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 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)

3. 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

4. *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

5. *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

6. 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
51% 49%
50% 50%
60% %
57% %
Alkaline phosphatase at BL Abnormal Normal
43% 57%
42% 58%
42% %
43% %
45% 55%
Prior adjuvant chemotherapy No Yes
74% %
72% %
76% %
75% %
74% %
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%

7. XELOX non-inferiority question

8. 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 ≤ (non-inferiority margin)
PFS estimate
8.0
8.5
Months
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumab N=1017; 813 events

9. 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 ≤ (non-inferiority margin)
PFS estimate
7.9
8.5
Months
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=937; 768 events XELOX/XELOX+placebo/XELOX+bevacizumab N=967; 779 events

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
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
Risk ratio

11. 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

12. Bevacizumab superiority question

13. 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 =
PFS estimate
8.0
9.4
Months
FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

14. PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups
1.0
0.8
0.6
0.4
0.2
Months
1.0
0.8
0.6
0.4
0.2
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 =
FOLFOX subgroup HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
p =

15. PFS superiority subgroup analysis
Prior adjuvant chemotherapy
FOLFOX subgroup No Yes
XELOX subgroup No Yes
Favours bevacizumab*
Favours placebo**
Category
All
ECOG PS at BL
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
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
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%

18. 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 AVF % 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

19. 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

20. 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

21. 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

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