Effects of Prior Bevacizumab Use on Outcomes From the VELOUR Study:
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Effects of Prior Bevacizumab Use on Outcomes From the VELOUR Study: A Phase 3 Study of Aflibercept and FOLFIRI in Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Regimen. Carmen Allegra,*

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Effects of Prior Bevacizumab Use on Outcomes From the VELOUR Study: A Phase 3 Study of Aflibercept and FOLFIRI in Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Regimen

Carmen Allegra,*

Josep Tabernero, Radek Lakomy, Jana Prausova, Paul Ruff, Guy Van Hazel, Vladimir M. Moiseyenko, David R. Ferry, Joe McKendrick, Eric Van Cutsem

*University of Florida, Gainesville, FL


Introduction

  • Giantonio BJ et al. J Clin Oncol. 2007;25:1539-1544.

  • NCCN Practice Guidelines in Oncology, Colon Cancer V.1.2008. available at: http://www.cdhd.org/pdfs/chec/providers_packet/NCCN%20Colon%20slides.pdf.

  • The pivotal Phase 3 trial of 2L bevacizumab plus FOLFOX4 for previously treated mCRC showed a significant survival benefit compared with FOLFOX4 alone1

    • Median OS: 12.9 vs 10.8 months, HR=0.75, P=0.0011

    • Median PFS: 7.3 vs 4.7 months, HR=0.61, P<0.0001

  • Bevacizumab is a standard component of frontline therapy & FOLFIRI remains a standard chemotherapy backbone for 2L mCRC2

  • The goal of the current analysis is to assess consistency of the effect of aflibercept on OS and PFS by prior bevacizumab use in a pre-specified analysis


Aflibercept

  • Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹

  • Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)²

  • High affinity – binds VEGF-A and PlGF more tightly than native receptors

  • Holash J et al. Proc Natl Acad Sci USA. 2002;99:11393-11398.

  • Tew WP et al. Clin Cancer Res. 2010;16:358-366.


VELOUR Study Design

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI

q2 weeks

R

A

N

D

O

M

I

Z

E

600

Metastatic Colorectal Cancer

1:1

Disease Progression

Death

  • Stratification factors:

  • ECOG PS (0 vs 1 vs 2)

  • Prior bevacizumab (Y/N)

Placebo IV, day 1

+ FOLFIRI

q2 weeks

600

Primary endpoint: overall survival

Sample size: HR=0.8, 90% power, 2-sided type I error 0.05

Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of 0.0466 (α spending function)


VELOUR Key Inclusion Criteria

Pathologically proven metastatic adenocarcinoma of the colon or rectum not amenable to curative treatment

Measurable or non-measurable disease (per RECIST criteria)

Only 1 prior oxaliplatin-containing chemotherapeutic regimen for metastatic disease

Patients who relapsed within 6 months of completion of oxaliplatin-based adjuvant chemotherapy were eligible


VELOUR Study

PFS

OS

  • Overall results

    • Adding aflibercept to FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen resulted in significant OS and PFS benefits

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.


Effect of Prior Bevacizumab: Analysis of a Pre-specified Subgroup

  • A Cox proportional hazard model was used for the overall population and treatment by parameter interactions

  • Interactions between treatment and each subgroup, including bevacizumab, were tested at the 2-sided 10% level

    • A P<0.1 would mean that there was a difference in the benefit associated with the use of aflibercept between the prior and no prior bevacizumab groups


Patient Demographics: Prior Bevacizumab


Consistency of OS and PFS With and Without Prior Bevacizumab

  • Interaction between “treatment arm” and “prior bevacizumab” factor was not significant at the 2-sided 10% level (P=0.57 for OS; P=0.2 for PFS)


Overall Survival: Stratified by Prior Bevacizumab – ITT Population


Progression-Free Survival: Stratified by Prior Bevacizumab – ITT Population


Response Rates


Safety: Anti-VEGF Associated Events


Safety:Adverse Events


Safety:AEs Leading to Discontinuation


Conclusions

  • This preplanned subgroup analysis demonstrates consistent trends of increased OS and PFS with aflibercept regardless of prior treatment with bevacizumab

  • Prior treatment with bevacizumab does not appear to impact the safety profile of aflibercept

  • Although analysis of a pre-specified subgroup, this study was not powered to show a treatment difference between arms, therefore no definitive conclusions may be drawn concerning the benefit of aflibercept in the prior bevacizumab-treated subgroup


Acknowledgements

Thank you to all patients, their families, and all the investigators who participated:

Chile

* Villanueva L

* Orlandi F

* Vogel C

* Loredo E

* Barajas O

Czech Republic

* Lakomy R

* Kiss I

* Prausova J

Denmark

* Pfeiffer P

* Yilmaz M

Estonia

* Leppik K

* Jõgi T

France

* Metges JP

* Faroux R

Germany

* Schmoll HJ

* Meiler J

* Welslau M

* Kroning H

* Karthaus M

Greece

* Georgoulias V

* Samantas E

* Kalofonos H

* Papakostas P

* Efremidis A

Italy

* Di Bartolomeo M

* Zampino M

* Gozza A

* Aglietta M

* Frustaci S

* Maiello E

* Santoro A

Netherlands

* Van der Velden A

* Kok T

* Erdkamp F

* Leeksma O.C

* Ten Tije A.J

New Zealand

* Thompson P

* Jeffery M

Norway

* Guren T

* Sorbye H

* Birkemeyer E.M

Poland

* Filipczyk-Cisarz E

* Wojcik E

* Dowgier-Witczak I

* Zander I

* Slomian G

* Koralewski P

Puerto Rico

* Baez-Diaz L

Romania

* Gutulescu N

* Stanculeanu D

* Mihailov A

* Curca R

* Volovat C

* Iorga P

Russia

* Tjulandin S

* Biakhov M

* Moiseyenko V

* Roman L

* Gorbunova V

* Orlova R

South Africa

* Ruff P

* Slabber C FS

* Raats J

* Mall R

* Malan J

* Bouwer J

* Pirjol A

South Korea

* Kim S Y

* Park Y S

* Oh D Y

* Kim T W

* Shin S J

Spain

* Tabernero J

* Lopez G

* Gravalos C

* Bellmunt J

* Cantos B

* Merino S

Sweden

* Glimelius B

* Karimi M

* Flygare P

Turkey

* Buyukberber S

* Oksuzoglu B

* Abali H

Ukraine

* Vinnik Y

* Basheyev V

* Bondarenko I

* Datsenko O

United Kingdom

* Samuel L

* Valle J

* Glynne-Jones R

* Bridgewater J

* Cunningham D

* Ross P

* Propper D

* Ferry D

* Hickish T

Argentina* Batagelj E

* Escudero M

* Costanzo M.V

Australia* Shannon J

* Parnis F

* McKendrick J

* Marx G

* Desai J

* Ng S

* Van Hazel G

Austria* Scheithauer w

Belgium

* Peeters M

* Van Laethem JL

* Van Cutsem E

* Humblet Y

* Delaunoit T

* d'Haens G

* Hendlisz A

Brazil

* Cubero D

* Vinholes,J

* Oliveira M

* Jobim De Azevedo S

* Prolla G

* Hoff P

* Azevedo F

* Vieira F


Acknowledgements (cont’d)

Thank you to all patients, their families and all the investigators who participated:

United States

* Radford J

* Atkins J

* Polikoff J

* Hantel A

* Gross H

* Julian T

* Guarino M

* Fuloria J

* Kirshner J

* Wade J

* Flynn P

* Reiling R

* Salmon S

* George T

* Mitchell E

* Robin E

* Choksi J

* Resta R

* d’Andre S

* Lee F.C

* Sigal D

* Birhiray R

* Stella P

* Wallmark J

United States (cont’d)

* Gousse R

* Charu V

* Van Veldhuizen P

* Thomas A

* Cosgriff T

* Geils Jr G

* Vrindavanam N

* Armas A

* Weiner R

* Nadeem A

* Skinner W

* Lin E

* Haghighat P

* Wong L

* Pandit L

* Fehrenbacher L

* Del Prete S

* Manges R

* Daugherty J.P

* Shearer H

* Fink M

* Ghraowi M.A

Disclosure

This study (NCT00561470) was funded by Sanofi. Aflibercept is being developed in oncology in a partnership between Regeneron and Sanofi.

NSABP, M. Guarino for US investigators coordination


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