CLINICAL STUDIES WITH ANTIANGIOGENIC STRATEGIES FOR MALIGNANT GLIOMA

Transcription

1 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

2 Integrin structure and signalling Harburger DS & Calderwood DA, J Cell Sci 2009;122: Askari JA, et al. J Cell Sci 2009;122:

3 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:

4 Statistical analysis of α v β 3 expression Positive detected tissue Mean staining intensity Overall tumor tissue * mild * moderate strong * Positive tissue in analyzed area (%) Staining intensity in relation to M21 (%) 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 * moderate strong * Staining intensity in relation to M21 (%) GBM LGG GBM LGG *p<0.05; Student's t test Schnell O, et al. Brain Pathol 2008;18:

5 [ 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

6 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 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: ; 2. Nisato RE, et al. Angiogenesis 2003;6: ; 3. Xiong JP, et al. Science 2002;296: ; 4. Friedlander M, et al. Science 1995;270: ; 5. Hammes HP, et al. Nat Med 1996;2: ; 6. Loges S, et al. Biochem Biophys Res Commun 2007;357: ; 7. Albert JM, et al. Int J Radiat Oncol Biol Phys 2006;65: ; 8. Taga T, et al. Int J Cancer 2002;98: ; 9. Tentori L, et al. Oncol Rep 2008;19: ; 10. Lode HN, et al. Proc Natl Acad Sci USA 1999;96:

7 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

8 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

9 Single agent: Partial response lasting >18 months August 2005 April 2007 Reardon D, et al. J Clin Oncol 2008;26:

10 EMD Phase I/IIa trial of cilengitide and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy, in patients with newly diagnosed glioblastoma

11 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 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 (updated information presented)

12

13

14

15 Cilengitide vs historical controls: Overall survival 1.00 Survival X X X Lausanne pilot X EORTC Cilengitide X 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

16 Cilengitide vs historical controls: Overall survival and MGMT MGMT gene-promoter status: Unmethylated Methylated X EORTC Lausanne pilot Cilengitide X X X Survival X X Survival X X 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:

17 Cilengitide vs historical controls: Overall survival and MGMT MGMT gene-promoter status: Unmethylated Methylated X EORTC Lausanne pilot Cilengitide X X X Survival X X Survival X X 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:

18 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

19 Adapted from Bergers, et al. Nature 2002 University Hospital Munich Großhadern Department of Neurosurgery, Germany

20 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

21 Normale Blutgefäße Abnormale, chaotische Blutgefäße Normalisierte Durchblutung 1. Sturk, Dumont. In: Basic Science of Oncology 2005 ; 2. Gerber, Ferrara. Cancer Res 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

22 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

23 Recurrent GBM Response to Bevazizumab + PC-Chemotherapy

27 Recurrent GBM Response to Bevazizumab + PC-Chemotherapy mismatch MRI / FET-PET

28

29

30 University Hospital Munich Großhadern Department of Neurosurgery, Germany

31 Überblick zur klinischen Wirksamkeit von Bevacizumab bei rezidiviertem Glioblastom Therapie Autor n Bevacizumab oder Bevacizumab + Irinotecan Ansprechrate (%) PFS-6 (%) Medianes Gesamtüberleben (Monate) Friedman ,2 / 37,8 42,6 / 50,3 9,2 / 8,7 Bevacizumab + Irinotecan Vredenburgh Bevacizumab, bei erneuter PD Bevacizumab + Irinotecan Bevacizumab + Irinotecan (retrospektiv) Bevacizumab + Irinotecan (retrospektiv) Bevacizumab + Irinotecan (retrospektiv) Kreisl ,5 Poulsen Norden n.a Zuniga 37 n.a ,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: Kreisl TN et al. J Clin Oncol 2009;27(5): Poulsen HS et al. Acta Oncol 2009;48: Norden AD et al. Neurology 2008;70(10): Zuniga RM et al. J Neurooncolog 2009;91(3): University Hospital Munich Großhadern Department of Neurosurgery, Germany

32 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 (n = 92) CCNU Van den Bent et al (n = 56) Retrospektive Studien BCNU oder TMZ Happold et al (n = 32) ACNU ±VM26/AraC Perry et al (n = 35) TMZ 28/ Wick et al (n = 47) TMZ Diverse Wick et al. J Clin Oncol 2009; in press. Van den Bent et al. J Clin Oncol 2009; 27: Happold C et al. J Neurooncol 2009; 92: Perry et al. Cancer 2008; 113: Wick et al. J Neurol 2009; 256: University Hospital Munich Großhadern Department of Neurosurgery, Germany

34 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, 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

35 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

40 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