1. Poster #382
XELOX-1/NO16966, a randomized phase III trial of first-line XELOX vs. FOLFOX-4 for patients with metastatic colorectal cancer (MCRC): Updated overall survival results
Cassidy J,1 Clarke S,2 Diaz-Rubio E,3 Scheithauer W,4 Figer A,5 Wong R,6 Koski S,7 Sirzen F,8 Bergstrom B,9 Gilberg F,8 Saltz L10
1Glasgow University, Glasgow, Scotland; 2University of Sydney and Sydney Cancer Centre, Sydney, Australia; 3Hospital Clínico San Carlos, Madrid, Spain; 4Vienna University Medical School, Vienna, Austria; 5Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 6Cancer Care Manitoba, St Boniface General Hospital, Winnipeg, MB, Canada; 7Cross Cancer Institute, Edmonton, AB, Canada; 8F Hoffmann-La Roche, Basel, Switzerland; 9Hoffmann-La Roche Inc., Nutley, USA; 10Memorial Sloan Kettering Cancer Center, New York, USA

2. Capecitabine plus oxaliplatin (XELOX) in MCRC: non-inferior to FOLFOX-4 for PFS
As first-line therapy for MCRC, and in stage III colon cancer, single-agent capecitabine provides equivalent efficacy compared with bolus 5-fluorouracil/leucovorin (5-FU/LV).1,2
Previously presented results from the XELOX-1/NO randomized phase III trial of capecitabine + oxaliplatin (XELOX) vs. FOLFOX-4 (both ± bevacizumab) showed that XELOX is non- inferior to FOLFOX-4 in terms of progression-free survival (PFS; primary endpoint).3
An update with an additional 12 months of follow-up compared with the primary analysis confirmed the non-inferiority in terms of PFS and also showed non-inferiority in terms of overall survival (OS; secondary endpoint).4
Here we present updated OS data with an additional 26 months of follow-up compared with the primary analysis.

3. Prospective, randomized, multicenter, phase III study comparing XELOX and FOLFOX-4
Original 2-arm, open-label study: XELOX (oxaliplatin 130 mg/m2 i.v. day 1 + capecitabine 1000 mg/m2 orally bid days 1−14, every 3 weeks) vs. FOLFOX-4 (oxaliplatin 85 mg/m2 i.v. day FU 400 mg/m2 i.v. day 1 + LV 200 mg/m2 i.v. day 1) (Figure 1).
In August 2003, after bevacizumab phase III data became available,5 design was amended to 2x2 partially blinded study by adding bevacizumab 7.5 mg/kg i.v. or placebo on day 1 every 3 weeks to XELOX and bevacizumab 5 mg/kg i.v. or placebo every 2 weeks to FOLFOX-4 (Figure 1).
The study was double-blind with regard to bevacizumab and placebo administration, but not for capecitabine and 5-FU, since these are administered orally and intravenously, respectively (Figure 1).
Recruitment occurred in two phases as the protocol was amended to include a placebo-controlled comparison with bevacizumab.
The first phase was an open-label comparison of XELOX vs. FOLFOX-4 only.

4. Figure 1. XELOX-1 / NO16966 study design
Recruitment June 2003 – May 2004
Recruitment Feb 2004 – Feb 2005
XELOX n=317
XELOX + placebo
n=350
XELOX + bevacizumab
n=350
FOLFOX-4
n=317
FOLFOX-4 + placebo n=351
FOLFOX-4 + bevacizumab
n=349
Initial 2-arm open-label study (n=634)
Protocol amended to 2x2 placebo- controlled design after bevacizumab phase III data5 became available (n=1400)

5. Figure 2. Treatment schedules
XELOX + bevacizumab (or placebo)
Bevacizumab (or placebo) 7.5 mg/kg i.v. over 30–90 min, day 1
Oxaliplatin mg/m2 i.v. over 2 hours, day 1
Capecitabine mg/m2 orally, twice daily, days 1–14
Schedule repeated every 21 days
FOLFOX-4 + bevacizumab (or placebo)
Bevacizumab (or placebo) mg/kg i.v. over 30–90 min, day 1
Oxaliplatin mg/m2 i.v. over 2 hours, day 1
Leucovorin 200 mg/m2 i.v. over 2 hours, days 1, 2
Fluorouracil mg/m2 i.v. bolus, days 1, 2
Fluorouracil mg/m2 i.v. infusion over 22 hours, days 1, 2
Schedule repeated every 14 days

6. Main inclusion criteria
Male or female ≥18 years old.
ECOG PS ≤1.
Histologically confirmed adenocarcinoma of colon or rectum with metastatic disease.
≥1 unidimensionally measurable lesion.
No prior systemic therapy for advanced/MCRC.
No prior treatment with oxaliplatin or bevacizumab.
If prior adjuvant therapy patients must not have progressed during or within 6 months of completion.
No CNS disease, including brain metastases.
No clinically significant cardiovascular disease.
No moderate or severe renal impairment.
No proteinuria ≤1+.
Neutrophils ≥1.5 x 109/L.

7. Primary and secondary endpoints
Primary endpoint:
PFS:
non-inferiority was concluded if the upper limit of the 97.5% confidence interval (CI) was ≤1.23.
Secondary endpoints:
OS.
Response rate assessed according to RECIST criteria.
Safety evaluated using NCI-CTC (version 3.0).

8. Study populations ITT (intent-to-treat) = all randomized patients.
EPP (eligible patient population) = ITT minus major protocol violators and patients not receiving at least 1 dose of study drug. Required by health authorities to be used for the primary XELOX non-inferiority analyses.
Safety population = all patients receiving at least one dose of the study drug.

9. Baseline characteristics
The original 2-arm study recruited 634 patients; after transition to 2x2 study design, an additional 1400 patients were recruited.
Baseline patient characteristics were well balanced between the groups (Table 1).

10. Table 1. Baseline patient characteristics
FOLFOX-4
(n=317)
XELOX
FOLFOX-4+
placebo
(n=351)
bevacizumab
(n=349)
XELOX+
(n=350)
Male/female, %
64/36
61/39
53/47
59/41
Median age, years 62 61 60
ECOG PS: 0/1, %
51/49
50/50
60/40
57/43
Alkaline phosphatase: Abnormal/normal, %
43/57
42/58
45/55
Prior adjuvant chemotherapy:
No/Yes, %
74/26
72/28
76/24
75/25
78/22
Cancer type at first diagnosis, %:
Colon and rectal
Colon
Rectal 5 63 32 9 64 26 7 66 27 8 28 67 25 23

11. XELOX is non-inferior to FOLFOX-4 in terms of overall survival
With an additional 26 months of follow-up compared with the primary analysis, XELOX was non-inferior to FOLFOX-4 in terms of OS (ITT population):
in the pooled analysis including all patients in the trial (XELOX / XELOX + placebo / XELOX + bevacizumab vs. FOLFOX-4 / FOLFOX-4 + placebo / FOLFOX-4 + bevacizumab)
in patients not receiving bevacizumab (XELOX / XELOX + placebo vs. FOLFOX-4 / FOLFOX-4 + placebo)
in patients receiving bevacizumab (XELOX + bevacizumab vs. FOLFOX-4 + bevacizumab)
in patients in the 2-arm part of the trial (XELOX vs. FOLFOX-4).
The results in the EPP population were similar to those in the ITT population.

12. Table 2. OS in treatment subgroup comparisons (ITT population)
No. of events
Median time to event (months)
Hazard ratio (97.5% CI)
FOLFOX-4/FOLFOX-4+placebo/ FOLFOX-4+bevacizumab
XELOX/XELOX+placebo/ XELOX+bevacizumab
847
19.5
820
19.8
0.95 (0.85–1.06)
FOLFOX-4/FOLFOX-4+placebo
XELOX/XELOX+placebo
573
18.9
546
19.0
0.95 (0.83–1.09)
FOLFOX-4+bevacizumab
XELOX+bevacizumab
274
21.0
21.6
0.95 (0.78–1.15)
FOLFOX-4
XELOX
284
17.7
266
18.8
0.87 (0.72–1.05)

13. Figure 3. OS (XELOX / XELOX + placebo / XELOX + bevacizumab vs
Figure 3. OS (XELOX / XELOX + placebo / XELOX + bevacizumab vs. FOLFOX-4 / FOLFOX-4 + placebo / FOLFOX-4 + bevacizumab)
FOLFOX-4 / FOLFOX-4 + placebo /FOLFOX-4 + bevacizumab
n=1017; 847 events
XELOX / XELOX + placebo / XELOX + bevacizumab
n=1017; 820 events
HR = 0.95 [97.5% CI: 0.851.06] (ITT)
HR = 0.96 [97.5% CI: 0.861.08] (EPP)
Survival
Study day
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800

14. Figure 4. OS (XELOX / XELOX + placebo vs
Figure 4. OS (XELOX / XELOX + placebo vs. FOLFOX-4 / FOLFOX-4 + placebo)
Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FOLFOX-4 / FOLFOX-4 + placebo
n=668; 573 events
XELOX / XELOX + placebo
n=667; 546 events
HR = 0.95 [97.5% CI: 0.831.09] (ITT)
HR = 0.97 [97.5% CI: 0.841.11] (EPP)
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
Study day

15. Figure 5. OS (XELOX + bevacizumab vs. FOLFOX-4 + bevacizumab)
Survival
Study day
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FOLFOX-4 + bevacizumab
n=351; 274 events
XELOX + bevacizumab
n=350; 274 events
HR = 0.95 [97.5% CI: 0.781.15] (ITT)
HR = 0.95 [97.5% CI: 0.781.16] (EPP)
100
200
300
400
500
600
700
800
900
1100
1200
1300
1400
1500
1600

16. Figure 6. OS (XELOX vs. FOLFOX-4)
n=317; 284 events
XELOX
n=317; 266 events
HR = 0.87 [97.5% CI: 0.721.05] (ITT)
HR = 0.89 [97.5% CI: 0.731.08] (EPP)
Survival
Study day
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800

17. FOLFOX-4 / FOLFOX-4 + placebo
Table 3. Adverse events of interest with FOLFOX-4 vs. XELOX (safety population)
AEs, % of patients
Grade
FOLFOX-4 / FOLFOX-4 + placebo
(n=649)
XELOX / XELOX + placebo
(n=655) 1 2 3 4
Diarrhea 28 22 11
<1 26 19
Nausea 40 5 – 34 23
Vomiting 13 16
Stomatitis 25 10
Hand-foot syndrome 7 8 6
Fatigue 20 17
Paresthesia 21
Peripheral neuropathy
Peripheral sensory neuropathy 9
Neutropenia 12 27 18
Febrile neutropenia
Thrombocytopenia 14

18. Figure 7. Most common grade 3/4 treatment-related adverse events (safety population, n=1304)

19. Discontinuations and mortality
Discontinuations due to AEs were comparable in XELOX- (26%) and FOLFOX-4-treated patients (24%).
All-cause 60-day mortality (2.3% vs. 3.4%) and treatment- related mortality up to 28 days after the last dose of study medication (1.7% vs. 2.1%) were also comparable in the two groups.

20. Conclusions: XELOX is non-inferior to FOLFOX-4 as first-line treatment for MCRC
This 26-month update confirms that XELOX is non-inferior to FOLFOX-4 in terms of OS.
XELOX and FOLFOX-4 safety profiles are well balanced.
XELOX is an alternative to FOLFOX-4 as first-line therapy in MCRC.

21. References & Acknowledgements
Van Cutsem E, et al. Br J Cancer 2004;90:1190−7.
Twelves C, et al. NEJM 2005;352:2696−704.
Cassidy J, et al. J Clin Oncol 2008;26:2006−12.
Cassidy J, et al. Proc ASCO GI 2008: abst 341.
Hurwitz H, et al. NEJM 2004;350:2335−42.
Sincere thanks to: The patients and their families; the co-investigators; the research nurses and data managers; the study management team at Roche.
Presented at the 2009 American Society for Clinical Oncology Gastrointestinal Cancers Symposium, January 15−17, 2009, San Francisco, USA.