1. www.OncologyEducation.ca 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

2. www.OncologyEducation.ca 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

3. www.OncologyEducation.ca RANDOMISERANDOMISE *Stratification factors: disease stage, ECOG PS, region, gender PD Avastin 2 2 1 1 Placebo 7.5 + CG Avastin 15mg/kg + CG Avastin 7.5mg/kg + CG Placebo 15 + CG Previously untreated, stage IIIb, IV or recurrent non- squamous NSCLC* R A N D O MI S E 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

4. www.OncologyEducation.ca 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

5. www.OncologyEducation.ca GC 347 GC + 7.5mg 345 GC + 15mg 351 RR20%34%30% MDR4.76.1 PFS (mo)6.26.86.6 OS (mo)13.113.6 (HR=.91)13.4 (HR=1.03) 2 nd -line Rx65%61% - TKI41%48%42% - CT73%65%69% Gemcitabine + Cisplatin +/- Bevacizumab as 1 st -line Treatment of Advanced NSCLC: AVAiL Study Manegold PASCO 25:#7514, 2007/Ann Oncol 19:LBA1, 2008

6. www.OncologyEducation.ca AVAIL: Cis/Gem +/- Avastin ESMO update: 7.5mg15mgplacebo median survival 13.4m13.6m13.1m PROGRESSION FREE SURVIVAL

7. www.OncologyEducation.ca 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 7576 81 Serious adverse event 35 44 Adverse events leading to death445 Manegold, et al. ASCO 2007

8. www.OncologyEducation.ca 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) (%) Bleeding244 Hypertension269 Proteinuria– 0.31 GI perforation 0.6– 0.3 Ischaemic events*523 Venous thromboembolic events 677

9. www.OncologyEducation.ca 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) Avastin 7.5mg/kg + CG (n=330) Avastin 15mg/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 pulmonary haemorrhage 1 (0.3) 4 (1.2) 3 (0.9) Manegold, et al. ASCO 2007

10. www.OncologyEducation.ca ECOG 4599 vs AVAiL E4599 (15) 424 AVAiL (7.5) 345 A-GC 347 E-TCb 431 RR35%34%20%15% PFS6.26.86.14.5 MST12.313.613.110.3 1 yr S51.9%--43.7%

11. www.OncologyEducation.ca 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 1 st line Rx with chemotherapy for selected pts with advanced NSCLC?  If so with which regimen?  And if so what dose – 7.5 vs 15?