1. www.esmo2012.org 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 Gruppo Oncologico Nord Ovest (GONO). G. Masi 1, F. Loupakis 1, L. Salvatore 1, L. Fornaro 1, C. Cremolini 1, M. Schirripa 1, E. Fea 2, C. Granetto 2, L. Antonuzzo 3, E. Giommoni 3, G. Allegrini 4, S. Cupini 5, C. Boni 6, M. Banzi 6, S. Chiara 7, C. Sonaglio 7, C. Valsuani 8, A. Bonetti 9, L. Boni 10, A. Falcone 1,11 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. www.esmo2012.org Disclosure: Gianluca Masi Honoraria: Roche, Merck-Serono, Amgen Research Funding: Roche

3. www.esmo2012.org 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. 1.Grothey et al. JCO 2008;26:5326-34 2.Cohn et al. JCO 2010;28(15s):Abstr 3596 3.Arnold et al. JCO 2012;30 (suppl; abstr CRA3503)

4. www.esmo2012.org Study Design B. Second-line CT § + BV I-line CT * + BV Stratification ‐Center ‐PS 0/1-2 ‐CT-free interval (> vs ≤ 3 mos) ‐II-line CT I-line CT * + BV Stratification ‐Center ‐PS 0/1-2 ‐CT-free interval (> vs ≤ 3 mos) ‐II-line CT RANDOMRANDOM RANDOMRANDOM FOLFIRI FOLFOX FOLFOXIRI Fluoropyrimidine mono-tx FOLFIRI FOLFOX FOLFOXIRI Fluoropyrimidine mono-tx * * FOLFIRI mFOLFOX-6 FOLFIRI mFOLFOX-6 § § A. Second-line CT § Study conducted in 19 Italian centers Supported by AIFA Study conducted in 19 Italian centers Supported by AIFA

5. Treatment schedules FOLFIRI IRINOTECAN 180 mg/sqm i.v. over 1 hr on day 1 concomitantly with l-LV 200 mg/sqm i.v. over 2 hrs on days 1 followed by 5-FU 400 mg/sqm i.v. bolus on days 1 followed by 5-FU 2400 mg/sqm i.v. by c.i. over 46 hrs on days 1 cycles repeated every 2 weeks mFOLFOX-6 OXALIPLATIN 85 mg/sqm i.v. over 1 hr on day 1 concomitantly with l-LV 200 mg/sqm i.v. over 2 hrs on days 1 followed by 5-FU 400 mg/sqm i.v. bolus on days 1 followed by 5-FU 2400 mg/sqm i.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: BEVACIZUMAB 5 mg/kg i.v. on day 1 (immediately before irinotecan or oxaliplatin) repeated every 2 weeks

6. www.esmo2012.org 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 8 th 2008 and was stopped prematurely on May 11 th 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. www.esmo2012.org Main Eligibility Criteria Pts with histologically confirmed colorectal adenoca 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. www.esmo2012.org Characteristics CT (92 pts) CT + BV (92 pts) % Age, median (range)66 yrs (38-75)62 yrs (38-75) Sex (M/F)75/2557/43 ECOG PS 0/1/282/17/182/16/2 Sites of disease (single/multiple)24/7623/77 Liver-only metastases1513 KRAS* (wt/mut/NA)36/31/3332/40/28 BRAF* (wt/mut/NA)64/3/3365/7/28 Patients’ characteristics (1) * By central analysis

10. www.esmo2012.org CharacteristicsCT (92 pts) CT + BV (92 pts) First-line CT Fluoropyrimidine FOLFIRI FOLFOX FOLFOXIRI 4% 58% 25% 13% 1% 59% 24% 16% First-line PFS, median10.3 mos CT-free interval > 3 mos66% Beva-free interval > 3 mos43%50% Patients’ characteristics (2)

11. www.esmo2012.org Second-line CT CT (92 pts) CT + BV (92 pts) FOLFOXFOLFIRIFOLFOXFOLFIRI All pts (N=184)66%34%66%34% First-line fluoropyrimidine (N=5)75%25%100%0% First-line FOLFIRI (N=107)98%2%98%2% First-line FOLFOX (N=45)0%100%5%95% First-line FOLFOXIRI (N=27)50% 47%53% 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. CT (N=92)CT + BV (N=92) Complete Response (CR)2%0% Partial Response (PR)16%21% Overall Response Rate (RR)*18%21% Stable Disease (SD)44%50% Disease Control Rate (DCR)**62%71% Progressive Disease30%24% Not Evaluable8%5% Response Rate * p not statistically significant (0,71) ** p not statistically significant (0,21)

15. www.esmo2012.org CT (92 pts) CT + BV (92 pts) Median number of cycles89 Any grade AE93%94% Grade 3-4 AEs43%44% Serious AEs7% Toxic Deaths0%1%* Overall Safety * CNS ischemia

16. Maximum Toxicities per patient (CT related) CT (n=92)CT + BV (n=92) Any G G 3-4 Any G G 3-4 Vomiting30 % 2 % 30 % 2 % Diarrhea41 % 5 % 49 % 7 % Stomatitis34 % 0 % 38 % 3 % Neutropenia49 % 27 % 47 % 24 % Febrile Neutropenia 3 %4 % Thrombocytopenia36 % 2 % 36 % 1 % Neurotoxicity47 % 5 % 45 % 9 %

17. CT (n=92)CT + BV (n=92) Any G G 3-4 Any G G 3-4 Hypertension3 % 1 % 25 % 2 % Bleeding3 % 1 % 21 % 0 % Venous thrombosis3 % 2 % 1 % Arterial thrombosis0 % 1 % GI perforation0 % Proteinuria0 % 30 % 4 % Ematuria0 % 7 % 1 % Maximum Toxicities per patient (Beva-related)

18. www.esmo2012.org Subsequent anti-cancer therapies CT (92 pts) CT + BV (92 pts) Pts who received ≥ 1 subsequent line70%69% Subsequent BEVA therapy1%3% Subsequent anti-EGFR therapy46%32%

19. www.esmo2012.org 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. www.esmo2012.org 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. www.esmo2012.org 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. www.esmo2012.org Acknowledgements Patients and their caregivers AIFA Dr. Luca Boni Centro Coordinamento Sperimentazioni Cliniche, Istituto Toscano Tumori 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)