Methods

• Patients: Unresectable GBM PS 0-2, MMS≥25• Centralized radiological Review RANO criteria• Centralized pathological Review: MGMT tissue &

MGMT serum• RT planning using post neoadjuvant MRI with GD T1

and FLAIR sequences• Endpoints:

– Primary: Overall Response Rate 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.Toxicity2.Percentage of neurological deterioration

before RT3.Progression free survival and Overall survival4.Quality of Life differences5.MGMT Serum vs Tissue to predict results

Salvador Villà et alAbst 1015

COI

• The project was funded by the Spanish Ministery of Science and Innovation: Projects on non-commercial investigation of human medications, Instituto de Salud Carlos III (ISCIII). Project EC08/00071

• ROCHE provided support for data collection• MSD provided pre-radiotherapy temozolomide

and funds for MGMT assessment• S. Villà: advisory boards, ROCHE

103 GBM patients registered

Centralized Randomization (1:1)

51 allocated to TMZ arm 48 allocated to BEV arm

45 started TMZ

48 started BEV & TMZ

TMZ /RDT per protocol 22 (48.9%)

BEV & TMZ & RDT per protocol 32 (66.7%)

Adjuvant TMZ completed 6 c: 6.7% completed ≥3 c: 15.6%

Adjuvant TMZ completed 6 c: 10.4% completed ≥3 c: 20.8%

3 withdrawal IC2 P before inclusion1 did not meet inclusion criteria

2 GBM not confirmed1 hemorrhage on MRI1 refusal

30 received 2 c37 completed 2 c9 progression

5 toxicity1 refusal

3 progression8 toxicity

Other treatment off-protocol12

(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 one treatment

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BEV-related Toxicity in Neoadjuvant Phase

TMZ arm BEV arm

All grade

s

Grade 3 & 4

Grade 5

All grade

s

Grade 3 & 4

Grade 53

patients

HTA - - - 8.4 4.2 -

Hemorrhage 2.2 - - 10.4 2.1 -

CNS hemorrhage

- - - 8.4 2.1 4.2

Arterial thrombosis

2.2 2.2 - - - -

Venous thrombosis

6.6 2.4 - 4.2 4.2 -

Digestive perforation

- - - 4.2 2.1 2.1To be added 2 patients more died in arm TMZ+BEV because diarrhea and pancytopenia

Salvador Villà et al Abst 1015

Endpoint resultsEndpoint TMZ Arm BEV Arm p

Neurological deterioration before RDT

22 (48.9%) 10 (20.8%) 0.004

Patients with 2 cycles pre-RDT 30 (66%) 37 (77%) 0.18

Patients who received full pre-specified protocol (RDT&TMZ)

22 (48.9%) 32 (66.7%) 0.08

Response PR+SD RANO 11 (26.1) 28 (65.1) 0.001

PFS (m, 95% CI) 2.2 (2.1-2.5) 4.8 (3.6-6.1) HR:0.79 (0.52-1.2) p=0.28

OS (m, 95% CI) 7.7 (5.7-14.5) 10.8 (7-14.5) HR:0.71 (0.46-

1.10) p=0.12

1 year survival 29.6 % 48.9% p=0.06PFS all pts: 2.8 m (95% CI, 0.9-4.7) OS all pts: 9.1 m (95% CI, 6.8-11-3)Salvador Villà et al

Abst 1015

PFS and OS by MGMT status

MGMT STATUS PFS (mo) HR (95%

CI) P OS (mo) HR (95% CI) P

NOT METHYLATED

2.3 (2.0-2.5) 0.49

(0.28-0.87)

0.014.5 (2.3-6.7)

0.36 (0.19-0.67) 0.001

METHYLATED 4.7 (4.1-5.2)

12.2 (8.7-15.6)

PFSOS

Conclusions

• Addition of BEV significantly improved ORR (primary endpoint):– PR in 7.1% of p in the TMZ Arm vs 25.6% in the BEV Arm

(p=0.001)– clinical benefit (PR + SD) in 26.1% vs 65%

• Addition of BEV also improved other measures of benefit:– Less pre-radiotherapy neurological deterioration (38.9% vs.

20.8%; p=0.004)– Higher rate of completion of pre-specified protocol (58.9% vs.

66.7%; p=0.08)• No significant differences in PFS, OS and 1-y survival were

observed• Neoadjuvant with TMZ alone is not advisable• More toxicity in the BEV Arm • MGMT methylation was associated with longer PFS and

OS

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