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![Page 1: 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.](https://reader035.fdocuments.in/reader035/viewer/2022062422/56649eef5503460f94bff1b1/html5/thumbnails/1.jpg)
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
Poster #382
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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/NO16966 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.
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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 1 + 5-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.
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XELOX + placebo n=350
FOLFOX-4 + placebo n=351
XELOX + bevacizumab
n=350
FOLFOX-4 + bevacizumab
n=349
XELOX n=317
FOLFOX-4 n=317
Initial 2-arm open-label study
(n=634)
Protocol amended to 2x2 placebo-controlled design after bevacizumab
phase III data5 became available (n=1400)
RecruitmentJune 2003 – May 2004
RecruitmentFeb 2004 – Feb 2005
Figure 1. XELOX-1 / NO16966 study design
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Figure 2. Treatment schedules
XELOX + bevacizumab (or placebo) – Bevacizumab (or placebo) 7.5 mg/kg i.v. over 30–90 min, day 1– Oxaliplatin 130 mg/m2 i.v. over 2 hours, day 1– Capecitabine 1000 mg/m2 orally, twice daily, days 1–14– Schedule repeated every 21 days
FOLFOX-4 + bevacizumab (or placebo)– Bevacizumab (or placebo) 5 mg/kg i.v. over 30–90 min, day 1– Oxaliplatin 85 mg/m2 i.v. over 2 hours, day 1– Leucovorin 200 mg/m2 i.v. over 2 hours, days 1, 2– Fluorouracil 400 mg/m2 i.v. bolus, days 1, 2– Fluorouracil 600 mg/m2 i.v. infusion over 22 hours,
days 1, 2– Schedule repeated every 14 days
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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.
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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).
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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.
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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).
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Table 1. Baseline patient characteristics
FOLFOX-4 (n=317)
XELOX(n=317)
FOLFOX-4+placebo(n=351)
FOLFOX-4+bevacizumab
(n=349)
XELOX+placebo(n=350)
XELOX+bevacizuma
b(n=350)
Male/female, % 64/36 61/39 53/47 59/41 59/41 61/39
Median age, years 62 61 60 60 61 61
ECOG PS: 0/1, % 51/49 50/50 60/40 57/43 59/41 59/41
Alkaline phosphatase: Abnormal/normal, % 43/57 42/58 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 Colon Rectal
56332
96426
76627
86428
96725
96723
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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.
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Table 2. OS in treatment subgroup comparisons (ITT population)
No. of eventsMedian time to event (months) 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 21.0 274 21.6 0.95 (0.78–1.15)
FOLFOX-4 XELOX
284 17.7 266 18.8 0.87 (0.72–1.05)
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Figure 3. OS (XELOX / XELOX + placebo / XELOX + bevacizumab vs. FOLFOX-4 / FOLFOX-4 + placebo / FOLFOX-4 + bevacizumab)
FOLFOX-4 / FOLFOX-4 + placebo /FOLFOX-4 + bevacizumabn=1017; 847 events
XELOX / XELOX + placebo / XELOX + bevacizumabn=1017; 820 events
HR = 0.95 [97.5% CI: 0.851.06] (ITT)HR = 0.96 [97.5% CI: 0.861.08] (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
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800
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Figure 4. OS (XELOX / XELOX + placebo vs. FOLFOX-4 / FOLFOX-4 + placebo)
FOLFOX-4 / FOLFOX-4 + placebon=668; 573 events
XELOX / XELOX + placebon=667; 546 events
HR = 0.95 [97.5% CI: 0.831.09] (ITT)HR = 0.97 [97.5% CI: 0.841.11] (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
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800
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Figure 5. OS (XELOX + bevacizumabvs. 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
0
FOLFOX-4 + bevacizumabn=351; 274 events
XELOX + bevacizumabn=350; 274 events
HR = 0.95 [97.5% CI: 0.781.15] (ITT)HR = 0.95 [97.5% CI: 0.781.16] (EPP)
100 200 300 400 500 600 700 800 900 100 1100 1200 1300 1400 1500 1600
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Figure 6. OS (XELOX vs. FOLFOX-4)
FOLFOX-4n=317; 284 events
XELOXn=317; 266 events
HR = 0.87 [97.5% CI: 0.721.05] (ITT)HR = 0.89 [97.5% CI: 0.731.08] (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
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800
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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 1 2 3 4
Diarrhea 28 22 11 <1 26 19 19 1
Nausea 40 19 5 – 34 23 5 –
Vomiting 22 13 4 – 22 16 5 –
Stomatitis 25 10 2 – 16 5 1 –
Hand-foot syndrome 7 2 1 – 16 8 6 –
Fatigue 20 17 8 <1 16 16 5 <1
Paresthesia 25 8 4 – 21 11 5 –
Peripheral neuropathy 11 5 4 – 11 5 4 –
Peripheral sensory neuropathy 9 4 3 – 10 4 3 –
Neutropenia 3 12 27 16 2 18 6 <1
Febrile neutropenia – – 2 3 – – <1 <1
Thrombocytopenia 6 14 3 <1 4 12 6 1
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Figure 7. Most common grade 3/4 treatment-related adverse events (safety population, n=1304)
0
20
40
60
% o
f p
ati
en
ts
XELOX / XELOX + placebo (n=655)
FOLFOX-4 / FOLFOX-4 + placebo (n=649)
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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.
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Conclusions: XELOX is non-inferior toFOLFOX-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.
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References & Acknowledgements
1. Van Cutsem E, et al. Br J Cancer 2004;90:1190−7.2. Twelves C, et al. NEJM 2005;352:2696−704.3. Cassidy J, et al. J Clin Oncol 2008;26:2006−12.4. Cassidy J, et al. Proc ASCO GI 2008: abst 341.5. 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.