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

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.

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.

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

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

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.

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).

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.

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).

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

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.

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)

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

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

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

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

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

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)

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.

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.

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.