Disclosure: Gianluca Masi

1. A randomized study evaluating the continuation of bevacizumab beyond progression in metastatic colorectal cancer patients who received bevacizumab as part of first-line treatment: results of the BEBYP trial by the GruppoOncologico Nord Ovest (GONO). G. Masi1, F. Loupakis1, L. Salvatore1, L. Fornaro1, C. Cremolini1, M. Schirripa1, E. Fea2,C. Granetto2, L. Antonuzzo3, E. Giommoni3, G. Allegrini4, S. Cupini5, C. Boni6, M. Banzi6, S. Chiara7, C. Sonaglio7, C. Valsuani8, A. Bonetti9, L. Boni10, A. Falcone1,11 1) Pisa, Italy; 2) Cuneo, Italy; 3) Firenze, Italy; 4) Pontedera, Italy; 5) Livorno, Italy 6) Reggio Emilia, Italy; 7) Genova, Italy; 8) Lido di Camaiore, Italy; 9) Legnago, Italy; 10) Istituto Toscano Tumori, Firenze, Italy; 11) Università di Pisa, Italy.

2. Disclosure: GianlucaMasi • Honoraria: Roche, Merck-Serono, Amgen • ResearchFunding: Roche

3. Background • BV plus fluoropyrimidine-based CT is a standard first-line treatment in mCRC pts. • Retrospective data from BRITE and ARIES studies suggested that the continuation of BV with second line CT beyond progression was associated with improved survival 1,2. • A recent phase III study (AIO/AMG ML18147) demonstrated an improved survival with BV beyond progression 3. • Grothey et al. JCO 2008;26:5326-34 • Cohn et al. JCO 2010;28(15s):Abstr 3596 • Arnold et al. JCO 2012;30 (suppl; abstr CRA3503)

4. Study Design R A N D O M A. Second-line CT§ • I-line CT * + BV • Stratification • Center • PS 0/1-2 • CT-free interval • (> vs ≤ 3 mos) • II-line CT B. Second-line CT§+ BV * • FOLFIRI • FOLFOX • FOLFOXIRI • Fluoropyrimidine mono-tx • FOLFIRI • mFOLFOX-6 § • Study conducted in 19 Italian centers • Supported by AIFA

5. Treatment schedules • FOLFIRI • IRINOTECAN 180 mg/sqmi.v. over 1 hr on day 1 concomitantly with • l-LV 200 mg/sqmi.v. over 2 hrs on days 1 followed by • 5-FU 400 mg/sqmi.v. bolus on days 1 followed by • 5-FU 2400 mg/sqmi.v. by c.i. over 46 hrs on days 1 • cycles repeated every 2 weeks • mFOLFOX-6 • OXALIPLATIN 85 mg/sqmi.v. over 1 hr on day 1 concomitantly with • l-LV 200 mg/sqmi.v. over 2 hrs on days 1 followed by • 5-FU 400 mg/sqmi.v. bolus on days 1 followed by • 5-FU 2400 mg/sqmi.v. by c.i. over 46 hrs on days 1 • cycles repeated every 2 weeks • In pts randomized to the BV containing arm the regimens were associated with: • BEVACIZUMAB5 mg/kgi.v. on day 1 (immediately before irinotecan or oxaliplatin) repeated every 2 weeks

6. Objectives • Primary • Progression Free Survival • Secondary • Response Rate • Overall Survival • Safety • Potential markers predictive of BV activity

7. Statistical Design / Accrual • Original Hypothesis • To detect a HR for PFS of 0.70 in favor of CT+BV • Power=80%; alpha, two-sided=0.05 • Required 249 events and a total of 262 pts • Accrual started on April 8th 2008 and was stopped prematurely on May 11th 2012 • Press release of TML study results with OS improvement • Slow accrual rhythm due to bevacizumab supply limitation • Randomized 185 pts (184 pts for ITT) (1 pt randomized twice)

8. Main Eligibility Criteria • Pts with histologicallyconfirmedcolorectaladenoca • Age >18 yrs and <75 yrs • ECOG PS 0-2 • Unresectable and measurable metastatic disease according to RECIST criteria • Progressive disease after or during first-line CT with fluoropyrimidine, FOLFIRI, FOLFOX + BV or >3 mos after the last dose of FOLFOXIRI + BV

9. Patients’ characteristics (1) * By central analysis

10. Patients’ characteristics (2)

11. Second-line CT on the basis of first-line CT

12. Primary Objective - PFS CT (85 events) median PFS = 4.97 mos CT+ B (87 events) median PFS = 6.77 mos HR=0.65 (95%CI 0.48-0.89) p=0.0062 Median follow up 18.0 mos

13. Subgroup Analysis of PFS * * Test of interaction

14. Response Rate * p not statistically significant (0,71) ** p not statistically significant (0,21)

15. OverallSafety * CNS ischemia

16. Maximum Toxicities per patient(CT related)

17. Maximum Toxicities per patient(Beva-related)

18. Subsequent anti-cancer therapies

19. Overall Survival • OS data are still immature • After a median follow up of 18 months we observed 52 events in arm A (CT) and 46 events in arm B (CT+BV)

20. Summary • Bevacizumab beyond progression significantly improved PFS • CT vs CT+BV: mPFS 4.97 vs 6.77 months • HR=0.65 (95% CI 0.48-0.89), p=0.0062 • Data from subgroup analyses for PFS consistent with overall population • No significant differences in RR and DCR • OS data still immature • Safety profile consistent with previously reported data

21. Conclusions • Second randomized trial investigating the impact of BV continuation beyond first progression • Our results are in line with those of TML • The prosecution of BV in combination with second-line CT represents a new treatment option

22. Acknowledgements • Patients and their caregivers • AIFA • Dr. Luca BoniCentro CoordinamentoSperimentazioniCliniche, IstitutoToscanoTumori • Investigators • Pisa (A. Falcone, G. Masi, F. Loupakis, L. Salvatore, C. Cremolini, M. Schirripa, L. Fornaro) • Cuneo (M. Merlano, C. Granetto, E. Fea) • Livorno (F. Cappuzzo, S. Cupini, C. Barbara) • Firenze (F. Di Costanzo, L. Antonuzzo, E. Giommoni) • Reggio Emilia (C. Boni, M. Banzi, R. Gnoni) • Genova IST (P. Pronzato, S. Chiara, C. Sonaglio) • Versilia (D. Amoroso, C. Valsuani) • Pontedera (G. Allegrini, L. Marcucci, S. Lucchesi) • Legnago (A. Bonetti, F. Greco) • Piombino (F. Dargenio, V. Safina) • Biella (M. Clerico) • Lecce (V. Lorusso, A. Gambino) • Novara (O. Alabiso) • Siena (S. Crispino, S. Biancanelli, A. Martignetti) • Fabriano (RR Silva, E. Galizia) • Pesaro (V. Catalano) • Caltanissetta (S. Vitello) • Empoli (G. Fiorentini) • Parma (A. Ardizzoni)