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Lee M Ellis, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005

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 Family and Receptors. PlGF VEGF-B. VEGF-A. VEGF-C, D. Bevacizumab T 1/2 ~20 days. X. X. X.

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Lee M Ellis, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005

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  1. FOLFOX4 with or without Bevacizumab in Previously Treated Advanced Colorectal Cancer: Results from ECOG-E3200 Lee M Ellis, MDColorectal Cancer Update Think Tank MeetingJune 24, 2005

  2. VEGF Family and Receptors PlGF VEGF-B VEGF-A VEGF-C, D Bevacizumab T1/2 ~20 days X X X Cell membrane VEGF-R1 (Flt-1) Migration Invasion VEGF-R2 (KDR) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Neuropilin Survival Migration Functions

  3. 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.

  4. 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.

  5. Primary end point: OS Secondary end points: ORR, PFS, safety ECOG 3200 Trial Design FOLFOX4 + placebo PD n = 290 Eligibility Previously treated MCRC ECOG PS 0-1 n = 829 FOLFOX4 + bevacizumab 10 mg/kg q2w PD R n = 289 Bevacizumab*10 mg/kg q2w PD n = 243 * Third arm discontinued after predetermined interim analysis demonstrated the inferiority of bevacizumab compared with FOLFOX4. Source: Giantonio BJ et al. Presentation. ASCO 2005.

  6. E3200: Overall Survival 1.0 0.9 0.8 HR = 0.76 A vs B: p = 0.0018 B vs C: p = 0.95 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 OS (months) TOTAL DEAD ALIVE MEDIAN A: FOLFOX4 + bevacizumab 289 246 43 12.9 B: FOLFOX4 290 257 33 10.8 C: Bevacizumab 243 216 27 10.2 Source: Giantonio BJ et al. Presentation. ASCO 2005.

  7. E3200: Progression-Free Survival 1.0 0.9 0.8 HR = 0.64 A vs B: p < 0.0001 B vs C: p < 0.0001 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 PFS (months) TOTAL FAIL CENS MEDIAN A: FOLFOX4 + bevacizumab 273 228 45 7.2 B: FOLFOX4 273 241 32 4.8 C: Bevacizumab 229 215 14 2.7 Source: Giantonio BJ et al. Presentation. ASCO 2005.

  8. E3200: Response Rates * FOLFOX + B versus FOLFOX: p < 0.0001 Source: Giantonio BJ et al. Presentation. ASCO 2005.

  9. E3200: Grade III/IV Toxicity Source: Giantonio BJ et al. Presentation. ASCO 2005.

  10. 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)

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