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

NO16966 study design Initial 2-arm open-label study (N=634) Recruitment June 2003 – May 2004 Recruitment Feb 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)

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

*chemotherapy = FOLFOX and XELOX 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

*with informed consent 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

Baseline characteristics FOLFOX N=317 XELOX N=317 FOLFOX+ placebo N=351 FOLFOX+ bevacizumab N=350 XELOX+ placebo N=350 XELOX+ bevacizumab N=350 Gender Male Female 64% 36% 61% 39% 53% 47% 59% 41% Age in years (median) 62 61 60 ECOG PS at baseline 0 1 51% 49% 50% 50% 60% 40% 57% 43% Alkaline phosphatase at BL Abnormal Normal 43% 57% 42% 58% 42% 58% 43% 57% 45% 55% Prior adjuvant chemotherapy No Yes 74% 26% 72% 28% 76% 24% 75% 25% 74% 26% 78% 22% Cancer type at first diagnosis Colon and rectal cancer Colon cancer Rectal cancer 5% 63% 32% 9% 64% 26% 7% 66% 27% 8% 64% 28% 9% 67% 25% 9% 67% 23%

XELOX non-inferiority question

PFS XELOX non-inferiority: primary objective met based on ITT 1.0 0.8 0.6 0.4 0.2 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 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 EPP 1.0 0.8 0.6 0.4 0.2 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 FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=937; 768 events XELOX/XELOX+placebo/XELOX+bevacizumab N=967; 779 events

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 *XELOX/XELOX+placebo/ XELOX+bevacizumab **FOLFOX/FOLFOX+placebo/ FOLFOX+bevacizumab 0.2 0.4 0.6 1 2 3 4 5 6 Risk ratio

Safety profile: FOLFOX vs XELOX FOLFOX* (N=649) XELOX** (N=655) Grade 3/4 AEs 78.3% 71.5% Diarrhoea grade 3/4 11.2% 20.2% Neutropenia/granulocytopenia grade 3/4 43.8% 7.0% Febrile neutropenia grade 3/4 4.8% 0.9% Hand-foot syndrome grade 3 1.2% 6.1% Neurosensory toxicity grade 3/4 16.5% 17.4% Venous thromboembolic events grade 3/4 6.3% 3.8% Cardiac disorders grade 3/4 1.4% Discontinuations due to AE 24.8% 26.0% All-cause 60-day mortality 2.3% 3.4% Treatment-related mortality up to 28 days after last dose 1.7% 2.1% *FOLFOX/FOLFOX+placebo; **XELOX/XELOX+placebo

Bevacizumab superiority question

PFS chemotherapy + bevacizumab superiority: primary objective met 1.0 0.8 0.6 0.4 0.2 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 FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

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

PFS superiority subgroup analysis 0.2 0.4 0.6 1 2 3 4 5 6 Prior adjuvant chemotherapy FOLFOX subgroup No Yes XELOX subgroup No Yes Favours bevacizumab* Favours placebo** 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

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

Safety profile: chemotherapy + placebo or bevacizumab FOLFOX/XELOX+ placebo (N=675) FOLFOX/XELOX+ bevacizumab (N=694) Grade 3/4 AEs 74.8% 80.0% Gastrointestinal perforations grade 3/4 0.3% 0.6% Bleeding grade 3/4 1.2% 1.9% Arterial thromboembolic events grade 3/4 1.0% 1.7% Hypertension grade 3/4 3.7% Proteinuria grade 3/4 – Wound-healing complication grade 3/4 0.1% Discontinuations due to AE 20.7% 30.7% All-cause 60-day mortality 1.6% 2.0% Treatment-related mortality up to 28 days after last dose 1.5%

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

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

Conclusions XELOX 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

Conclusions Bevacizumab 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

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