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Gemcitabine + Cisplatin +/- Bevacizumab as 1st-line Treatment of Advanced NSCLC: AVAiL Study
Manegold PASCO 25:#7514, 2007/Ann Oncol 19:LBA1, 2008
Reviewed By: Dr. Ron Burkes
Date posted: December 2008
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BO 17704 (AVAIL): A Phase III Randomised Study of First-line Bevacizumab Combined with Cisplatin/Gemcitabine (CG) in Patients (PTS) with Advanced or Recurrent Non-Squamous, Non-small Cell Lung Cancer
(NSCLC)
Authors: Manegold et al
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RANDOMISE
RANDOMISE
*Stratification factors: disease stage, ECOG PS, region, gender
PDPD
PDPD
PDPD
Avastin
Avastin
2
2
1
1
Placebo 7.5 + CGPlacebo 7.5 + CG
Avastin15mg/kg + CG
Avastin15mg/kg + CG
Avastin7.5mg/kg + CG
Avastin7.5mg/kg + CG
Placebo 15 + CGPlacebo 15 + CG
Previously untreated,
stage IIIb, IV or recurrent non-
squamous NSCLC*
Previously untreated,
stage IIIb, IV or recurrent non-
squamous NSCLC*
RANDOMISE
RANDOMISE
Primary endpoint: progression-free survival Secondary endpoints: overall survival, time to treatment failure,
response rate Excluded patients with tumours invading or abutting major blood vessels
Manegold, et al. ASCO 2007
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• PS 0,1• No uncontrolled hypertension• No squamous pathology• No CNS mets• No previous thromboembolic disease• No NSAIDs• No anticoagulants• No central tumors near or abutting major blood
vessels• No hemoptysis > gr 2
Highly Selected Patients
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GC
347
GC + 7.5mg
345
GC + 15mg
351
RR 20% 34% 30%
MDR 4.7 6.1 6.1
PFS (mo) 6.2 6.8 6.6
OS (mo) 13.1 13.6 (HR=.91) 13.4 (HR=1.03)
2nd-line Rx 65% 61% 61%
- TKI 41% 48% 42%
- CT 73% 65% 69%
Gemcitabine + Cisplatin +/- Bevacizumab as 1st-line Treatment of Advanced NSCLC:
AVAiL StudyManegold PASCO 25:#7514, 2007/Ann Oncol 19:LBA1, 2008
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AVAIL: Cis/Gem +/- Avastin
ESMO update: 7.5mg 15mgplacebo
median survival 13.4m 13.6m
13.1m
PROGRESSION FREE SURVIVAL
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Phase III trial of Avastin plus GC in NSCLC (AVAiL): Safety summary
Event
Placebo
+ CG
(n=327) (%)
Avastin
7.5mg/kg + CG
(n=330) (%)
Avastin
15mg/kg + CG
(n=329) (%)
Any grade 3–5 adverse event
75 76 81
Serious adverse event
35 35 44
Adverse events leading to death 4 4 5
Manegold, et al. ASCO 2007
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Phase III trial of Avastin plus GC in NSCLC (AVAiL): Severe adverse events of special interest
*Includes arterial thromboembolic events
Manegold, et al. ASCO 2007
Grade ≥3 event
Placebo
+ CG
(n=327) (%)
Avastin
7.5mg/kg + CG
(n=330) (%)
Avastin
15mg/kg + CG
(n=329) (%)
Bleeding 2 4 4
Hypertension 2 6 9
Proteinuria – 0.3 1
GI perforation 0.6 – 0.3
Ischaemic events* 5 2 3
Venous thromboembolic events
6 7 7
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Pulmonary Haemorrhage Events
Of note:• 38% of patients in AVAiL had central lesions
4/10 patients with severe pulmonary haemorrhage had central lesions• 9% of patients in AVAiL had therapeutic anticoagulation
– but none of them had a severe pulmonary haemorrhage
Event, n (%)
Placebo+ CG
(n=327)
Avastin7.5mg/kg + CG
(n=330)
Avastin15mg/kg + CG
(n=329)
Pulmonary haemorrhage(all grades) 17 (4.9) 23 (7.0) 32 (9.7)
Pulmonary haemorrhage(grade 3)
2 (0.6) 5 (1.5) 3 (0.9)
Fatal pulmonaryhaemorrhage 1 (0.3)
4 (1.2) 3 (0.9)
Manegold, et al. ASCO 2007
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ECOG 4599 vs AVAiL
E4599 (15)
424
AVAiL (7.5)
345
A-GC
347
E-TCb
431
RR 35% 34% 20% 15%
PFS 6.2 6.8 6.1 4.5
MST 12.3 13.6 13.1 10.3
1 yr S 51.9% - - 43.7%
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Study Commentary
Does this trial confirm ECOG 4599? there is a very modest improvement in PFS BUT no survival benefit!!!
If one uses Taxol/Carboplatin then Bevacizumab appears to be necessary; however with a Cisplatin-based (GC) doublet the incremental benefit of bevacizumab is modest
Should we be using Bevacizumab as 1st line Rx with chemotherapy for selected pts with advanced NSCLC?
If so with which regimen?
And if so what dose – 7.5 vs 15?