Antiangiogenic drugs in unresectable glioblastoma Dra. Carmen Balañá. /
Outcome for unresectable GBM Overall survival for unresectable GBM without further treatment is: 3 months at most. Radiotherapy increases OS to 6.6 months. Radiotherapy and temozolomide increases survival for patients with KPS 70% to 9.4months. Median survival for recurrent GBM treated with second line therapy is 7-9.5 months. Median survival for patients with only a biopsy is then similar to those GBM treated at recurrence. Prestwitch RJ 2005, Hart MG, et al. Cochrane Database Syst Rev. 2005; Stupp R, 2005-.; Laws ER 2003; Mirimanoff RO 2006; Lacroix M, 2001, Wick 2012, Malström 2012
Patients with biopsy only included in clinical trials Trial Phase N (total) Only biospy % Standard EORTC 2005. (Stupp) III 573 16 NABTT (historical) RT+No TMZ III 217 12 Talampanel +/-standard (Grossman ) II 132 23 RTOG histórical II-III severa NABTT+TMZ+ new agent II-III several 244 23 III 921 11.2 AVAGLIO 17
Incidence of only biopsy pts in the clinical setting Author/country N Source Period Biopsy Partial resection Complete resection Bauchet/France 952 French Brain Tumor DataBase 2004-2006 43.9 24.2 31.7 Scoccianti/italy* 1059 18 RDT UNIT 2002-2007 11.6% 41 45.8 Graus/Spain 833 Neurologist 2008-2010 33.6 28.5 37.4 Chang/USA 418 Glioma outcomes project 1997-2000 21.1 78.9 % resection first or second surgery *only patients who are sent for treatment, underestimation of patients who are even not biopsied 78.5% craneotomies
Biopsy patients and standard treatment No previous decompressive effect of surgery Clinically unstable: big tumours /eloquent areas/multifocality Large radiotherapy fields for big tumours Difficulty in completing treament Edema/pseudoprogression on eloquent areas Corticoid dependence Cushing QoL of a pal.liative treatment?. Balana 2007, Nieder 2005
Pre-radiation treatment/ Neo-adjuvant therapy? Objective: To obtain an objective response ( tumour burden) Improve or stabilize the patient-- better tolerance to radiation therapy Test of Therapeutic Efficaccy: Fewer confusion factors in interpreting MRI (no pseudoprogression) Better setting to apply RANO criteria Test of bioavailibity if administered previous to surgery (tipifarnib/imatinib) Does radiotherapy delay worsens survival? Yes (resected patients). Valduvieco, Irwin No: (experience of the Old NABTT CNS Consortium who rejected the activity of 4 agents (Taxol, 9-AC, CI-980, PZA, and oxaliplatin) with only 149 patients exposed), Class A studies. ASCO 2002 if 6 weeks RTOG 2855p. Blumenthal 2009. Hochberg et al., 2000, Fetell et al 1997, Balana et al 2014, Lustig 2008 et al, Razis et al 2009.
Pre-radiation treatments before 2005 No TMZ
Pre-radiation treatments before 2005 TMZ
TMZ alone upfront Autor Study Nº TRAT RT + TMZ % RT RESP OS m 1y S % Chinot 2007 Single Inst Phase II 29 TMZ 150mg/m2 /15d & TMZ x 4 post RT NO 76% / 55% 24% PR 6.1 28 Brada 2005 Multicente Phase II 139 TMZ 200MG/m 2: 1-5/28 X2 NO?? 20% PR+MR 9 37
Neo-adjuvant treatment has never been compared to standard treatment in a randomized study
Unresectable GBM: neo-adjuvant treatment vs standard treatment. Retrospective study Cohort 1: 2003-2005 23p CDDP+TMZ x 2 cycles Cohort 2: 2006-2010 23p STUPP REGIMEN RDT or STUPP REGIMEN Capdevila et al. 2014 J Neuro-oncology
Patient Characteristics Age < 50 50 Histology Anaplastic Ast Glioblastoma PS 0-1 2 Barthel index >70 70 Neurological impairment No Yes Dexamethasone No Yes Convulsions No Yes Second-line bev No Yes MGMT Unmethylated Methylated Neoadjuvant Cohort N (%) 3 (13.0) 20 (87.0) 5 (21.7) 18 (78.3) 15 (65.2) 8 (34.8) 15 (65.2) 8 (34.8) 6 (26.1) 17 (73.9) 1 (4.3) 22 (95.7) 13 (56.5) 10 (43.5) 19 (82.6) 4 (17.4) 12 (54.5) 10 (45.5) Adjuvant Cohort N (%) 2 (8.7) 21 (91.3) 7 (30.4) 16 (69.6) 14 (60.9) 9 (39.1) 18 (78.3) 5 (21.7) 11 (47.8) 12 (52.2) 3 (13.0) 20 (87.0) 17 (73.9) 6 (26.1) 15 (65.2) 8 (34.8) 14 (70.0) 7 (30.0) P 0.64 0.50 11/12 AA were IDH1 wild type 0.76 0.33 0.13 0.30 0.22 0.18 0.35 Capdevila et al. 2014 J Neuro-oncology
Results retrospective study PFS OS P=0.9 1 YEAR SURVIVAL 38.5% Cohort 1 and 45% Cohort 2 P=0.9
Fig. 2: Progression-free survival according to MGMT methylation status Cohort 1: Neo-Adj A Cohort 2: Stupp B MGMT MGMT - MGMT + MGMT + P=0.09 P=0.04 Un-Methylated pts don t get benefit of a Neoadjuvant TMZ based treatment
Achievements of Neo-adjuvant trials No randomized/prospective trials comparing neoadjuvant versus standard. Al least 6 agents have been rejected for further study in neo-adjuvant trials. (Taxol, 9AC, CI-980, PZA, oxaliplatin, sunitinib) The availability and pharmacokinetics of some agents have been studied administering them before surgery: tipifarnib, imatinib Hochberg et al., 2000, Fetell et al 1997, Balana et al 2014, Lustig 2008 et al, Razis et al 2009.
HOW TO REJECT AND AGENT FOR FURTHER STUDY WITH ONLY 12 PATIENTS
Statistical assumptions Main objective: to determine activity in inducing tumor response, in accordance with the RANO criteria. The Simon 2-phase design was used, with an alpha error of 0.05 and a beta error of 0.10. Based on responses achieved in previous studies, in which the treatment was considered inactive if the response rate obtained was <10%, and with a maximum calculated objective response of 40%. the initial number of patients planned for recruitment in the first phase was 12. If one response was observed in the first 12 patients, the sample size was to be increased by 20 patients in the second phase (a total of 32 patients). The treatment would be considered effective if a minimum of four responses were observed.
GENOM-008: Sunitinib NA
OS /PFS sunitinb before standard treatment
Bevacizumab induces fast responses Neo-adjuvant trials with Bevacizumab
41 GBM 4 cycles: TMZ 200mg/m2/dx5/28+BEV 10MG/Kg/15d. if no progression keep on If progression standard treatment Responses 10 (24,4%) PR 28 (68,3%) SD 1 (2,4%) P OS median 11,7m 12m survival 48,8%
BEV &IRI vs BEV& TMZ BEV+IRI x 8 weeks RDT +BEV+IRI BEV+IRI x 8 weeks 32p R BEV+TMZx 8 weeks RDT +BEV+TMZ BEV+TMZx 8 weeks 31p No unresectable patients Primary endpoint : objective Response after 8 weeks BEV+ IRI: ORR 32%; CI 95%: 17-51%, PFS: 7.7m better than BEV+IRI : ORR 23%; CI 95%: 9-44%, PFS: 7.3m Holland 2014
TEMAVIR TRIAL (ANOCEF) 120p 2009-2011 No central review of images/ histology
TEMAVIR results Pre-defined main objective a PFS6m of 66% in the experimental arm (37/60 p without progression at 6 months, only 30/60 were without progression- negative study
TEMAVIR Toxicity GIII-V
GENOM 009
GENOM 009 GBM Biopsy of minimal Surgery PS 0-2 TMZ 85 mg/m2/21d/ 28d, 2 cycles RT 60 Gy / 2 Gy / 6 w TMZ 75 mg/m2/d TMZ 150-200 mg/m2 d1-d5 q 28d, 6 cycles RT 60 Gy / 2 Gy / 6 w TMZ 75 mg/m2/d Bev 10 mg/kg q2w TMZ 150-200 mg/m2 d1-d5 q 28d, 6 cycles (N=45) R 4w rest (N=48 TMZ 85 mg/m2/21d q 28d Bev 10 mg/kg /2w 2 cycles w9 MRI RANO Central pathology review Tissue MGMT (tmgmt) Serum MGMT (smgmt) Neoadjuvant phase w21 Concomitant phase w25 Adjuvant phase
Methods Endpoints: Primary: ORR (RANO) after 2 pre-rt cycles powered to detect a 30% difference between arms (α and β errors of 0.05 and 0.20). Secondary: 1. Toxicity 2. % neurological deterioration before RT 3. PFS 4. OS 5. 1y OS 6. MGMT Serum vs Tissue as predictive biomarkers CENTRAL RADIOLOGICAL REVIEW-CENTRAL PATHOLOGY REVIEW
102 patients registered 2 GBM not confirmed 1 hemorrhage on MRI 51 allocated to TMZ arm 3 withdrawal Centralized Randomization (1: 1) IC 2 P before inclusion 1 did not meet inclusion criteria 48 started BEV & TMZ 3 progression 37 completed 2 8 toxicity c 45 started TMZ 30 received 2 c 9 progression 5 toxicity 1 refusal TMZ /RDT per protocol 22 (48.9%) Adjuvant TMZ completed 6 c: 6.7% completed 3 c: 15.6% 48 allocated to BEV arm Other treatment off-protocol 12 (26.7%) Palliative Care 5 (10.4%) 2 (4.4%) RDT 1 (2.1%) 8 (17.8%) RDT&TMZ 6 (12.5%) 1 *(2.2%) Other 4 (8.3%) *MORE THAN 1 TREATMENT BEV & TMZ & RDT per protocol 32 (66.7%) Adjuvant TMZ completed 6 c: 10.4% completed 3 c: 20.8%
Patient characteristics Characteristic TMZ Arm (n) BEV Arm (n) p Age median±range <50 50 62±9.5 4 41 62.9±7.4 1 47 0.73 Gender (M/F) 25/20 31/17 0.37 ECOG PS 0 1 2 0.19 0.819 9 20 16 12 23 13 0.07 MMS <27 27 23 22 16 32 Neurological deficit 27 27 0.71 0.21 Surgery Biopsy Craneotomy 35 10 42 6 DXM at inclusion (yes) 34 39 0.26 37.5% 56.3% 0.16 MGMT analyzed in tissue
HUGTIP Pathology Service Tissue revision & t MGMT Molecular Lab smgmt
Response Criteria by RANO/ centralized response revision CR PR SD PROGRESSION 0 50% >50% <25 % 25 % * =, =, =, =, * NEW LESIONS 0 0 0 0. +* DXM 0 =, =, =, * =, =, =, =, * T1-GD T2/FLAIR NEURO STATUS ALL ASCO 2009 ALL ALL ANY*
303 MRI 221.689 images revised
Algorithm for central radiological review A Worsening of neurological status Disease progression Increase of dexametasone dose P by MRI with clinics and DXM stable B All responses (SD/PR/CR) by MRI CENTRALIZED RANO RESPONSE C D MRI revision mandatory Any change PI communication: revise and accept or no accept Eventual change of response and also data of progression Search the real data of progression
MRI review Review OK 72 No MRI to review (neurological deterioration or toxicity) 14 (15.1%) MRI sub-optimal 7 (7.5%) 20 discussed with the IP 17 IP accept review 1 IP didn t accept the review 2 no answer
Change of MRI response criteria MRI CENTRALIZED ASSESSMENT RMN IP CHANGE OF RESPONSE % CHANGE RESPONSE NO CHANGE % NO CHANGE RP 6 (to SD) 8.3 8 11.1 SD 7 (to PR) 4 (to P) 15.3 14 19.4 P 7 (to SD) 9.7 26 36.1 % CHANGE 33.3 OVER CASES WITH MRI EVALUABLE: 72 66.7
FINAL RANO criteria change CHANGE % CHANGE = %= RP 6 to SD 6.4 8 8.6 EE 7 to PR 4 to P 11.8 14 15.0 P 3 to SD 3.2% 44 47.3 % CHANGES 21.5% CHANGE 70.9% NO CHANGE OVER ALL PATIENTS INCLUDED IN THE TRIAL=93
Response by IP or centralized: final results By IP (evaluable) TMZ Arm N (%) BEV Arm N (%) CR - - PR 3 (7.0) 11 (25.0) SD 8 (18.6) 18 (40.9) PR & SD 11 (25.5) 29 (65.9) PD 32 (74.4) 15 (34,1) NE* 2 4 Centralized (evaluable) p TMZ Arm N (%) (95%CI) BEV Arm N (%) (95%CI) - - 4 ( 9.3) 0.001 p 11 (25.6) 6 (14.0) 17 (39.5) 10 (23.3) 28 (65.1) 33 (76.7) 15 (34.9) 2 5 0.000
SLP by IP and centralized -BEV Arm -TMZ Arm ARM BY IP TMZ 2.2 BEV 4.8 CENTRALIZED P=0.09 HR 95% CI 0.70 (0.46-1.07) 2.2 4.8 P=0.05 HR 95% CI 0.66 (0.431.01)
Overall survival -BEV Arm -TMZ Arm Arm mos 95%CI TMZ 7.7 (5.4-10) P 10.6 (6.9-14.3) 1 y Suv 33% 0.068 BEV HR; 95% CI 0.78 (0.44-1.04) 48%
Results by MGMT status - MET - UnMET MGMT STATUS NOT METHYLATED METHYLATED PFS (mo) 2.2 (2.0-2.4) 5.7 (4.9-6.5) HR (95% CI) 0.31 (0.18-0.55) P OS (mo) 5.3 (3.2-7.4) 0.000 13.3 (11.2-15.3) HR (95% CI) P 0.40 (0.24-0.68) 0.001
Conclusions A signal of higher efficacy is seen with the addition of Bevacizumab in this randomized neo-adjuvant trial. More responses and almost a significant tendency to better PFS and OS for patients treated with bevacizumab. Results seem to be reproduced in the BELOP trial with recurrent patients. Neo-adjuvant trials can be useful to identify signs of activity of new agents. Unmethylated patients should not be treated with neo-adjuvant therapy based on TMZ