A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon:Survival results of NSABP Protocol C-07

N. Wolmark, S. Wieand, P. J. Kuebler, L. Colangelo, M. J. O'Connell, G. Yothers

Disclosure:Norman Wolmark is an

unpaid member of Sanofi-Aventis advisory boards

50 YEARSProtocol C-07

NSABP C-07

Stage ll + lll

FLOXFULV

Randomize

Strat: # Pos. N

FU B RestLV 500

FU 500 B

RestLV 500 2hr

OHP 8585 2hr2hr

500

Week 1 2 3 4 5 6 7 8

R

NSABP C-07

2hr

x3

NSABP C-07Opened: 02-00Closed: 11-02Accrual: 2492

MFU: 34 mo 5’05MFU: 42.5 mo 6’07MFU: 67 mo

C-07Accrual

FULV FLOX

Randomized

Inelig/No F-U

Analysis

1245

36

1209

1247

47

1200

NSABP C-07

Primary Endpoint: DFS

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

NSABP C-07

Secondary Endpoint: Overall Survival

Formal analysis of survival: 5 years after the last patient was entered (11’02)

Consequently the power to detect the protocol specified 0.214 reduction in the annual death rate was decreased from 0.89 to 0.81.

Expected # deaths: 700Actual # deaths: 560

C-07Patient Characteristics

Pos Nodes FULV % FLOX %

01-3≥4

28.9 45.825.3

28.8 45.325.8

DFS Update

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7

Years

p = 0.002HR: 0.81 [0.70 – 0.93]

19% risk reduction

C-07 DFS

3y 5yFLOX 76.1% 69.4%FULV 71.5% 64.2% Δ 4.6% 5.2%

≥ 65 yr

Overall

< 65 yr

N 0

1-3

>3

FLOX Better FULV Better

DFS Hazard Ratio

Overall Survival

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7

D(n) 5y 6yFLOX 259 80.3% 77.7%FULV 301 78.3% 73.5% Δ 42 2.0% 4.2% p = 0.06HR: 0.85 [0.72 – 1.01]

15% risk reduction

C-07 Survival

≥ 65 yr

Overall

< 65 yr

Stage II

Stage III

S Hazard Ratio

FLOX Better FULV Better

5y S Δ HR

C-07 80.3 % 2.0 % 0.85

Mosaic 81.3 % 2.2 % 0.85

C-07 and Mosaic oxaliplatin benefit

Is 5 years the appropriate time to assess overall

survival?

P<0.0001

ACCENT Survival After Recurrence

O’Connell JCO May 2008

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Ali

ve,

%

1978-19851986-19921993-1999

Median C-04 ‘89 12.7C-05 ’91 12.6C-06 ’97 16.4C-07 ’00 19.6

P < 0.0001 N~8000

C-04 - C-07 Survival after Recurrence

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5

Years

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5

Years

Median FLOX 17.6 FULV 22.2

P = 0.02HR: 1.24

C-07 Survival after Recurrence

ConclusionsThere is a trend toward improved survival (p=0.06) with the addition of oxaliplatin to weekly FULV at 67m MFU

The benefit of oxaliplatin (S and DFS) is independent of the schedule of FULV administration

ConclusionsThe durable consistency between the results of C-07 and Mosaic validates the benefit of oxaliplatin

Longer follow-up (>5 yrs) in future colon adjuvant trials appears to be appropriate to reliably detect survival benefit

H. Samuel Wieand

February 19, 1944 - June 10, 2006