First results of BIG 2-98 trial - IBCSG

Docetaxel given concurrently or sequentially to
anthracycline-based adjuvant therapy for patients with
node-positive breast cancer. A comparison with nontaxane
combination chemotherapy. First results of the
BIG 2-98 Trial at 5 years median follow-up.
J. Crown 1 , P. Francis 1 , A. Di Leo², M. Buyse³, A. Balil, M.
Andersson, B. Norderskjöld, R. Jakesz, J. Gutierrez, M.
Piccart 1 , on behalf of the BIG 02-98 Collaborative Investigators
1
Study Chairs, 2 Assistance with trial coordination, 3 Study Statistician

Background
Node-positive breast cancer frequently fatal
Adjuvant anthracycline-containing regimens prolong
disease-free and overall survival
• Classic combinations e.g. AC, FAC, FEC
• Sequential Anthracycline-CMF (e.g. Milan, Anglo-Celtic,
NEAT trials)
Activity of docetaxel in metastatic breast cancer
mandated adjuvant study
Benefits of combination vs sequential remain undefined

BIG 02-98 Study Design
Operable N+ BC
Stratification:
-Center
-Nodes (1-3; >4)
-Age (50)
R
A
N
D
O
M
I
Z
E
*
Arm A (n=481)
24 weeks
Arm AC (n=487)
24 weeks
Arm A-T (n=960)
30 weeks
Arm AT (n=959)
24 weeks
A75 x 4 CMF x 3
AC 60/600 x 4 CMF x 3
A75 x 3 T100 x 3 CMF x 3
AT 50/75 x 4 CMF x 3
Control
Arms
Exp arms
with similar
cumulative
A and T
doses
A, doxorubicin; C, cyclophosphamide; T, docetaxel
CMF: cyclophosphamide 100 mg/m 2 p.o.days 1-14, methotrexate 40 mg/m 2
days 1 & 8, 5-fluorouracil 600 mg/m 2 days 1 & 8
* Unbalanced randomization favouring experimental arms 2:1 over control

BIG 02-98 Endpoints
Primary endpoint:
Disease-free survival (A + AC) vs (A-T + AT)
Secondary endpoint:
- DFS: A-T vs A (sequential arms)
AT vs AC
A-T vs AT
(combination arms)
(best docetaxel schedule?)
- OS, Toxicity, Pathologic and molecular markers, and
Socio-economic data

Eligibility Criteria
Histologically proven, axillary node+ breast cancer
T1-3, resected with clear margins
Written informed consent
Mastectomy +/-RT or, breast conservation + RT
Axillary dissection at least 8 lymph nodes
>18 and

Analysis Plan
Three planned analyses (O’Brien-Fleming)
• 405, 810, and 1215 (Final) events, respectively
Rate of relapse slower than expected
• 810 events would not occur at 5-year follow-up
• 1215 events would not occur until 8 years of follow-up
Protocol amended 2005 to have results available in a clinically
relevant time frame
• analyze at 5 years or 810 events, whichever came first
Actual analysis performed at 62.5 months, with fewer than 2/3
events originally planned (732 not 1215)
Stratify by age (

Accrual
Total patients: 2,887
10 Other Countries
502
Hungary
109
Australia / NZ
605
First patient: June 1998
Last patient: June 2001
Median patient: July 2000
Database cut off: March 2006
South Africa
115
Switzerland
143
Denmark
156
Italy
169
Austria
174
Ireland
190
Belgium
334
Spain
239
Sweden
202

Baseline Data (1)
N=2,887 (ITT)
% Patients
A
N=481
AC
N=487
A-T
N=960
AT
N=959
Stratification factor, age
< 50 years
53
54
53
53
≥ 50 years
47
46
47
47
Stratification factor, nodes
1-3 positive
54
55
54
54
≥ 4 positive
46
45
46
46
Type of surgery
Breast conserving
46
45
46
44
Mastectomy
54
55
54
56

Baseline Data (2)
N=2,887 (ITT)
% Patients
A
N=481
AC
N=487
A-T
N=960
AT
N=959
Grade
G1 well diff
10
9
9
8
G2 moderate diff
40
43
45
44
G3 poor diff
45
44
43
44
Hormone Receptor Status
ER and/or PR+
Receptor negative
75
24
75
25
75
24
76
24
Pre-menopausal
Post-menopausal
55
38
57
38
55
40
58
37
Stage pT1-2
pT3
94
6
92
7
93
6
91
8

Treatments
N=2,887 (ITT)
% Patients
Started protocol
treatment
Completed protocol
treatment
Received hormonal
therapy
A
N=481
AC
N=487
A-T
N=960
AT
N=959
98 99 99 99
93 94 91 94
71 74 74 75
Received radiotherapy 82 81 81 82
Lost to follow-up 3 1 2 2

First Events
N=2,887 (ITT)
% Patients
A
N=481
AC
N=487
A-T
N=960
Treatment failure 27 28 22 26
Br Ca relapse
Second primary
Death
22
4
1
25
2
1
20
2
0.3
AT
N=959
23
2
1

Event-free Survival
Comparison Hazard ratio [95% C.I.]* P-value
A-T+AT vs A+AC
0.86 [0.74 - 1.00] 0.051
A vs AC
AT vs AC
A-T vs A
A-T vs AT
1.03
0.93 [0.75 – 1.14]
0.79 [0.64 – 0.98]
0.83 [0.69 - 1.00]
0.48
0.035
0.047
Hypothetical 0.78
* Primary analysis stratified for nodal status and age

Event-free Survival:Docetaxel vs None
1.0
0.9
A + AC
A–T + AT
Probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
A + AC
A–T + AT
Patients
968
1919
Events
266 (27%)
466 (24%)
HR= 0.86 [0.74 – 1.00]
p= .051
0
0 12 24 36 48 60
72 84
Time (months)
96

Event-free Survival: Sequential A-T vs A
1.0
0.9
A
A–T
Probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Patients Events
A
A–T
481
960
129 (27%)
214 (22%)
HR= 0.79 [0.64 – 0.98]
p= .035
0
0 12 24 36 48 60 72 84
Time (months)
96

Event-free Survival:
Sequential A-T vs Combination AT
1.0
0.9
A–T
AT
Probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
A–T
AT
Patients
960
959
Events
214 (22%)
252 (26%)
HR= 0.83 [0.69–1.00]
p= .047
0
0 12 24 36 48 60
72 84
Time (months)
96

Event-free Survival in Pre-defined Subsets
A-T vs A N Hazard ratio [95% C.I.]*
Overall 1441
0.79 [0.64 - 0.98]
1-3 nodes
4+ nodes
Receptor+
Receptor-
Age < 50
Age ≥ 50
781
660
1082
359
765
676
0.85 [0.58 – 1.23]
0.76 [0.58 – 1.00]
0.79 [0.61 - 1.05]
0.80 [0.55 - 1.15]
0.84 [0.62 – 1.15]
0.75 [0.55 – 1.03]
* Stratified by age

Overall Survival
Comparison Hazard ratio [95% C.I.]* P-value
A-T+AT vs A + AC
0.92 [0.75 - 1.13] 0.34
A-T vs A
AT vs AC
0.82 [0.61 - 1.10]
1.16 [0.94 - 1.45]
0.19
0.17
A-T vs AT
0.80 [0.63-1.02 ]
0.069
* Stratified for nodal status and age

Safety
Percentage of patients with at least one NCI-CTC grade 3/4
or another severe/life-threatening toxicity reported at any
time during treatment or follow-up
40
37.8%
32.0%
Percent of Patients
30
20
10
25.6%
27.0%
0
A
AC
A-T
AT

Grade 3/4 NCI gradable or severe/life-threatening
NCI non gradable toxicities
N=2,865*
Toxicity, (%)
A
N=472
AC
N=485
A-T
N=950
AT
N=958
Asthenia 3.8 3.7 7.4 5.7
Infection 4.9 3.9 5.9 6.4
Stomatitis 5.3 1.6 7.1 4.4
Nausea 5.5 9.1 4.3 5.3
Vomiting 4.9 8.0 4.4 4.1
* Safety population

NCI gradable toxicities of any grade
N=2,865*
Toxicity, (%)
A
N=472
AC
N=485
A-T
N=950
AT
N=958
Diarrhea 31.8 29.5 43.2 39.7
Allergy 6.6 5.6 14.3 14.5
Fever w/o infection 17.2 14.2 25.8 31.5
Infection 44.9 45.4 50.0 41.9
Neuro-sensory 11.7 12.6 46.3 23.1
Skin 24.4 19.2 40.1 29.7
Stomatitis 65.7 54.6 71.1 67.4
* Safety population

Toxicity
N=2865*
Toxicity
A-CMF
N=472
AC-CMF
N=485
A-T-CMF
N=950
AT-CMF
N=958
Febrile neutropenia (%
patients)
4.9 3.5 7.5 11.6
Treatment-related deaths #
(all neutropenic)
1(0.2%)
Pneumonia
0 1(0.1%)
Sepsis
2(0.2%)
-Sepsis+
enteritis
-Meningitis
* Safety population

Conclusions
Lower than expected relapse rate reduced statistical power
• Control had 73% EFS at 5 years, despite 46% having > 4 nodes
Docetaxel resulted in improved EFS which was of borderline
significance (p=0.051), however
Sequential A-T-CMF produced superior event-free survival
over both combination AT-CMF (p=0.047) and A-CMF
(p=0.035)
This is the first demonstration of an improved outcome for
sequential over combination anthracycline/taxane
chemotherapy
This result is consistent with the Norton-Simon Hypothesis

ACKNOWLEDGEMENTS
All 2887 women who participated in the BIG 02-98 trial!
STATISTICS & DATAMANAGEMENT &
E. Quinaux
D. Antoine JY. Leroy
MEDICAL SUPERVISION
R. Giuliani E. Azambuja
F. Ferreira
ABCSG
ANZ BCTG
BREAST
BIG GROUPS
DBCG
GEICAM
GOCCHI
IBCSG/SAKK
ICORG
SBCG
MONITORING COORDINATION
IDMC MEMBERS
BIG COORDINATION
S. Jamin/ M. Vicente C. Straehle
INVESTIGATOR WITH LARGEST ACCRUAL
I Lang
Sanofi-Aventis staff