Glioblastoma is a highly angiogenetic malignancy.

Transcription

1 Glioblastoma is a highly angiogenetic malignancy silvia.hofer@usz.ch

2 for glioma cells to expand further there are two possibilities..

3 .. lining up blood vessels (co-option, diffusion)

4 cross section

5 .... forming new capillaries from preexisting vessels + forming new endothelial cells from cancer stem cells* angiogenic switch = hallmark of Glioblastoma VEGF vascular endothelial growth factor, proangiogenic cytokine *Ricci Nature 2010 Wang Nature 2010

6 2007 WHO grading of astrocytic gliomas extensive network of abnormal vasculature Diffuse astrocytoma WHO grade II Anaplastic astrocytoma, OA WHO grade III (6-10%) Glioblastoma WHO grade IV Cellularity: Pleomorphism: Nuclear atypia: Mitotic activity: Vascular proliferation: Necrosis: low/moderate low/moderate moderate low absent absent high moderate/marked marked high absent absent high marked marked high present present Molecular lesions TP53 mutations EGFR ampl. + mut. PTEN mutations

7 Glioblastoma Angiogenic (tumor rim) phenotype Invasive (white matter tracks and blood vessels)

8 Glioblastoma Angiogenic (tumor rim) phenotype Invasive (white inert matter to antiangiogenic tracks and blood vessels) tx

9 invasive component Ratio tumor cells/ normal cells

10 Rationale Angiogenesis-Inhibitors

11 Rationale Angiogenesis-Inhibitors vascularity of GBM (abnormal phenotype, leaky vessels with poor quality)

12 Rationale Angiogenesis-Inhibitors VEGF-A highly expressed in GBM perinecrotic hypoxic tumor cells mostly at tumor periphery upregulated in response to RT mediates resistance to RT VEGF AB in cytoplasm VEGF (permeability factor) causes vasodilatation, partly through stimulation of nitric oxide synthase in endothelial cells. VEGF can also stimulate cell migration and inhibit apop

13 Wang Nature 2010 Ricci Nature 2010 Rationale Angiogenesis-Inhibitors Glioma stem cells produce VEGF

14 20-90% of endothelial cells in GBM carry same genomc alteration as tumor cells, deriving from glioma stem cells Wang Nature 2010 Ricci Nature 2010 Self Supply! Stem-cell like CD133 (+) cells are multipotent tumor lineage endothelial progenitors tumor derived endothelium NOTCH 1st signal VEGF 2nd signal

15 Topics clinically used drugs Cilengitide Bevacizumab Cediranib Dasatinib (Merck) (Roche) (AZ) (BMS) ongoing trials Neuroimaging: new criteria 2010 and beyond Pattern of recurrence

16 not to be discussed today too toxic, not effective or in evaluation Thalidomid Lenalidomid Imatinib Enzastaurin Sorafenib Sunitinib Aflibercept XL 184 Vatalanib Vandetanib ABT-510 others (Celgene) (Celgene) (Novartis) (Eli Lilly) (Bayer) (Pfizer) (VEGF Trap) (multi TKI)

17 Bevacizumab extracellular matrix + Cilengitide endothelial+ GBM cells influence gene expression of MMP, VEGF, TGF beta cell membrane Cediranib Dasatinib intracellular nucleus Survival, Invasion, Proliferation, Angiogenesis, Anti-Apoptosis Wen NEJM 2008

18 Substances Cilengitide Bevacizumab Cediranib Dasatinib

19 Cilengitide synthetic peptide selectively inhibits α+β subunits of integrins on GBM and vessels - αvβ 3+5 specific for tumor angiogenesis binds to transmebrane receptor and induces detachement anti-angiogenic anti-invasiv GBM αvβ3/β5 C 27 H 40 N 8 O 7 molar mass g mol 1 migration attachment formation of vessels EMA: orphan drug status ACTIVATION

20 Cilengitide 2000mg 2x/week i.v. continuously safety profile: favourable over years Integrin inhibitor Phase II, n= 81 recurrent GBM (single agent) med. OS 9.9 months Phase I/II n= 52 newly diagnosed GBM add on approach : C + standard (RT/TMZ+TMZ ) PFS6 (1 end point) 69% med. OS 16.1 months (salvage treatment?*) med. OS 22.3 months in MGMT methylated tumors Reardon JCO 2008 Fink ASCO 10 (54 m FU) transmemembrane receptor cell-matrix cell-cell interactions Stupp, JCO 2010 Phase III (CENTRIC) n=504 (150 centers) newly diagnosed GBM, methylated (35%) C + RT/TMZ+TMZ vs RT/TMZ+TMZ recruting Phase II (CORE) n= 240 (85 centers), newly diagnosed, non methylated - C 2000mg 2x /week + standard vs - C 2000mg 5x/week + standard vs control recruting *Stupp 2005 standard tx: med OS 14.6

21 FLAIR: fluid attenuated inverse recovery Fink ASCO 10 (54 m FU) ASCO 1

22 Cilengitide Phase III for GBM (EORTC) Diagnosis central MGMT methylation status assay n = 1440 max 28 days MGMT methyl. 35% R versus Control + Cilengitide TMZ MGMT not methyl. or undetermined 65% Radiotherapy concomitant Phase maintenance Phase 18 months/pd n= 504, 150 centers 2 1/2 years accrual

23 Substances Cilengitide Bevacizumab Cediranib Dasatinib

24 VEGF inhibitor Bevacizumab (Avastin ) FDA and Swissmedic accelerated* approval May 2009 for recurrent GBM (single agent) health insurance (KK) June 2010 for recurrent GBM orphan status for recurrent malignant glioma (2007, Desjardin 2008, Chamberlain 2009 ) NCCN Guidelines BV+/- CT in recurrent high grade glioma *upon surrogate endpoints (RR+ PFS 6)

25 2011 there is no current standard of treatment in recurrent high grade glioma PFS 6 15% OS 5.7 mo Wong JCO 1999

26 Bevacizumab recurrent malignant gliomas: multiple phase II trials population based cohort (n= 225, now 262) no phase III unusual high RR (on conventional MRI criteria!), rapidly achieved (days) reducing edema (leaky vessels) rapid clinical benefit + reduced need for steroids PFS ~ 4 months PFS6 ~ 30% Treatment duration median ~ 5.5 months, 19% > 1 year OS ~ 9 months (no Phase III trials) Any true antitumor effect?? difficult to interpret clinically meaningful

27 Bevacizumab recurrent malignant gliomas: multiple phase II trials population based cohort (n= 225) no phase III unusual high RR (conventional MRI criteria!), rapidly achieved (days) reducing edema rapid clinical benefit reduced need for steroids PFS ~ 4 months PFS6 ~ 30% Treatment duration median ~ 5.5 months, 19% > 1 year OS ~ 9 months (no Phase III trials) Any true antitumor effect??

28 Bevacizumab recurrent malignant gliomas: multiple phase II trials population based cohort (n= 225) no phase III unusual high RR (on conventional MRI criteria!), rapidly achieved (days) reducing edema rapid clinical benefit reduced need for steroids PFS ~ 4 months PFS6 ~ 30% (7-64%) Treatment duration median ~ 5.5 months, 19% > 1 year OS ~ 9 months Any true antitumor effect?? Side effects as expected (brain hemorrhage 2%)

29 Bevacizumab recurrent malignant gliomas: multiple Phase II trials population based cohort (n= 225) no Phase III unusual high RR (up to 60%!), rapidly achieved (days) reducing edema rapid clinical benefit reduced need for steroids PFS ~ 4 months PFS6 ~ 30% (7-64%) Treatment duration median ~ 5.5 months, 19% > 1 year OS ~ 9 months Any true antitumor effect?? Side effects as expected (brain hemorrhage 2%, wound healing 1-2%) difficult to interpret clinically meaningful

30 T1gd T2 prior to BEV 3d post BEV 21d post BEV (size!) 88d 188d= ½ year

31 Response criteria in Glioma Macdonald 1990 RANO 2010 Future dimensional CR no steroids, neurologically stable endpoints PR CR T2 stable or improved PR steroids stable SD PD radiologically or neurologically worse 2011 RECIST still a dilemma T2 stable or improved SD steroids stable PD T2 increase FET PET /DCE/ ADC/spectroscopy k_trans (microvacular permeability) Blood brain barrier disruption RECIST response evaluation in solid tumors: measurable + non measurable lesions, target + non-target lesions

32 Response criteria in Glioma Macdonald 1990 CR PR SD PD no steroids, neurologically stable steroids stable radiologically or neurologically worse RANO 2010 Future 2011 RECIST CR T2 stable or improved PR T2 stable or improved SD steroids stable PD T2 increase FET PET /DCE/ ADC/spectroscopy k_trans (microvacular permeability) Blood brain barrier 2 disruption dimensional T1gd-MRI RECIST response evaluation in solid tumors: measurable + non measurable lesions, target + non-target lesions

33 T1gd 6 week 6 months Bevacizumab FLAIR 6 week 6 months luzernernorden kantonsspital 2008

34 T1gd 6 week Pseudoresponse? 6 months FLAIR 6 week 6 months FLAIR: fluid attenuated inverse recovery luzerner kantonsspital Norden 2008

35 Response criteria in Glioma Macdonald 1990 RANO Criteria dimensional, T1gd CR no steroids, neurologically stable PR steroids stable SD PD radiologically or neurologically worse RECIST CR T2/FLAIR stable or improved PR T2/FLAIR stable or improved SD steroids stable PD T2/FLAIR increase considers FET T1gd PET /DCE/ and T2/FLAIR ADC/spectroscopy discrepancies k_trans (microvacular permeability) Blood brain barrier disruption Wen JCO 2010 luzerner kantonsspital RECIST response evaluation in solid tumors: measurable + non measurable lesions, target + non-target lesions Response Assessment

36 ? FLAIR: fluid attenuated inverse recovery T2/FLAIR

37 FLAIR/ T2- MRI Edema (Post seizure) Gliosis after irradiation Ischemia Demyelination Infiltrating tumor: clinical status mass effect lesion outside the radiation field ADC Molecular movments in extracelluar space Low ADC = high cellular density FLAIR: fluid attenuated inverse recovery ADC apparent diffusion coefficient

38 FLAIR/ T2- MRI Edema Post Seizure Gliosis after radiation Ischemia Demyelination Infiltrating tumor Diffusion (DWI, ADC) Molecular movements in extracelluar space (water mobility in tissue) independend of contrast leakage, edema or bbb ADC: apparent diffusion coefficient (measured diffusion time, mm2/s)

39

40 T1gd FLAIR Diffusion restricted luzerner kantonsspital

41 T1gd Diffusion IHC restricted MIB labeling index 35%

42 Response criteria in Glioma Macdonald 1990 RANO 2010 Biomarker 2011 antivascular effects AVIRMA trial 2 dimensional CR no steroids, neurologically stable PR steroids stable SD inadequat PD RECIST CR T2 stable or improved PR inadequat radiologically or neurologically worse T2 stable or improved SD steroids stable PD T2 increase FET-PET /DCE-MRI / Diffusion (DWI, ADC) MR-spectroscopy k_trans (microvascular permeability, bbb disruption) RECIST: response evaluation in solid tumors: measurable + non measurable lesions, target + non-target lesions

43 shift to angiogenesis independece vascular normalisation restoration of an intact bbb escape mechanisms with invasion and migration along preexisting vessels alternative pro-angiogenic pathways

44 summary BEV in recurrent glioma high probability of rapid clinical benefit (intracranial pressure / ) palliation! transient in nature, median 5.5 months (range 0.5 m to >2 years) Hofer, ESMO 2010 classical radiological endpoints not appropriate

45 BEV mono or combined? 2 phase II trials

46 BRAIN Study non comparative phase II GBM 1 st or 2 nd Bevacizumab (n=85) Cross over PFS % mos 9.3 relapse (n=167) Bevacizumab/CPT11 (n=82) PFS % mos 8.9 median time on treatment 4 resp 5.5 months median duration of response: 5.6 resp 4.3 months Friedman JCO 2009

47 Kreisl Study phase II PD recurrent GBM GBM (pretreated) (n=48) BEV BEV/CPT11 PFS 6 29% med OS 31 weeks, 7 mo PFS 30 days no response Kreisl JCO 2009

48 Irradiation VEGF and EGFR upregulation

49 Irradiation VEGF and EGFR upregulation

50 ongoing trials: BEV upfront GBM synergism to RT Vredenburgh ASCO, SNO 2010 phase II, n=125 med OS 21 mo (vs Stupp 15 mo) wound healing and bleeding 1% Lai JCO 2011 single arm phase II, n= 70 med OS 19.6 mo wound healing 6%, bleeding 3%

51 ongoing trials: BEV upfront GBM synergism to RT AVAGlio n= 920 BEV + RT/CT vs RT/CT RTOG 0825 phase III, stratified for RPA + country results expected 2014 n= 720 BEV + RT/CT vs RT/CT phase III, stratified for molecular profile +MGMT results expected 2014 ARTE RT alone vs RT+ BEV randomised (2:1)phase II, > 65 n= 60

52 Substances Cilengitide (Merck) phase II, ongoing phase III Bevacizumab (Roche) randomised phase II, ongoing phase III Cediranib (AZ) phase II and III Dasatinib (BMS) ongoing random. phase II

53 Cediranib oral 1x/d, half-life 22 h side effects: fatigue (16.4), hypertension (14%) diarrhea (6.3%) Phase II n= 31 - monotherapy C 45mg/d recurrent GBM: promising, RR of 30% PFS6 25.8% Batchelor JCO Phase III (REGAL) n=325 C 30mg/d vs C 20mg/d + CCNU vs CCNU recurrent GBM: PFS + OS: stat. not sign. PFS6 16% for Mono C dose problem? (toxicity with higher doses) Pan-VEGF PDGF c-kit abstr. ESMO, SNO 2010 luzerner kantonsspital

54 days T1gd k_trans (permability) FLAIR Diffusion day 1

55 ongoing trials Cediranib 8030 (IRUS ) PI Tracy Batchelor 75% Enrollment A Phase Ib/II Study of AZD2171 in Combination with Daily TMZ and Radiation in newly diagnosed GBM Not Taking Enzyme-Inducing Anti-Epileptic Drugs ABTC-0903 (IRUS ): PI Gerstner A Phase Ib Study Cediranib in Combination with Cilengitide in recurrent GBM RTOG 0837 (ISSRECE0025): PI Batchelor Randomized, Phase II Double-blind/Placebo-controlled Trial Conventional Chemoradiation and Adjuvant TMZ Plus Cediranib Vs Conventional Chemoradiation and Adjuvant TMZ Plus Placebo in newly diagnosed GBM DORIC (ISSRECE0007): PI Dr Paul Mulholland Phase II study cediranib in combination with gefitinib in recurrent GBM Last update

56 Substances Cilengitide (Merck) Bevacizumab (Roche) Cediranib (AZ) Dasatinib (BMS)

57 non-receptor tyrosine kinases INVASION

58 Dasatinib (Sprycel ) oral 150 mg/d, half-life 1.3-5h, excretion 85% fecal side effects: myelosuppression, pleural effusion (requiring thorcacentesis/pleurodesis) mild to moderate diarrhea, peripheral edema, headache, reversible abnormal liver function tests, mild hypocalcemia, Tc retrospective study in recurrent GBM after BEV, n= 14 after median 4 regimens, PFS6 = 0 Concerns: BBB, P-gP Lu-Emerson J Neurooncol BCR/ABL c-kit Src family (9) PDGFR random. Phase II (EORTC) n=98 D 100 mg BID + CCNU (90mg/m2) vs CCNU (max 6x) 1 line recurrent GBM accrual starts April 2011

59 what exactly have we learned so far from these agents? rapid

60 escape escape mouse Paez-Ribes, modelscancer proinvasiv cell pathways 2009 luzerner kantonsspital

61 Recurrence pattern Concern Ø VEGF blockade enhances invasive phenotype Gliomatosis cerebri like pattern? Wick A et al Bevacizumab does not increase the risk of remote relapse in malignant glioma Ann of Neurology in press

62 Recurrence pattern local distant diffuse Wick A et al Bevacizumab does not increase the risk of remote relapse in malignant glioma Ann of Neurology in press

63 T1gd FLAIR Start End Start End Local Distant Contralateral Diffuse USZ, Heidelberg, Ann Neurology 20

64 Patterns of progression Oh (n= 67) Pope (n=167) BRAIN Norden Iwamoto Silbergeld (n=117) Wick matched pair (n=44) BEV pre pre pre post post post autopsy pre post pre Gruber (n=58) post Chamb erlain (n= 80) local 87% 72 77% 64% 46% 82% 44% X distant 2 1% 18% multifocal 8 8% 16% 13% 17% diffuse 18 18% 18 16% 35% 56% local 18% diffuse

65 Anti- angiogenesis compared to CT in rgbm Phase II trials drug CR + PR (%) median progression-free survival (weeks) Progression-free survival at 6 monts (%) Median OS (weeks) Wong 1999 (n=225) Various Yung 2000 (n=113) TMZ 5/ nd Wick 2007 (n=64) TMZ 7/ Vredenburgh 2007 (n=32) Bev + CPT Friedman 2009 (n= 85+82) Bev +/- CPT Kreisl 2009 (n=48) Bev Bev +CPT Reardon 2008 (n=40) Cilengitide 2000 mg

66 How to asses treatment effects? useful ref clinical assessment MRI + new Markers Dhermain F, Lancet Neurology 2010 normalisation of vessels Φ Fischer I, Neuro-Oncol 2008 VGEF expression levels Φ Salmaggi A J Neuroonocl 2003 Takano S, Cancer Res 1996 Nam DH, Oncol Rep 2004 circulating endothelial? Pantel K, Cell 2010 progenitor cells

67 Conclusions Antiangiogenetic therapy in brain tumor patients often rapidly active in symptomatic patients acceptable safety profile many questions remain open» Is there a true anticancer effect? Escape mechanisms?» Best response assessment in brain tumors ( Biomarker?)» Combinations (chemotherapy, radiation therapy, small molecules)?» Sequence? beyond progression?» Best timepoints for treatment (upfront, at recurrence)?» Predictors, genetic subgroups (GBM mesenchymal type)?» Maintenance? Review: Beal K. BioMed Central 2011

68 Soon..

69 Case presentation O.H preoperative lesion

70

71 what could it be?

72 Pseudoprogression Up to 30% shortly after chemo-irradiation 50% of all increasing lesions Symptoms? Methylation Status? Radiological assessment? Brandsma Lancet Oncology 2008

73 TMZ 7/

74 TMZ 7/7 2 Mte interdisciplinary tumorboard

75 Re Surgery

76 Re-Surgery Histology?

77 radiation induced fibrinoid blood vessels gliotic brain tissue

78 Re Surgery CCNU weeks

79 Re Surgery How to preceed? CCNU weeks

80 Drugs for recurrent GBM, P II Wong, 1999 (n=225) MDA drug Various Kein TMZ! median PFS (weeks) PFS 6 months (%) Median OS (weeks/months) 9 15 % 25 Lamborn, 2008 (n=437) NABTC TMZ other % 9 % Yung, 2000 (n=113) Wick, 2007 (n=64) Brandes, 2004 (n=40) Kappelle, 2001 (n=63) Friedman,1999 (n=60) Schmidt, 2005 (n=86) Vredenburgh 2007 (n=32) + ASCO 08 Kreisl 2009 (n= 48) TMZ 5/ % nd TMZ 7/ % 38 BCNU % 32 PCV % 33 Irinotecan % 24 PCV % 34 Bevacizumab/ Irinotecan % 40/9.2 Bevacizumab % 31

81 Re Operation Bevacizumab symptoms

82 Surgery RT/CT TMZ 5/28 (3) TMZ 7/7 (2 ) Re-Surgery Bevacizumab 1 year 1 year

83 Surgery RT/CT TMZ 5/28 (3) TMZ 7/7 (2 ) Re-Surgery Bevacizumab 1 year 1 year Ť

84