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Carmen Allegra,*

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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Carmen Allegra,*

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  1. 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

  2. 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

  3. 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.

  4. 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)

  5. 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

  6. 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.

  7. 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

  8. Patient Demographics: Prior Bevacizumab

  9. 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)

  10. Overall Survival: Stratified by Prior Bevacizumab – ITT Population

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

  12. Response Rates

  13. Safety: Anti-VEGF Associated Events

  14. Safety:Adverse Events

  15. Safety:AEs Leading to Discontinuation

  16. 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

  17. 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

  18. 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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