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ECCO ESMO 2011 GI Cancer Updates

“VELOUR” Study

Author: J Tabernero et al

Reviewed by: Dr. Scott Berry

Date posted: October 27, 2011

http://www.oncologyeducation.com/


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



R

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks

FOLFIRI q2 weeks

N=1200

Primary Outcome:OS

Study Design



RESULTS

FOLFIRIFOLFIRI+

AFLIBERCEPTp-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=0.82P=0.0032



GR 3/4 TOXICITY

FOLFIRI

%

FOLFIRI+

AFLIBERCEPT

%

Diarrhea 7.8 19.3Neutropenia 29.5 36.7Complicated Neutropenia 2.8 5.7Stomatitis 5.0 13.7Infections 6.9 12.3Hand Foot Syndrome 0.5 2.8

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 0.2

GI origin 1.0 2.0

Venous TE 6.3 7.9

PE 3.5 4.7

ATE 0.5 1.8

Fistula (GI origin) 0.2 0.3

Wound healing 0 0.3

GI perforation 0.3 0.5



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



7

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



ESMO STOCKHOLM 2011 8

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



15

Prior Treatment with Bevacizumab

Placebo/FOLFIRIN=614

Aflibercept/FOLFIRIN = 612

Yes 187 (30.5%) 186 (30.4)

No 427 (69.5%) 426 (69.6%)



16

Overall Survival: Patients with or without Prior Treatment with

Bevacizumab - ITT Population

Placebo/ FOLFIRI

Median (mos)N = 614

Aflibercept/FOLFIRI

Median (mos)N = 612

P-value for interaction

All Patients

12.1 13.5

Prior BEV

No 12.4 13.9P=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



20

Safety:Anti-VEGF Associated Events (Gr 3/4)Overall Population vs Patients With Previous Bev

OVERALL PREV BEV

N = 611 N =187

% %

Proteinuria* 7.9 8.6

Hypertension 19.3 16.6

Haemorrhage 2.9 3.2

Epistaxis 0.2 0GI origin 2.0 2.7

Venous thromboembolic event 7.9 8.0

Pulmonary embolism 4.7 2.7

Arterial thromboembolic event 1.8 2.1

Fistula 0.3 0

Compromized wound healing 0.3 0.5

GI perforation 0.5 0



Major Adverse Events (Grade 3/4)

AFLIBERCEPTPlacebo

(N = 605)

Grade 3/4 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

0

2.7

0.5

1.1

8.0

2.7

2.1

0

0.5

0

7.5

20.5

2.8

0.2

1.7

0.5

1.9

7.8

5.7

1.7

0.5

0.2

0.7

1.2

1.5

1.7

0

1.0

0

0.3

6.3

3.5

0.5

0.2

0

0.3



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

Prospective, open-label, randomised phase III studyPrimary endpoint: OSSecondary endpoints: OS from start of first-line therapy, PFS, ORR,

safety

First progression

Standardfirst-line

chemotherapy + bevacizumab

(n=810)R

AN

DO

MIS

AT

ION

Standard second-line chemotherapy + bevacizumab

Standard second-line chemotherapy

Results Expected ASCO 2011

www.oncologyeducation.com ecco esmo 2011 gi cancer updates “ velour” study author: j tabernero...

Documents

aflibercept slide

study of aflibercept

line folfiri

randomized study slide

bevacizumab slide

toxicity folfiri

esmo slide

os study design slide