FOLFOX4 with or without Bevacizumab in Previously Treated Advanced Colorectal Cancer: Results from ECOG-E3200 Lee M Ellis, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005

VEGF-A VEGF-R1 (Flt-1) Migration Invasion VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR) Proliferation Survival Permeability Cell membrane PlGF VEGF-B VEGF-C, D Functions Neuropilin Survival Migration XX X Bevacizumab T 1/2 ~20 days VEGF Family and Receptors

Underlying Hypothesis The addition of a neutralizing VEGF antibody (bevacizumab) improves the effects of FOLFOX in the second-line setting. The addition of a tyrosine kinase inhibitor to VEGF receptors improves the effects of FOLFOX in the front-line setting.

Background: Advances in Therapy for Metastatic CRC ASCO 2003  Hurwitz et al. The addition of bevacizumab to IFL chemotherapy achieved a median OS of ~20 months  Goldberg et al. FOLFOX led to a 20 month median survival  Will the addition of anti-VEGF therapy to FOLFOX improve results, or do we achieve maximal benefit with FOLFOX alone? Bevacizumab — MoAB to VEGF-A PTK/ZK (vatalanib) — tyrosine kinase inhibitor targeting VEGF receptors Sources: Hurwitz et al. Proc ASCO 2003; Goldberg et al. Presentation. ASCO 2003.

Primary end point: OS Secondary end points: ORR, PFS, safety n = 290 n = 289 n = 243 Bevacizumab* 10 mg/kg q2w PD FOLFOX4 + bevacizumab 10 mg/kg q2w PD Eligibility Previously treated MCRC ECOG PS 0-1 * Third arm discontinued after predetermined interim analysis demonstrated the inferiority of bevacizumab compared with FOLFOX4. Source: Giantonio BJ et al. Presentation. ASCO ECOG 3200 Trial Design FOLFOX4 + placebo PD R n = 829

E3200: Overall Survival Probability OS (months) ALIVEDEADMEDIANTOTAL A: FOLFOX4 + bevacizumab B: FOLFOX C: Bevacizumab HR = 0.76 A vs B: p = B vs C: p = 0.95 Source: Giantonio BJ et al. Presentation. ASCO 2005.

Probability PFS (months) CENSFAILMEDIANTOTAL A: FOLFOX4 + bevacizumab B: FOLFOX C: Bevacizumab HR = 0.64 A vs B: p < B vs C: p < Source: Giantonio BJ et al. Presentation. ASCO E3200: Progression-Free Survival

E3200: Response Rates FOLFOX4 + bevacizumab n = 271 FOLFOX4 n = 271 Bevacizumab n = 230 OR*21.8%9.2%3.0% CR1.9%0.7%0% PR19.9%8.5%3.0% SD51.7%45.0%29.1% Source: Giantonio BJ et al. Presentation. ASCO * FOLFOX + B versus FOLFOX: p <

E3200: Grade III/IV Toxicity FOLFOX4 + bevacizumab n = 287 FOLFOX4 n = 284 Bevacizumab n = 234p GIIIGIVGIIIGIVGIIIGIVA vs B Hypertension5%1%2%<1%7%0%0.018 Bleeding3%<1% 0%2%0%0.011 Neuropathy16%<1%9%<1% Vomiting9%1%3%<1%5%0%0.010 Bowel perforation 1%0%13% Source: Giantonio BJ et al. Presentation. ASCO 2005.

ECOG 3200 The addition of BV to FOLFOX in second-line therapy improves efficacy (PFS, RR, OS)  Efficacy of FOLFOX can be improved with targeted therapy (BV, Cetuximab?)  Be cognizant of HTN, bowel perforations and hemorrhage (infrequent, but important)  Single-agent BV in second-line therapy was inferior to FOLFOX (currently, there is no role for use of BV as a single agent in mCRC)