ECCO ESMO 2011 GI Cancer Updates “VELOUR” Study Author: J Tabernero et al Reviewed by: Dr. Scott Berry Date posted: October 27, 2011

Results from VELOUR, a Phase 3 Study Of Aflibercept Versus Placebo In Combination With FOLFIRI For The Treatment Of Patients With Previously Treated Metastatic Colorectal Cancer Results from Prespecified Subgroup Analyses Presenter: J Tabernero (Vall d’Hebron University Hospital / Barcelona/ Spain)

Background Aflibercept Soluble fusion protein Consists of portion of extracellular domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion Binds all VEGF-A isoforms, VEGF-B and PlGF VELOUR study clinical results presented at World GI – this review summarizes that clinical data and the subgroup analyses presented at ESMO

Part 1: Clinical Study Results

Aflibercept 4 mg/kg IV, day 1 + Study Design N=1200 Primary Outcome:OS Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks R FOLFIRI q2 weeks Patient mCRC Previous Oxaliplatin Based Tx

RESULTS 11.1 19.8 4.67 6.90 12.06 13.5 HR=0.82 Response Rate (%) FOLFIRI FOLFIRI+ AFLIBERCEPT p-value Response Rate (%) 11.1 19.8 P= 0.0001 PFS/TTP (median, mos) 4.67 6.90 P=0.00007 OS (median, mos) 12.06 13.5 HR=0.82 P=0.0032

GR 3/4 TOXICITY FOLFIRI % FOLFIRI+ AFLIBERCEPT Diarrhea 7.8 19.3 Neutropenia 29.5 36.7 Complicated 2.8 5.7 Stomatitis 5.0 13.7 Infections 6.9 12.3 Hand Foot Syndrome 0.5 Dehydration 1.3 4.3

GR 3/4 TOXICITY FOLFIRI % FOLFIRI+ AFLIBERCEPT Proteinuria* 1.2 7.9 Hypertension 1.5 19.3 Haemorrhage 1.7 2.9 Epistaxis 0.2 GI origin 1.0 2.0 Venous TE 6.3 PE 3.5 4.7 ATE 0.5 1.8 Fistula (GI origin) 0.3 Wound healing GI perforation

STUDY COMMENTARY Adding aflibercept to FOLFIRI in mCRC in 2nd Line mCRC in OS and PFS benefits : statistically significant but of questionable clinical significance However there were signifcant toxicities associated with FOLFIRI and aflibercept

BOTTOM LINE FOR MEDICAL ONCOLOGISTS Given the 6 wk improvement in OS in the face of significant toxicities, aflibercept has a poor therapeutic ratio In addition – given the Canadian standard of first line FOLFIRI ? how to extrapolate results of this trial (efficacy and toxicity) to use with second line FOLFOX

Part 2: Subset Analyses of Patients Previously Treated With Bevacizumab

Background Non-randomized data from the BRiTE observational study suggested that bevacizumab post progression first line might be beneficial to patients (Grothey, JCO, 2008) This observation needs to be confirmed in a randomized study

Background (cont’d) This is the first randomized study of a 2nd line VEGF inhibitor where some patients had been treated previously with Bevacizumab Although this will not give a definitive answer, the subset analyses of patients previously treated with bev in this study can provide some insight into whether there might be merit in continuing VEGF inhibition post progression

Pre-Specified Subgroup Analyses Goal: to confirm consistency of the effect of aflibercept on OS and PFS Methodology: impact assessment on pre-specified subgroups: FOCUS ON : Stratification factors Prior bevacizumab 7

Methodology for Pre-Specified Subgroups Analyses For each parameter, a Cox Proportional Hazard Model was used for the overall population, including the parameter, the treatment effect and the treatment by parameter interaction. Interactions between treatment and each subgroup were tested at the 2-sided 10% level ie, a p-value > 0.1 indicates no evidence of heterogeneity of treatment effect across the subgroups for each factor. Safety was analyzed according to prior treatment with bevacizumab Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA 8 ESMO STOCKHOLM 2011

Prior Treatment with Bevacizumab Placebo/FOLFIRI N=614 Aflibercept/FOLFIRI N = 612 Yes 187 (30.5%) 186 (30.4) No 427 (69.5%) 426 (69.6%) 15

P-value for interaction Overall Survival: Patients with or without Prior Treatment with Bevacizumab - ITT Population Placebo/ FOLFIRI Median (mos) N = 614 Aflibercept/FOLFIRI N = 612 P-value for interaction All Patients 12.1 13.5 Prior BEV No 12.4 13.9 P=0.7231 Yes 11.7 12.5 Interaction between “treatment arm” and “prior bevacizumab” factor was not significant at the 2-sided 10% level (p = 0.7231). Improvement in OS was consistent regardless of prior treatment with bevacizumab 16

Safety:Anti-VEGF Associated Events (Gr 3/4) Overall Population vs Patients With Previous Bev PREV BEV N = 611 N =187 % Proteinuria* 7.9 8.6 Hypertension 19.3 16.6 Haemorrhage 2.9 3.2 Epistaxis 0.2 GI origin 2.0 2.7 Venous thromboembolic event 8.0 Pulmonary embolism 4.7 Arterial thromboembolic event 1.8 2.1 Fistula 0.3 Compromized wound healing 0.5 GI perforation 20

Major Adverse Events (Grade 3/4) AFLIBERCEPT Placebo (N = 605) Grade 3/4 Prior Bev (N=187) No Prior Bev (N=424) % Proteinuria Hypertension Haemorrhage Epistaxis GI Origin Dysphonia (PT) Headache (PT) Venous thromboembolitic event Pulmonary embolism Arterial thromboembolitic event Fistula Compromised wound healing GI perforation 8.6 16.6 3.2 2.7 0.5 1.1 8.0 2.1 7.5 20.5 2.8 0.2 1.7 1.9 7.8 5.7 0.7 1.2 1.5 1.0 0.3 6.3 3.5

Summing Up Pre-planned subgroup analyses supported consistency and of the efficacy results across all domains, including prior treatment with bevacizumab. Prior treatment with bevacizumab does not appear to significantly impact the safety profile of aflibercept This subset analyses supports the observations from the BRiTE study regarding the potential benefit of contiued VEGF inhibiton after progression on a VEGF inhibitor The first definitive answer will come next year at ASCO from the German randomized study outlined on the next slide

TML (ML18147): bevacizumab post-progression randomised phase III trial Results Expected ASCO 2011 Standard second-line chemotherapy + bevacizumab RANDOMISATION Standard first-line chemotherapy + bevacizumab (n=810) First progression Standard second-line chemotherapy Prospective, open-label, randomised phase III study Primary endpoint: OS Secondary endpoints: OS from start of first-line therapy, PFS, ORR, safety