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 J 1, Clarke S 2, Diaz-Rubio E 3, Scheithauer W 4, Figer A 5 Wong R 6, Koski S 7, Lichinitser M 8, Yang T 9, Saltz L 10 1 Glasgow University, Glasgow, Scotland, 2 University of Sydney and Sydney Cancer Centre, Sydney, Australia, 3 Hospital Clínico San Carlos, Madrid, Spain, 4 Vienna University Medical School, Vienna, Austria, 5 Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, 6 Cancer Care Manitoba, St Boniface General Hospital, Winnipeg, MB, Canada, 7 Cross Cancer Institute, Edmonton, AB, Canada, 8 Russian Cancer Research Center, Moscow, Russian Federation, 9 Chang-Gung Memorial Hospital, Taipei, Taiwan, 10 Memorial 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/m 2 i.v. day 1 + capecitabine 1000mg/m 2 orally bid days 1−14, every 3 weeks) vs. FOLFOX-4 (oxaliplatin 85mg/m 2 i.v. day FU 400mg/m 2 i.v. day 1 + FA 200mg/m 2 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 data 8 became available (n=1400) Recruitment June 2003 – May 2004 Recruitment Feb 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/m 2 i.v. over 2 hours, day 1 – Capecitabine1000 mg/m 2 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/m 2 i.v. over 2 hours, day 1 – Folinic acid 200 mg/m 2 i.v. over 2 hours, days 1, 2 – Fluorouracil 400 mg/m 2 i.v. bolus, days 1, 2 – Fluorouracil 600 mg/m 2 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 10 9 /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≤ 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+ bevacizumab (n=349) XELOX+ placebo (n=350) XELOX+ bevacizumab (n=350) Male/female, %64/3661/3953/4759/41 61/39 Median age, years ECOG PS: 0/1, %51/4950/5060/4057/4359/41 Alkaline phosphatase: Abnormal/normal, %43/5742/58 43/5745/55 Prior adjuvant chemotherapy: No/Yes, %74/2672/2876/2475/2574/2678/22 Cancer type at first diagnosis, %: Colon and rectal Colon Rectal

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 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)

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 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) 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 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)

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 Months Proportion of patients n=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)

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) Diarrhea282211< Nausea4019 5–3423 5– Vomiting2213 4–2216 5– Stomatitis2510 2–16 5 1– Hand-foot syndrome 7 2 1–16 8 6– Fatigue2017 8<116 5<1 Paresthesia25 8 4–2111 5– Peripheral neuropathy11 5 4– 5 4– Peripheral sensory neuropathy 9 4 3–10 4 3– Neutropenia <1 Febrile neutropenia––23––<1 Thrombocytopenia 614 3<

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

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 to FOLFOX-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 families The co-investigators The research nurses and data managers The study management team at Roche

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