D. Haller,1 J. Cassidy,2 J. Tabernero,3 J. Maroun,4 F. de Braud,5 T. Price,6 E. Van Cutsem,7 M. Hill,8 F. Gilberg,9 H-J. Schmoll10

1University of Pennsylvania, Philadelphia, USA; 2Glasgow University, Glasgow, Scotland; 3Vall d'Hebron University Hospital, Barcelona, Spain;

4Ottawa Regional Cancer Centre, Ottawa, Canada; 5Istituto Europeo di Oncologia, Milan, Italy; 6The Queen Elizabeth Hospital, Adelaide, Australia; 7University Hospital Gasthuisberg, Leuven, Belgium; 8Maidstone Hospital, Maidstone, UK; 9Hoffmann-La Roche, Basel, Switzerland; 10Martin Luther

University, Halle, Germany

Phase III Trial of Capecitabine + Oxaliplatin vs Bolus 5-FU/LV in

Stage III Colon Cancer (NO16968): Impact of Age on DFS and OS

2

Background

1. Sargent et al. NEJM 2001;345:1091–1097; 2. Twelves et al. NEJM 2005;352:2696–2704 3. André et al. J Clin Oncol 2009;27:3109–3116; 4. McCleary et al. ASCO 2009 (poster 4010)

• Adjuvant 5-FU/LV demonstrated benefit in older patients compared with surgery alone1

• Oral capecitabine is at least equivalent to bolus 5-FU/LV for disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in patients with stage III colon cancer2

• Older patients (≥70 years) treated with capecitabine also showed improved outcomes vs. 5-FU/LV (X-ACT)2

• Recent data from the MOSAIC trial and ACCENT database demonstrated that newer adjuvant regimens (e.g. oxaliplatin combinations) were not associated with significant efficacy benefits vs. 5-FU/LV in patients ≥65 years compared with younger patients3,4

3

MOSAIC: DFS by age3

• MOSAIC trial demonstrated efficacy of FOLFOX4 vs. LV5FU2 is not maintained in patients ≥65 years

3. André et al. J Clin Oncol 2009;27:3109–3116

Prognostic factor (n) Hazard ratio (95% CI)

FOLFOX4 better LV5FU2 better

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

Overall

Age

≥65 years (n=463)

<65 years (n=884)

4

ACCENT: efficacy not maintained in patients ≥70 years of age in overall population4

AgeEndpoint HR (95% CI)

Experimental vs. Control IV 5-FU/LV

Deaths within 6 mo Exp vs. Control %

(p-value)

DFS* OS* TTR*

<70 yearsn=10,499

0.85 (0.79, 0.91)

0.84 (0.79, 0.91)

0.85 (0.79, 0.91)

0.89 vs. 0.79 (p=0.58)

≥70 yearsn=2,170

1.11 (0.97, 1.28)

1.13 (0.96, 1.32)

1.13 (0.97, 1.32)

2.71 vs. 2.11 (p=0.37)

Interaction of age by treatment

p=0.005 p=0.005 p=0.004

*Values <1 favor experimental arm (oxaliplatin-based regimens)

4. McCleary et al. ASCO 2009 (poster 4010)

5

ACCENT: efficacy of oxaliplatin-based (MOSAIC/C-07) combinations by age4

AgeEndpoint HR (95% CI)

Experimental vs. Control IV 5-FU/LV

Deaths within 6 moExp vs. Control %

(p-value)

DFS* OS* TTR*

<70 yearsn=3,977

0.77 (0.68, 0.86)

0.81(0.71, 0.93)

0.76(0.67, 0.86)

0.81 vs. 0.81 (p=1.0)

≥70 yearsn=703

1.04 (0.80, 1.35)

1.19 (0.90, 1.57)

0.92(0.69, 1.23)

2.57 vs. 1.37 (p=0.25)

Interaction of age by treatment

p=0.016 p=0.037 p=0.21

*Values <1 favor experimental arm (oxaliplatin-based regimens)

4. McCleary et al. ASCO 2009 (poster 4010)

6

Chemo/radiotherapy-naïve stage III colon cancer ≤8 weeks since resection (n=1886)

n=944 n=942

RANDOMIZATION

NO16968 (XELOXA): trial design5

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

orRoswell Park (n=278)

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

oxaliplatin130 mg/m2 d1 q3w

8 cycles

5. Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)

7

NO16968 (XELOXA): patient demographics

Characteristic

XELOX (n=944)

5-FU/LV (n=942)

Male, % 54 53

Median age, years (range) <70 years, n (%) ≥70 years, n (%)

61 (22–83)752 (80)192 (20)

62 (24–82)725 (77)217 (23)

ECOG PS, % 0 1

7525

7822

CEA, % normal 92 93

Creatinine clearance, % 30–50 mL/min 50–80 mL/min >80 mL/min

340 57

34256

8

NO16968 (XELOXA) primary endpoint met: superior DFS with XELOX and benefit maintained and increased over time

Years

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

ITT population

Δ at 4 years: 6.1%Δ at 5 years: 6.3%

Δ at 3 years: 4.5%

70.9%

3-yearDFS

66.5%

5-yearDFS

59.8%66.1%

XELOX

5-FU/LV

4-yearDFS

62.3%68.4%

HR=0.80 (95% CI: 0.69–0.93)p=0.0045

9

NO16968 (XELOXA): trend toward 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%

10

NO16968 (XELOXA): subgroup analysis

Survival outcomes by age – analysis performed to:

• Compare with data presented from ACCENT and MOSAIC

• Assess treatment effects of XELOX vs. 5-FU/LV in patients by age:

– ≥65 (planned) and ≥70 years (unplanned)

• Determine if findings from ACCENT meta-analysis also apply to XELOX regimen

• Determine relapse-free survival (RFS) overall and according to age

11

NO16968 (XELOXA): subgroup analysis of DFS by age

Age group3-year DFS

Hazard ratio(95% CI)XELOX 5-FU/LV

<65 vs. ≥65 years

<65 years (n=1142) 72% 69% 0.80 (0.65–0.98)

≥65 years (n=744) 68% 62% 0.81 (0.64–1.03)

<70 vs. ≥70 years

<70 years (n=1477) 72% 69% 0.79 (0.66–0.94)

≥70 years (n=409) 66% 60% 0.87 (0.63–1.18)

Interaction of age by treatment*

p=0.6222

ITT population

*Multiple Cox regression This non-significant p-value indicates that XELOX efficacy is positive, irrespective of age

12

NO16968 (XELOXA): subgroup analysis of OS by age

ITT population

Age group5-year OS

Hazard ratio(95% CI)

XELOX 5-FU/LV

<65 vs. ≥65 years

<65 years (n=1142) 80% 77% 0.87 (0.67–1.13)

≥65 years (n=744) 73% 70% 0.90 (0.68–1.19)

<70 vs. ≥70 years

<70 years (n=1477) 80% 76% 0.86 (0.69–1.08)

≥70 years (n=409) 69% 67% 0.94 (0.66–1.34)

Interaction of ageby treatment*

p=0.7065

*Multiple Cox regression This non-significant p value indicates that XELOX efficacy is positive, irrespective of age

13

NO16968 (XELOXA): subgroup analysis of RFS by age

Age group

3-year RFSHazard ratio

(95% CI)XELOX 5-FU/LV

Overall (n=1886) 72% 67% 0.78 (0.67–0.92)

<70 vs. ≥70 years

<70 years (n=1477) 73% 69% 0.78 (0.65–0.93)

≥70 years (n=409) 69% 61% 0.83 (0.60–1.15)

ITT population

14

Comparison with ACCENT analysis

*Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV; †Data for oxaliplatin-based regimens

4. McCleary et al. ASCO 2009 (poster 4010)

Hazard ratio (95% CIs)*DFS OS

ACCENT analysis4†

<70 years (n=3877) 0.77 (0.68–0.86) 0.81 (0.71–0.93)

≥70 years (n=703) 1.04 (0.80–1.35) 1.18 (0.90–1.57)

Interaction of age by treatment p=0.016 p=0.037

NO16968 (XELOXA)

<70 years (n=1477) 0.79 (0.66–0.94) 0.86 (0.69–1.08)

≥70 years (n=409) 0.87 (0.63–1.18) 0.94 (0.66–1.34)

Interaction of age by treatment p=0.6222 p=0.7065

15

NO16968 (XELOXA): safety by age

*Includes granulocytopeniaSafety population

Grade 3/4 AEs, %

XELOX 5-FU/LV

<70 years(n=748)

≥70 years(n=190)

<70 years(n=711)

≥70 years(n=215)

All grade 3/4 AEs 57 70 51 60

Diarrhea 18 26 19 25

Nausea/vomiting 8 11 6 5

Stomatitis <1 1 9 8

Neutropenia* 9 10 16 17

Febrile neutropenia <1 <1 4 4Hand-foot syndrome 6 4 <1 <1Neurosensory 11 11 <1 0

16

NO16968 (XELOXA): conclusions

• XELOX results in superior DFS compared with bolus 5-FU/LV as adjuvant treatment for patients with stage III colon cancer

• These findings confirm the benefits previously demonstrated with the addition of oxaliplatin to 5-FU in stage III patients

• Efficacy benefits are maintained in patients ≥65 and ≥70 years in contrast to results from ACCENT and MOSAIC in which no significant benefit is shown with FOLFOX in this age group:

– reasons for this apparent difference are unknown

• OS data thus far indicate a trend toward superior survival with XELOX

• XELOX is an effective adjuvant therapy and should be considered for all eligible patients, without an arbitrary upper age limit

17

Acknowledgments

• Thank you to the:

– 1886 patients and their families

– 226 participating centers and investigators

– nurses and study coordinators

– NO16968 (XELOXA) Steering Committee

– others who made this contribution to the advancement of patient care possible

18

References

1. Sargent et al. NEJM 2001;345:1091–1097

2. Twelves et al. NEJM 2005;352:2696–2704

3. André et al. J Clin Oncol 2009;27:3109–3116

4. McCleary et al. J Clin Oncol 2009;27(15S):4010

5. Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)