NO16968: XELOXAAdjuvant Treatment with

Capecitabine and Oxaliplatin (XELOX) in Stage III Colon Cancer

ESMO/ECCO Presidential Session III

D. Haller, J. Tabernero, J. Maroun, F. de Braud, T. Price, E. Van Cutsem, M. Hill, F. Gilberg, K. Rittweger,

H.-J. Schmoll

Rationale for XELOXA trial

• In 2002, when planning the study, the standard of care for adjuvant treatment of colon cancer was bolus 5-FU/LV (either Mayo Clinic or Roswell Park regimen)

• Based on upcoming results of X-ACT trial, capecitabine was expected to be at least equivalent to bolus 5-FU/LV in stage III colon cancer

• Two large trials were ongoing investigating the additional benefit of oxaliplatin to bolus or infusional 5-FU/LV (NSABP C-07 and MOSAIC)

Rationale for XELOXA trial

• In order to investigate oral fluoropyrimidines plus oxaliplatin, based on the X-ACT trial, capecitabine was chosen as a partner with oxaliplatin vs the standard of care at the time (bolus 5-FU/LV)

• XELOXA became the third of 3 parallel conducted studies (NSABP C-07, MOSAIC and XELOXA) investigating the role of oxaliplatin in adjuvant treatment of colon cancer

• In contrast to NSABP C-07 and MOSAIC, which included stage II and III patients, XELOXA investigated only stage III given the preliminary results of the X-ACT trial (stage III disease only)

Chemo/radiotherapy-naive

stage III colon ≤8 weeks since resection

N=1886

• Primary endpoint: superiority of DFS

• Secondary endpoints: RFS, OS, tolerability

n=944

n=942

RANDO MISATION

Adjuvant XELOX vs 5-FU/LV: NO16968 (XELOXA) Phase III trial

Bolus 5-FU/LV (6 months) Mayo Clinic [n=664]

orRoswell Park [n=278]

XELOX (6 months) capecitabine 1000mg/m2 bid d1–14

oxaliplatin130mg/m2 d1 q3w

8 cycles

Eligibility

18 years old, ECOG 1

• Stage III colon carcinoma, 1 positive lymph node

• Randomised 8 weeks after surgery

• Informed consent

• Normal or mild renal impairment

• No seizures, CNS disorders, psychiatric disability, cardiac disease (CHF, symptomatic CAD or arrhythmias), or MI 12 months

• Normal neutrophils, platelets, creatinine, bilirubin, ALAT, ASAT, alkaline phosphatase

Stratification factors

• Patients stratified by

– geographic region

– number of lymph nodes involved (≤3 vs ≥4)

– baseline CEA (normal vs abnormal)

– 5-FU/LV regimen (Mayo vs Roswell Park)

– number of lymph nodes sampled per geographical region

XELOX n=944

5-FU/LV n=942

Male (%) 54 53

Age (median, range) 61 (22–83) 62 (24–82)

ECOG (0/1) (%) 75/25 78/22

CEA (normal/abnormal) (%) 92/8 93/7Cr clearance (mL/min) (%) 30–50 50–80 >80

340 57

34256

ITT population

Patient demographics

Safety

Grade 3/4 AEs (%)XELOXn=938

5-FU/LVn=926

Febrile neutropenia 0.4 4.2

Neutropenia 8.8 15.9

Diarrhoea 19.4 20.2

Stomatitis 0.6 8.9

Nausea 5.2 4.5

Vomiting 6.2 3.3

HFS 5.4 0.6

Neurosensory 11.4 0.1

Schmoll et al. JCO 2007

Cross-trial comparison with MOSAIC

Schmoll et al. JCO 2007*MOSAIC trial: André et al. NEJM 2004

Grade 3/4 AEs (%)XELOXn=938

FOLFOX4(MOSAIC)*

n=1108

Febrile neutropenia 0.4 1.8

Neutropenia 8.8 41.1

Diarrhoea 19.4 10.8

Stomatitis 0.6 2.7

Nausea 5.2 5.1

Vomiting 6.2 5.8

HFS 5.4 2.0

Neurosensory 11.4 12.4

Efficacy Results

Primary endpoint met:superior DFS with XELOX

HR=0.80 (95% CI: 0.69–0.93)p=0.0045

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

XELOX 5-FU/LV

3-year DFS:benefit with XELOX maintained and increased over time

XELOX 5-FU/LV 1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

ITT population

Δ at 3 years: 4.5%

70.9%

3-yearDFS

66.5%

4-year DFS:benefit with XELOX maintained and increased over time

XELOX 5-FU/LV 1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

ITT population

Δ at 4 years: 6.1%

Δ at 3 years: 4.5%

70.9% 68.4%

3-yearDFS

66.5% 62.3%

4-yearDFS

5-year DFS:benefit with XELOX maintained and increased over time

XELOX 5-FU/LV 1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

ITT population

Δ at 4 years: 6.1% Δ at 5 years: 6.3%

Δ at 3 years: 4.5%

70.9% 68.4%

3-yearDFS

66.5% 62.3%

4-yearDFS

5-yearDFS

59.8%66.1%

DFS across stratification factors

All

Positive lymph nodes

CEA baseline value

5-FU/LV regimen

n CI HR

1886 0.69–0.93 0.80

1222664

0.59–0.900.71–1.11

0.730.89

1401724

0.56–1.320.66–0.92

0.860.78

1331

555

0.64–0.92

0.64–1.17

0.77

0.87

HR

4

≤3≥4

AbnormalNormal

Mayo

Roswell

10.60.40.2 2

ITT population

53

Favours XELOX Favours 5-FU

Superior RFS with XELOX(excludes all non-cancer-related mortality)

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX 5-FU/LV

72.1% 69.7%

3-yearRFS

67.5% 63.3%

4-yearRFS

5-yearRFS

60.9%67.8%

HR=0.78 (95% CI: 0.67–0.92)p=0.0024

Δ at 4 years: 6.4% Δ at 5 years: 6.9%

Δ at 3 years: 4.6%

Years

Trend to improved OS with XELOX

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX 5-FU/LV

Δ at 5 years: 3.4%

HR=0.87 (95% CI: 0.72–1.05)p=0.1486

Years

77.6%

5-yearOS

74.2%

Years

2 4 6

0.4

0.6

0.8

1.0

0

0.4

0.6

0.8

1.0

Years

1. André et al. JCO 2009

8 2 4 60 8

Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease

XELOX

5-FU/LV

FOLFOX4

LV5FU2

XELOXA(57 mo) MOSAIC1

(81.9 mo)

ITT population

1.0

0.6

0.8

1. André et al. JCO 2009

1 2 3 4 5 6 7 8

Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease

Years

XELOX (n=944)

FOLFOX4 (n=672) –

5-yr OS 6-yr OS

72.9%

77.6%

NO16968 (XELOXA)*

MOSAIC1**

–

*Median observation time: 57.0 months**Median follow-up: 81.9 monthsITT population

0.4

0

• Efficacy– XELOX significantly improves DFS and RFS compared

with bolus 5-FU/LV

– trend to improved OS with XELOX; follow-up ongoing

• Ease of administration

– fewer study visits, no pumps or catheters

• Favourable safety profile

• XELOX is a new option and a new standard for patients with stage III colon cancer

NO16968 (XELOXA): conclusions

Thank you

• To the 1886 patients and their families

• To the participating 226 centres and investigators

• To the nurses and study coordinators

• To the NO16968 (XELOXA) Steering Committee

• And everybody else who made this contribution to the advancement of patient care possible