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Professor Jim Cassidy Cancer Research UK Department of Oncology, University of Glasgow

First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer. Professor Jim Cassidy Cancer Research UK Department of Oncology, University of Glasgow

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Professor Jim Cassidy Cancer Research UK Department of Oncology, University of Glasgow

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  1. First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer Professor Jim Cassidy Cancer Research UK Department of Oncology, University of Glasgow On behalf of the XELOX-1/NO16966 investigators

  2. NO16966 study design RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX N=317 XELOX + placebo N=350 XELOX + bevacizumab N=350 FOLFOX4 N=317 FOLFOX4 + placebo N=351 FOLFOX4 + bevacizumab N=350 Initial 2-arm open-label study (N=634) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data1 became available (N=1401) 1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

  3. FOLFOX4 + bevacizumab/placebo: 14-day cycle BV or PL 5mg/kg IV 30–90 min OX 85mg/m2 IV 2 h 5-FU 400mg/m2 IV bolus 5-FU 600mg/m2IV 22 h 5-FU 400mg/m2 IV bolus 5-FU 600mg/m2IV 22 h LV 200mg/m2 IV 2 h LV 200mg/m2 IV 2 h D1 D2 D3 XELOX + bevacizumab/placebo: 21-day cycle BV or PL 7.5mg/kg IV 30–90 min OX 130mg/m2 IV 2 h Rest Oral capecitabine 1,000mg/m2 bid D1 D2 D15 D21 Study drugs OX = oxaliplatin; LV = leucovorin; BV = bevacizumab; PL = placebo; 5-FU = 5-fluorouracil

  4. Study objectives • Main endpoint = progression-free survival (PFS) • Two primary objectives • XELOX is non-inferior to FOLFOX • Non-inferiority concluded if upper limit of 97.5% CI ≤ 1.23 • Bevacizumab + chemotherapy* is superior to placebo + chemotherapy • Superiority concluded if p ≤ 0.025 *chemotherapy = FOLFOX and XELOX

  5. Study populations • ITT (intent-to-treat) = all randomised* • used for the bevacizumab superiority analyses • EPP (eligible patient population) = ITT minus major protocol violators and patients not receiving at least one dose of study drug • used for the XELOX non-inferiority analyses due to health authority requirements • Safety population = all patients receiving at least one dose of the respective study drug *with informed consent

  6. Baseline characteristics

  7. XELOX non-inferiority question

  8. FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumab N=1017; 813 events PFS XELOX non-inferiority: primary objective met based on ITT 1.0 0.8 0.6 0.4 0.2 0 HR = 1.04 [97.5% CI 0.93–1.16] Upper limit ≤ 1.23 (non-inferiority margin) PFS estimate 8.0 8.5 0 5 10 15 20 25 30 Months

  9. FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=937; 768 events XELOX/XELOX+placebo/XELOX+bevacizumab N=967; 779 events PFS XELOX non-inferiority: primary objective met based on EPP 1.0 0.8 0.6 0.4 0.2 0 HR = 1.05 [97.5% CI 0.94–1.18] Upper limit ≤ 1.23 (non-inferiority margin) PFS estimate 7.9 8.5 0 5 10 15 20 25 30 Months

  10. PFS non-inferiority subgroup analysis Favours XELOX* Favours FOLFOX** Category All ECOG PS at BL 0 1 No. of metastatic sites at BL =1 >1 Alkaline phosphatase Abnormal Normal Liver as metastatic site at BL No Yes Sex Female Male Age subgroup Age < 65 years Age  65 years Prior adjuvant chemotherapy No Yes Ethnicity Asian or Pacific Islander White 0.2 0.4 0.6 1 2 3 4 5 6 *XELOX/XELOX+placebo/XELOX+bevacizumab**FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab Risk ratio

  11. Safety profile: FOLFOX vs XELOX *FOLFOX/FOLFOX+placebo; **XELOX/XELOX+placebo

  12. Bevacizumab superiority question

  13. FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events PFS chemotherapy + bevacizumab superiority: primary objective met 1.0 0.8 0.6 0.4 0.2 0 HR = 0.83 [97.5% CI 0.72–0.95] (ITT) p = 0.0023 PFS estimate 8.0 9.4 0 5 10 15 20 25 Months

  14. 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups PFS estimate 8.6 9.4 7.4 9.3 FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT) p = 0.0026 FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT) p = 0.1871

  15. Prior adjuvant chemotherapy FOLFOX subgroup No Yes XELOX subgroup No Yes Favours bevacizumab* Favours placebo** 0.2 0.4 0.6 1 2 3 4 5 6 PFS superiority subgroup analysis Category All ECOG PS at BL 0 1 No. of metastatic sites at BL =1 >1 Alkaline phosphatase Abnormal Normal Liver metastases at BL No Yes Sex Female Male Age subgroup Age < 65 years Age  65 years Prior adjuvant chemotherapy No Yes Ethnicity Asia/Pacific Caucasian Favours bevacizumab* Favours placebo** *FOLFOX+bevacizumab/XELOX+bevacizumab**FOLFOX+placebo/XELOX+placebo 0.2 0.4 0.6 1 2 3 4 5 6 Risk ratio

  16. Hypothesis: FOLFOX + placebo patients with prior adjuvant therapy have better baseline prognosis FOLFOX+placebo with prior adjuvant therapy FOLFOX+bevacizumab with prior adjuvant therapy FOLFOX+placebo with prior adjuvant therapy FOLFOX+bevacizumab with prior adjuvant therapy Months

  17. Safety profile: chemotherapy + placebo or bevacizumab

  18. Treatmentduration Placebo +/- 0 Bevacizumab NO16966 Placebo + 1.4 PFS Bevacizumab Months • In AVF2107 77% of patients received bevacizumab treatment within 4 weeks from PD or death vs 46% of patients in NO16966 Comparison of treatment duration and PFS in AVF2107 vs NO16966 Treatmentduration Placebo Bevacizumab + 2.8 AVF21071 Placebo PFS + 4.4 Bevacizumab Months 1Hurwitz H, et al. N Engl J Med 2004;350:2335–42

  19. Treatmentduration Placebo +/- 0 Bevacizumab NO16966 Placebo + 1.4 PFS Bevacizumab Months Comparison of treatment duration and PFS in AVF2107 vs NO16966 Treatmentduration Placebo Bevacizumab + 2.8 AVF21071 Placebo PFS + 4.4 Bevacizumab Months • Early bevacizumab discontinuation, largely unrelated to bevacizumab-specific toxicity, occurred at a ~3-fold higher rate in NO16966 compared with AVF2107

  20. ConclusionsXELOX • XELOX is non-inferior to FOLFOX • XELOX and FOLFOX safety profiles are balanced • XELOX offers the advantage of oral fluoropyrimidine administration • XELOX is a good alternative to FOLFOX

  21. ConclusionsBevacizumab • 1st evidence from 1st line CRC phase III trial that bevacizumab adds • clinically meaningful • statistically superior benefit to oxaliplatin-based chemotherapy • Safety profile overall in line with previous trial experience in colorectal cancer • The outcome of this trial adds to the large body of evidence supporting the use of bevacizumab in combination with standard 1st line chemotherapy

  22. Thank you to… • The patients participating in this trial and their families • The investigators • The study nurses and site coordinators • The study management team at Roche

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