XELOX vs. FOLFOX4: survival and response results from XELOX-1 / NO16966,

a randomized phase III trial of first-line treatment for patients with metastatic

colorectal cancer (MCRC)

Cassidy J1, Clarke S2, Diaz-Rubio E3, Scheithauer W4, Figer A5

Wong R6, Koski S7, Lichinitser M8, Yang T9, 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, 8Russian Cancer Research Center, Moscow, Russian Federation,

9Chang-Gung Memorial Hospital, Taipei, Taiwan,

10Memorial Sloan Kettering Cancer Center, New York, USA

Capecitabine plus oxaliplatin (XELOX) in MCRC: non-inferior to FOLFOX-4 for PFS

As first-line therapy for MCRC, capecitabine provides superior response rates, improved tolerability and convenience benefits vs. 5-FU/FA (Mayo Clinic regimen).1,2

In stage III colon cancer, single-agent capecitabine is at least as effective as i.v. 5-FU plus FA, with superior safety vs. Mayo Clinic bolus 5FU/FA.3–5

Previously presented results from a 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) in the following groups:6

– original 2-arm non-inferiority study of XELOX vs. FOLFOX-4 alone

– all patients/ITT population (XELOX/XELOX+bevacizumab/XELOX+placebo vs. FOLFOX/FOLFOX+bevacizumab/FOLFOX+placebo)

– bevacizumab-treated patients (XELOX+bevacizumab vs. FOLFOX+bevacizumab).

XELOX was also non-inferior to FOLFOX-4 for overall survival in the original 2-arm study.

Here we present updated PFS and overall survival data with an additional 1 year of follow-up.

Prospective, randomized, multicenter, phase III study comparing XELOX and FOLFOX-4

Original 2-arm, open-label study: XELOX (oxaliplatin 130mg/m2 i.v. day 1 + capecitabine 1000mg/m2 orally bid days 1−14, every 3 weeks) vs. FOLFOX-4 (oxaliplatin 85mg/m2 i.v. day 1 + 5-FU 400mg/m2 i.v. day 1 + FA 200mg/m2 i.v. day 1)7 (Figure 1).

In August 2003, after bevacizumab phase III data became available,8 design was amended to 2x2 partially blinded study by adding bevacizumab 7.5mg/kg i.v. or placebo on day 1 every 3 weeks to XELOX and bevacizumab 5mg/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. FOLFOX4.

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 data8 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) – Bev (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)– Bev (or placebo) 5 mg/kg i.v. over 30–90 min, day 1– Oxaliplatin 85 mg/m2 i.v. over 2 hours, day 1– Folinic acid 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. inf 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 objectives:

Primary objectives: Non-inferiority of XELOX vs. FOLFOX-4:– non-inferiority was concluded if the upper limit of the 97.5%

confidence interval (CI) was ≤1.23.

Bevacizumab + chemotherapy (XELOX and FOLFOX-4) is superior to placebo + chemotherapy:– superiority was concluded if p≤0.025.

Secondary objectives:

Overall survival.

Response rate assessed according to RECIST criteria. Assessments made by investigators and also an independent response committee (IRC).

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 primaryXELOX 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)

FOLFOX4+placebo(n=351)

FOLFOX4+bevacizuma

b(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 PFS and overall survival

The primary objective of the study was met:

– XELOX/XELOX+placebo/XELOX+bevacizumab was non-inferior to FOLFOX-4/FOLFOX-4+placebo/FOLFOX-4+ bevacizumab in terms of PFS (ITT and EPP populations, Figure 3).

XELOX/XELOX+placebo/XELOX+bevacizumab was also non-inferior to FOLFOX-4/FOLFOX-4+placebo/FOLFOX-4+ bevacizumab in terms of overall survival (ITT and EPP populations, Figure 4).

Figure 3. XELOX is non-inferior to FOLFOX-4 for PFS (ITT population)

FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab

XELOX/XELOX+placebo/XELOX+bevacizumab

X/P

F/P

X/BV

F/BV

X

F

n=1017, 919 events

n=1017, 886 events

0 5 10 15 20 25 30 35 400.0

0.1

0.2

0.3

0.4

0.5

1.0

0.9

0.8

0.7

0.6

Proportion of patients

Months

HR = 1.02 [97.5% CI: 0.92–1.14] (EPP)HR = 1.01 [97.5% CI: 0.91–1.12] (ITT)

8.58.0

Figure 4. XELOX is non-inferior to FOLFOX-4 for OS (ITT population)

FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab

XELOX/XELOX+placebo/XELOX+bevacizumab

X/P

F/P

X/BV

F/BV

X

F

0.0

0.1

0.2

0.3

0.4

0.5

1.0

0.9

0.8

0.7

0.6

0 5 10 15 20 25 30 35 40

Months

n=1017, 695 events

n=1017, 692 events

HR = 1.00 [97.5% CI: 0.88–1.13] (EPP)HR = 0.99 [97.5% CI: 0.88–1.12] (ITT)

19.6 19.8

Proportion of patients

Figure 5. XELOX+bevacizumab is non-inferior to FOLFOX-4+bevacizumab for OS (ITT population)

FOLFOX+bevacizumab

XELOX+bevacizumab

X/P

F/P

X/BV

F/BV

X

F

350 5 10 15 20 25 300.0

0.1

0.2

0.3

0.4

0.5

1.0

0.9

0.8

0.7

0.6

Months

Proportion of patients

n=349, 209 events

n=350, 211 events

HR = 0.97 [97.5% CI: 0.77–1.22] (EPP)HR = 0.99 [97.5% CI: 0.80–1.23] (ITT)

21.2 21.4

Figure 6. XELOX is non-inferior to FOLFOX-4 for OS in the 2-arm part of the study (ITT population)

FOLFOX

XELOX

X/P

F/P

X/BV

F/BV

X

F

0 5 10 15 20 25 30 35 400.0

0.1

0.2

0.3

0.4

0.5

1.0

0.9

0.8

0.7

0.6

Months

Proportion of patientsn=317, 262 events

n=317, 250 events

HR = 0.92 [97.5% CI: 0.75–1.13] (EPP)HR = 0.90 [97.5% CI: 0.74–1.10] (ITT)

17.7 18.8

45

Table 2. 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

80% of patients 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

The new dataset confirms that XELOX +/– bevacizumab is non-inferior to FOLFOX-4 +/– bevacizumab in terms of PFS.

Mature data show equivalence of XELOX and FOLFOX-4 in terms of overall survival.

XELOX and FOLFOX-4 safety profiles are balanced.

XELOX is an alternative to FOLFOX-4 as first-line therapy in MCRC, and offers the option of oral fluoropyrimidine administration.

Acknowledgements

Sincere thanks to:

The patients and their familiesThe co-investigatorsThe research nurses and data managersThe study management team at Roche

References

1. Van Cutsem E, et al. Br J Cancer 2004;90:1190−7.

2. Cassidy J, et al. Ann Oncol 2002;13:566−75.

3. Twelves C, et al. NEJM 2005;352:2696−704.

4. Scheithauer W, et al. Ann Oncol 2003;14:1735−43.

5. Cassidy J, et al. Br J Cancer 2006;94:1122−9.

6. Cassidy J, et al. Proc ASCO GI 2007;219(Abst 270).

7. De Gramont A, et al. J Clin Oncol 2000;18:2938−47.

8. Hurwitz H, et al. NEJM 2004;350:2335−42.

Presented at the American Society of Clinical Oncology Congress, 1−5 June, 2007