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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


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


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


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


• 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


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


AVAIL: Cis/Gem +/- Avastin

ESMO update: 7.5mg 15mgplacebo

median survival 13.4m 13.6m

13.1m

PROGRESSION FREE SURVIVAL


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



Phase III trial of Avastin plus GC in NSCLC (AVAiL): Severe adverse events of special interest

*Includes arterial thromboembolic events


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


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)


(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)



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%


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?

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