A Phase III Trial Comparing FULV to FULV + A Phase III Trial Comparing FULV to FULV + Oxaliplatin in Stage II or III Carcinoma of the Oxaliplatin in Stage II or III Carcinoma of the

Colon: Results of NSABP-C-07Colon: Results of NSABP-C-07

Norman Wolmark, MDColorectal Cancer Update Think Tank Meeting

June 24, 2005

RandomizeRandomize

LV5FU2

Stage ll+lll

FOLFOX4

MOSAICMOSAIC

0 10 20 30 40 50

23% risk reduction in the FOLFOX arm

DFS (months)

Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01

3-yearFOLFOX (n = 1,123) 77.8%LV5FU2 (n = 1,123) 72.9%

1.0

0.9

0.8

0.7

0.6

0.5

Pro

po

rtio

n o

f p

atie

nts

Source: de Gramont A. Presentation. ASCO 2003.

DFSDFS

On November 4, 2004, the FDA approved oxaliplatin in combination with infusional FULV for

adjuvant Stage III colon cancer. The approval was based on improvement in DFS…

RandomizeRandomize

FULVBolus 5-FU/leucovorin

Stratification: Number of positive nodes

FLOXBolus 5-FU/leucovorin

+ oxaliplatin

Stage ll+lll

NSABP-C-07NSABP-C-07

NSABP-C-07: 5-FU/LV versus 5-FU/LV plus NSABP-C-07: 5-FU/LV versus 5-FU/LV plus Oxaliplatin in Stage II/III Colon CancerOxaliplatin in Stage II/III Colon Cancer

x 3

LV

R

Week 1 2 3 4 5 6 7 8

FU

LV

FU

500

500

500

500

OHP 85 2hr

Re

st

Re

st

Source: Wolmark N. Presentation. ASCO 2005.

NSABP-C-07NSABP-C-07

Opened: 02-00

Closed: 11-02

Accrual: 2,407

MTS: 34 mo.

Endpoint: 3 yr DFS

Event: first recurrence, second primary, death (any cause)

89% power to detect: 5.4% ↑ DFS

Source: Wolmark N. Presentation. ASCO 2005.

C-07C-07AccrualAccrual

FULV FLOX

RandomizedIneligible/Lost

1,24538

1,24747

Analysis 1,207 1,200

Source: Wolmark N. Presentation. ASCO 2005.

C-07C-07Patient CharacteristicsPatient Characteristics

Age FULV % FLOX %

<6060-6970+

50.433.016.6

52.431.915.7

Location FULV % FLOX %

Left ColonRight ColonSigmoidMultiple + Unk

20.841.536.81.9

19.845.732.61.9

Positive Nodes FULV % FLOX %

01-3≥4

28.845.725.3

28.944.825.6

Source: Wolmark N. Presentation. ASCO 2005.

Grade FULV FLOX

0-IIIIIIVV

494191

3850101

Source: Wolmark N. Presentation. ASCO 2005.

C-07C-07Overall Toxicity (%)Overall Toxicity (%)

C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity

Gr I P/D that do not interfere with function

Gr II P/D interfering with function, but not ADL

Gr III P/D with pain or interference with ADL

Gr IV Persistent P/D that are disabling or life-threatening

Source: www.eloxatin.com/hep/patientmgmt5.asp

P = paresthesia; D = dysesthesia; ADL = activities of daily living

Grade ≥ 1 (All) Neurotoxicity (%)

During Tx

100

80

60

40

20

0

C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity

Grade > 1 (All) Neurotoxicity (%)

During Tx 12 months

100

80

60

40

20

0

85.4 85.4

29.4

Source: Wolmark N. Presentation. ASCO 2005.

C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity

Grade III Neurotoxicity (%)

10

8

6

4

2

0

8

0.5

During Tx 12 months

Source: Wolmark N. Presentation. ASCO 2005.

OxaliplatinOxaliplatinProtocol-Stipulated Cumulative DoseProtocol-Stipulated Cumulative Dose

C-07 765 mg/m2

MOSAIC 1,020 mg/m2

Source: Wolmark N. Presentation. ASCO 2005.

73% received protocol-stipulated cumulative dose

1 2 3

100

80

60

40

20

0

Percent of Full Dose Oxaliplatin/CyclePercent of Full Dose Oxaliplatin/Cycle

86.9

68.662.5

Source: Wolmark N. Presentation. ASCO 2005.

N

FULV 34 (2.7%)

FLOX 56 (4.5%)

Source: Smith RE et al. Proc ASCO GI 2004.

C-07C-07Bowel Wall InjuryBowel Wall Injury

C-07C-07Deaths During TreatmentDeaths During Treatment

N

FULV 14 (1.1%)

FLOX 15 (1.2%)

Source: Wolmark N. Presentation. ASCO 2005.

1.0

0.9

0.8

0.7

0.6

0.5

Pro

po

rtio

n o

f p

atie

nts

0 1 2 3 4

21% risk reduction

p < 0.004HR: 0.79 [0.67 – 0.93]

C-07 C-07 Disease-Free SurvivalDisease-Free Survival

Events 3y DFSFLOX 272 76.5%FULV 332 71.6%

Source: Wolmark N. Presentation. ASCO 2005.

Years

The global test for interaction between treatment and

tumor stage (II+III) was not significant (p = 0.70).

Benefit from Oxaliplatin in NSABP-C-07 and Benefit from Oxaliplatin in NSABP-C-07 and MOSAIC TrialsMOSAIC Trials

3y DFS Δ HR

C-07 76.5% 4.9% 0.79

MOSAIC 77.9% 4.9% 0.77

Sources: Wolmark N. Presentation. ASCO 2005; de Gramont A. Presentation. ASCO 2003.

ConclusionsConclusions

The addition of oxaliplatin to weekly bolus FULV significantly improves 3-year DFS in patients with Stage II and III colon cancer.

The data confirm and extend the results of the MOSAIC trial.

The benefit of oxaliplatin does not appear to be dependent on the schedule of FULV administration.

The data support the use of weekly bolus FULV in combination with oxaliplatin in adjuvant colon cancer.