hegi ME, et al. CCR 2004 including update; Hegi ME, et al. N Engl J Med 2005;352:997 1003
Cilengitide vs historical controls: Overall survival and MGMT MGMT gene-promoter status: Unmethylated Methylated X EORTC Lausanne pilot Cilengitide 1.00 0.75 X 1.00 0.75 X X Survival 0.50 0.25 X X Survival 0.50 0.25 X X 0.00 0.00 0.0 5 10 15 20 25 0.0 5 10 15 20 25 Time (months) Time (months) Stupp R, et al. Society for Neuro-Oncology, 12th Annual Meeting, Dallas, TX, USA, November 2007, Abstract No. MA-10; Hegi ME, et al. CCR 2004 including update; Hegi ME, et al. N Engl J Med 2005;352:997 1003
A collaboration of EORTC & Merck Cilengitide phase III for newly diagnosed GBM Step 1: Central MGMT methylation status assay Step 2: Randomization versus control Diagnosis Max. 28 days MGMT methyl. MGMT not methyl. or undetermined R Novel strategies per local policy or phase II trials + cilengitide TMZ Radiotherapy Concomitant phase Adjuvant (maintenance) phase
Adapted from Bergers, et al. Nature 2002 University Hospital Munich Großhadern Department of Neurosurgery, Germany
Bevacizumab (Avastin) VEGF VEGFR-2 VEGFR-2 VEGF Bevacizumab Extracellular Endothelial cell Intracellular ANGIOGENESIS Angiogenesis is mediated primarily through the interaction between VEGF and VEGFR-2 ANGIOGENESIS Bevacizumab inhibits VEGF extracellularly and, therefore, may inhibit angiogenesis without disrupting targets outside the VEGF pathway Hicklin, Ellis. JCO 2005 University Hospital Munich Großhadern Department of Neurosurgery, Germany
Normale Blutgefäße Abnormale, chaotische Blutgefäße Normalisierte Durchblutung 1. Sturk, Dumont. In: Basic Science of Oncology 2005 ; 2. Gerber, Ferrara. Cancer Res 2005 3. Jain. Nat Med 2001; 4. Jain. Science 2005; 5. Kerbel. Science 2006 Figure reprinted by permission from Macmillan Publishers Ltd: Jain. Nature Med;7(9):987 9, copyright 2001 University Hospital Munich Großhadern Department of Neurosurgery, Germany
FRÜHE EFFEKTE ANHALTENDE EFFEKTE 1 Regression 2 Normalisation 3 Inhibition Abnahme der Tumorgröße Verbesserte Verteilung von Chemotherapie Unterdrückung von Gefäßeinsprossung Reduktion Rezidivwachstum Willett, et al. Nat Med 2004; Gerber, Ferrara. Cancer Res 2005 University Hospital Munich Großhadern Department of Neurosurgery, Germany
Recurrent GBM Response to Bevazizumab + PC-Chemotherapy
Recurrent GBM Response to Bevazizumab + PC-Chemotherapy
Recurrent GBM Response to Bevazizumab + PC-Chemotherapy
Recurrent GBM Response to Bevazizumab + PC-Chemotherapy
Recurrent GBM Response to Bevazizumab + PC-Chemotherapy mismatch MRI / FET-PET
University Hospital Munich Großhadern Department of Neurosurgery, Germany
Überblick zur klinischen Wirksamkeit von Bevacizumab bei rezidiviertem Glioblastom Therapie Autor n Bevacizumab oder Bevacizumab + Irinotecan Ansprechrate (%) PFS-6 (%) Medianes Gesamtüberleben (Monate) Friedman 167 28,2 / 37,8 42,6 / 50,3 9,2 / 8,7 Bevacizumab + Irinotecan Vredenburgh 35 57 46 10 Bevacizumab, bei erneuter PD Bevacizumab + Irinotecan Bevacizumab + Irinotecan (retrospektiv) Bevacizumab + Irinotecan (retrospektiv) Bevacizumab + Irinotecan (retrospektiv) Kreisl 48 35 29 7,5 Poulsen 27 30 40 7 Norden 33 34 42 n.a Zuniga 37 n.a. 64 11,5 Friedman HS et al. J Clin Oncol 2009; published ahead of print on August 31. Vredenburg JJ et al. J Clin Oncol 2008;25:4722 4729. Kreisl TN et al. J Clin Oncol 2009;27(5):740 745. Poulsen HS et al. Acta Oncol 2009;48:52 58. Norden AD et al. Neurology 2008;70(10):779 87. Zuniga RM et al. J Neurooncolog 2009;91(3):329 336 University Hospital Munich Großhadern Department of Neurosurgery, Germany
Medikamentöse Therapie des rezidivierten Glioblastoms: Patienten mit Temozolomid-Vorbehandlung Behandlung CR + PR (%) Progressionsfreies Überleben nach 6 Monaten (%) Medianes Gesamt- Überleben (Wochen) Prospektive Studien Wick et al. 2009 (n = 92) CCNU 4 19 30 Van den Bent et al. 2009 (n = 56) Retrospektive Studien BCNU oder TMZ 10 24 31 Happold et al. 2009 (n = 32) ACNU ±VM26/AraC Perry et al. 2008 (n = 35) TMZ 28/28 14 31 Wick et al. 2009 (n = 47) TMZ Diverse Wick et al. J Clin Oncol 2009; in press. Van den Bent et al. J Clin Oncol 2009; 27: 1268 1274. Happold C et al. J Neurooncol 2009; 92: 45 8. Perry et al. Cancer 2008; 113: 2152 7. Wick et al. J Neurol 2009; 256:734-41 6 20 29 10 28 25 University Hospital Munich Großhadern Department of Neurosurgery, Germany
University Hospital Munich Großhadern Department of Neurosurgery, Germany
Zulassungsstudie Bevacizumab bei rezidiviertem Glioblastom Patienten mit Glioblastom randomisiert nach erstem oder zweitem Rezidiv (N = 167) 1:1 Bevacizumab* (n = 85) Bevacizumab/ Irinotecan** (n = 82) Erkrankungsprogression (PD) Optionale Post-PD- Phase Bevacizumab + Irinotecan Stratifikation nach: KPS: 70 80, 90 100 Erstes, zweites Rezidiv * Bevacizumab: 10 mg/kg alle 2 Wochen ** Irinotecan: EIAED: 340 mg/m 2 i.v. über 90 min Non-EIAED: 125 mg/m 2 i.v. über 90 min Enzyminduzierende Antiepileptika (EIAED) Ein Behandlungszyklus = 6-wöchige Therapiephase Friedman HS et al. J Clin Oncol 2009; University Hospital Munich Großhadern Department of Neurosurgery, Germany
Wirksamkeit Medianes Gesamtüberleben, Monate (95% KI) Bevacizumab (n = 84) 9,2 (8,2 10,7) Bevacizumab + Irinotecan (n = 82) 8,7 (7,8 10,9) PFS, Monate (95% KI) PFS-6, % (97,5% KI) Ansprechrate, % (97,5% KI) CR PR Mediane Ansprechdauer, Monate (95% KI) 4,2 (2,9 5,8) 42,6 (29,6 55,5) 28,2 (18,5 40,3) 1,2 27,1 5,6 (3,0 5,75) 5,6 (4,4 6,2) 50,3 (36,8 63,9) 37,8 (26,5 50,8) 2,4 35,4 4,4 (4,17 ) Friedman HS et al. J Clin Oncol 2009; University Hospital Munich Großhadern Department of Neurosurgery, Germany
Wirksamkeit Medianes Gesamtüberleben, Monate (95% KI) Bevacizumab (n = 84) 9,2 (8,2 10,7) Bevacizumab + Irinotecan (n = 82) 8,7 (7,8 10,9) PFS, Monate (95% KI) PFS-6, % (97,5% KI) Ansprechrate, % (97,5% KI) CR PR Mediane Ansprechdauer, Monate (95% KI) 4,2 (2,9 5,8) 42,6 (29,6 55,5) 28,2 (18,5 40,3) 1,2 27,1 5,6 (3,0 5,75) 5,6 (4,4 6,2) 50,3 (36,8 63,9) 37,8 (26,5 50,8) 2,4 35,4 4,4 (4,17 ) Friedman HS et al. J Clin Oncol 2009; University Hospital Munich Großhadern Department of Neurosurgery, Germany
Wirksamkeit Medianes Gesamtüberleben, Monate (95% KI) Bevacizumab (n = 84) 9,2 (8,2 10,7) Bevacizumab + Irinotecan (n = 82) 8,7 (7,8 10,9) PFS, Monate (95% KI) PFS-6, % (97,5% KI) Ansprechrate, % (97,5% KI) CR PR Mediane Ansprechdauer, Monate (95% KI) 4,2 (2,9 5,8) 42,6 (29,6 55,5) 28,2 (18,5 40,3) 1,2 27,1 5,6 (3,0 5,75) 5,6 (4,4 6,2) 50,3 (36,8 63,9) 37,8 (26,5 50,8) 2,4 35,4 4,4 (4,17 ) Friedman HS et al. J Clin Oncol 2009; University Hospital Munich Großhadern Department of Neurosurgery, Germany
University Hospital Munich Großhadern Department of Neurosurgery, Germany
University Hospital Munich Großhadern Department of Neurosurgery, Germany
AVAGLIO A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of Bevacizumab, Radiotherapy and Temozolomide (TMZ) Followed by Bevacizumab and TMZ, Versus Placebo Radiotherapy and TMZ Followed by Placebo and TMZ on Survival in Patients With Newly Diagnosed Glioblastoma University Hospital Munich Großhadern Department of Neurosurgery, Germany
University Hospital Munich Großhadern Department of Neurosurgery, Germany