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

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.

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)

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 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

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 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)

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

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

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

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

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

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 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 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.