Phase III Trial Comparing AC-T with AC-TH and with TCH
in the Adjuvant Treatment of HER2 positive Early Breast Cancer Patients:
Second Interim Efficacy Analysis
Study sponsored by Sanofi-AventisSupport from Genentech
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M,
Falkson C, Pinter T, Fornander T, Shiftan T, Valero V, Von Minckwitz G, Mackey J, Tabah-Fisch I, Buyse M,
Lindsay MA, Riva A, Bee V, Pegram M, Press M, Crown J, on behalf of the BCIRG 006 Investigators.
Slamon D., SABCS 2006BCIRG 006
After the presentation these slides will be available at:
www.sabcs.orgwww.cirg.org
The HER2 AlterationThe HER2 Alteration
IHC
Southern
Northern
Western
Slamon et al. Science 1987,1989
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
6 x Docetaxel and Carboplatin75 mg/m2 AUC 6
1 Year Trastuzumab
N=3,222
1 Year Trastuzumab
ACèT
ACèTH
TCH
Her 2+(Central FISH)
N+or highrisk N-
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
Slamon D., SABCS 2006
BCIRG 006
Stratified by Nodes and Hormonal Receptor Status
Slamon D., SABCS 2006BCIRG 006
Endpoints
Primaryà Disease-free Survival
Secondaryà Overall Survivalà Toxicityà Pathologic & Molecular Markers
Slamon D., SABCS 2006BCIRG 006
Patient characteristics
%%%
51
61
63
79
52
AC-THn=1,074
5150Hormonotherapy
5452 Age < 50 years
80 80 KPS = 100
63 63 Radiotherapy
60 60 Mastectomy
TCHn=1,075
AC-Tn=1,073
Randomized (n=3,222)
Enrollment: April 2001 to March 2004
Slamon D., SABCS 2006BCIRG 006
Tumor Characteristics
29 29 29 0
54
7
55
38
%
9
24
38
%
AC-THn=1,074
54 54 ER and/or PR +
%%Number of nodes +
39 38 1 – 3
23 22 4 – 10
10 11 > 10
%%Tumor Size (cm)
6 6 > 5
54 53 > 2 and ≤ 5
40 41 ≤ 2
TCHn=1,075
AC-Tn=1,073
Randomized (n=3,222)
Slamon D., SABCS 2006BCIRG 006
Crossover
After the trastuzumab efficacy results were announced in April ’05, to date:
ü A total of 17 patients (1.6%) of 1,073 randomized to the the ITT control arm (AC-T) crossed-over toreceive trastuzumab
ü Leaving 98.4% of the control arm enrollment intact for subsequent DFS, OS and safety comparison analyses
Slamon D., SABCS 2006BCIRG 006
First Interim Efficacy Analysis(cutoff date June 30, 2005 )
à Median follow-up time = 23 monthsà 322 DFS Events
ü Breast Cancer Relapseü Second Primary Malignancyü Death
à 84 Deaths
/Second/November 01, 2006
/36/462
/185
Slamon D., SABCS 2006BCIRG 006
Disease Free Survival – 1st interim analysis%
Dis
ease
Fre
e0.
50.
60.
70.
80.
91.
0
0 1 2 3 4 5Year from randomization
77%
86%
80%
73%
84%
80%86%
93%
91%
Patients Events1073 147 AC->T1074 77 AC->TH1075 98 TCH
HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002
Slamon D., SABCS 2006BCIRG 006
Disease Free Survival - 2nd Interim AnalysisAbsolute DFS benefits
(from years 2 to 4):AC→TH vs AC→T: 6%
TCH vs AC→T: 5%
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events1073 192 AC->T1074 128 AC->TH1075 142 TCH
81%
87%
86%
77%
83%
82%87%
93%
92%
HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003
Year from randomization
Slamon D., SABCS 2006BCIRG 006
p-values at Interim Efficacy Analyses
at 1st interim analysisp=0.0000005
p=0.00015
p=0.16
77
AC-THn=1,074
98147Patients with event
AC-Tn=1,073
TCHn=1,075
67 / 9852 / 93113 / 143Metastatic events
HR at 1st interim analysis
0.61
0.49AC-TH
TCH
0 0.2 0.6 0.8 1.00.4
/ 0.000011
/ 0.00028
/ 0.42
/ 192 / 128 / 142
at 2nd interim analysis
HR at 2nd interim analysis
0.67
0.61
TCH
AC-TH
0 0.2 0.6 0.8 1.00.4
Slamon D., SABCS 2006BCIRG 006
Overall Survival – 2nd Interim Analysis
HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017
% S
urvi
val
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events1073 80 AC->T1074 49 AC->TH1075 56 TCH
97%
99%98%
93%
97%
95% 92%
91%
86%
Year from randomization
Slamon D., SABCS 2006BCIRG 006
Deaths at Interim Efficacy Analyses
20
AC-THn=1,074
2836 Total number of deathsfrom any cause
AC-Tn=1,073
TCHn=1,075
21 / 4719 / 4433 / 69Breast Cancer Deaths
at 1st interim analysis p=0.004
p=0.017
p=0.58
/ 80 / 49 / 56
at 2nd interim analysis
Slamon D., SABCS 2006BCIRG 006
DFS Lymph Node Negative2nd Interim Analysis
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events
309 35 AC->T310 12 AC->TH309 17 TCH
92%
99%
97%
88%
95%
94%
86%
94%
93%
HR (AC->TH vs AC->T) = 0.32 [0.17;0.62] P=0.0007HR (TCH vs AC->T) = 0.47 [0.26;0.83] P=0.0096
Year from randomization
Slamon D., SABCS 2006BCIRG 006
Overall Survival Lymph Node Negative2nd Interim Analysis
% S
urvi
val
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events307 12 AC->T309 2 AC->TH307 5 TCH
99%
100%
98% 96%
100%
98%
93%
97%
98%
HR (AC->TH vs AC->T) = 0.16 [0.04;0.73] P=0.018HR (TCH vs AC->T) = 0.42 [0.15;1.2] P=0.106
Year from randomization
Slamon D., SABCS 2006BCIRG 006
DFS Subpopulations
1.00.0 2.0
AC-THbetter
AC-Tbetter
Subgroup
Node neg
Node pos
HR -
HR +
Tsize<2cm
Tsize=2cm
AC-TH vs AC-T
1.00.0 2.0
Subgroup
Node neg
Node pos
HR -
HR +
Tsize<2cm
Tsize=2cm
TCH vs AC-T
TCHbetter
AC-Tbetter
Slamon D., SABCS 2006BCIRG 006
Overall Survival Subpopulations
1.00.0 2.0
AC-THbetter
AC-Tbetter
Subgroup
Node neg
Node pos
HR -
HR +
Tsize<2cm
Tsize=2cm
AC-TH vs AC-T
1.00.0 2.0
Subgroup
Node neg
Node pos
HR -
HR +
Tsize<2cm
Tsize=2cm
TCH vs AC-T
TCHbetter
AC-Tbetter
Slamon D., SABCS 2006BCIRG 006
Grade 3/4 Non-Hematological toxicity
4.85.76.0Nausea
1.85.25.2Myalgia
26.424.227.1Irregular menses
1.43.13.6Stomatitis
5.55.73.0Diarrhea
3.46.86.1Vomiting
0.01.41.9Hand-foot syndrome
7.3
3.3
AC-THn=1,068
%
1.43.2Arthralgia
7.27.0Fatigue
TCHn=1,056
%
AC-Tn=1,050
%
**
*
*
*
Yellow = numerically less events AC-TH or TCH*Statistically significant AC-TH or TCH
Slamon D., SABCS 2006BCIRG 006
Specific non-hematological toxicity (all grades)
0.20.30.6Creatinine Grade 3/4
4.26.35.2Neuropathy-motor
0.10.00.0Renal failure
38.655.552.8Myalgia
43.6
49.7
AC-THn=1,068
%
36.148.3Neuropathy-sensory
28.749.2Nail changes
TCHn=1,056
%
AC-Tn=1,050
%
*
*
*
*
Yellow = numerically less events AC-TH or TCH*Statistically significant AC-TH or TCH
Slamon D., SABCS 2006BCIRG 006
Grade 3/4 Hematological Toxicity
11.012.011.3Neutropenic infection
48.260.251.5Leucopenia
9.811.09.1Febrile neutropenia
66.271.363.3Neutropenia
1.2
3.1
AC-THn=1,068
%
5.82.5Anemia
5.41.0Thrombocytopenia
TCHn=1,056
%
AC-Tn=1,050
%
0 pts1 pt (0.1)3 pts (0.3)Leukemia (%)
**
*
*
Yellow = numerically less events AC-TH or TCH*Statistically significant AC-TH or TCH
Cardiovascular risk factors
284312234190
364710242177
385420214177
Risk factors (# of Pts)DiabetesHypercholesterolemiaHyperlipidemiaObesity (BMI > 30)Hypertension
671333
656320
662346
Radiotherapy (# of Pts)After chemotherapyTo left chest
AgeMedianRange
Randomized (n=3,222)
49 yrs(23 - 73 yrs)
49 yrs(22 - 74 yrs)
49 yrs(23 - 74 yrs)
TCHn=1,075
AC-THn=1,074
AC-Tn=1,073
Slamon D., SABCS 2006BCIRG 006
Cardiac Deaths and CHF as per Independent Review Panel
4 17 3 Cardiac left ventricular function (CHF)
Grade 3 / 4
Cardiac related death 0 0 0
TCHn=1,056
AC-THn=1,068
AC-Tn=1,050
first interim analysissecond interim analysis
/ 0 / 0 / 0
/ 4 / 20 / 4
P = 0.0015
Slamon D., SABCS 2006BCIRG 006
Patients with >10% relative LVEF decline
817.39%
8218091Patients
TCHn = 1029
AC-THn = 1040
AC-Tn = 1012
first interim analysis
P <0.0001 P <0.0001
P = 0.5second interim analysis
/102 /189 /89
/10 /18 /8.6
/1014 /1042 /1030
P = 0.002 P <0.0001
P = 0.5
Slamon D., SABCS 2006BCIRG 006
Mean LVEF - All Observations1st Interim Analysis
59
60
61
62
63
64
65
66
0 100 200 300 400 500 600 700 800
Days
LVE
F
AC->T (N=1012)AC->TH (N=1040)TCH (N=1029)
AC->T
TCH
AC->TH
Slamon D., SABCS 2006BCIRG 006
58
Mean LVEF - All Observations2nd Interim Analysis
59
60
61
62
63
64
65
66
0
LVEF
poi
nts
%
100 200 300 400 500 600 700 800 900 1000
Time since randomization (days)AC->T (N=1014)AC->TH (N=1042)TCH (N=1030)
AC->T
TCH
AC->TH
Slamon D., SABCS 2006BCIRG 006
HER2 and TOPO II in BCIRG 0062120 of 3222 patients analyzed
HER2Core region
17 q 12 17 q 21.1 17 q 21.2
1285 pts (60%)
N=2120
91 pts (4%)
Topo IINonCo-Amplified
Normal Amplified Deletion
TOPO II region
744 pts (35%)Co-Amplified
first interim analysissecond interim analysis
N=2990
1788 pts (60%)
145 pts (5%)
1057 pts (35%)
2990 of 3222 patients analyzed
Slamon D., SABCS 2006BCIRG 006
TOPO IIa (not HER2) Amplification as a Predictor of Anthracycline Response in Breast Cancer
3542002Di Leo et al.
352002Coon et al.
1882003Park et al.
8052005Knoop at al.
5252006Tanner et al.
2842006Park et al.
NYrStudy
Since 2002, at least 6 studies have been published demonstrating the association between topo II alphaamplification and improved anthracyline response.
Slamon D., SABCS 2006BCIRG 006
DFS Topo II Co-Amplified vs Non Co-Amplified All Patients (1st interim analysis)
Patients Events Topo II
744 57 Co-Amplified1376 191 Non Co-amplified
% D
isease Free
0.50.6
0.70.8
0.91.0
0 1 2 3 4 5Year from randomization
Logrank P<0.001
Co-Amplified
Non Co-amplified
Slamon D., SABCS 2006BCIRG 006
DFS Topo II Co-Amplified vs Non Co-Amplified All Patients (2nd interim analysis)
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events Topo II
1044 1191904 325
94%
88%
88%
82%
84%
78%
Co-Amplified
Non Co-amplified
Year from randomization
HR (Co-Amp vs Non Co-Amp) = 1.44 [1.16;1.78] P<0.001Co-AmplifiedNon Co-amplified
Slamon D., SABCS 2006BCIRG 006
DFS Co-Amplified Topo II by Arm (1st Interim Analysis)
Year from randomization
% D
isea
se F
ree
0.5
0.6
0.8
1.0
0 1 2 3 4 5
Patients Events227 23 AC->T265 13 AC->TH252 21 TCH
Logrank P= 0.24
TCH
AC->TH
AC->T
Slamon D., SABCS 2006BCIRG 006
DFS Co-Amplified Topo II by Arm (2nd Interim Analysis)
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events328 42 AC->T357 35 AC->TH359 42 TCH
92%
95%
94%
87%
89%87%
85%
83%83%
Year from randomization
P=0.336P=0.648
Slamon D., SABCS 2006BCIRG 006
DFS Non Co-Amplified Topo II by Arm (1st Interim Analysis)
% D
isea
se F
ree
0.6
0.8
1.0
0 1 2 3 4 5
Patients Events458 92 AC->T472 45 AC->TH446 54 TCH
Logrank P= <0.001
TCHAC->TH
AC->T
0.5
Year from randomization
Slamon D., SABCS 2006BCIRG 006
DFS Non Co-Amplified Topo II by Arm (2nd Interim Analysis)
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events643 146 AC->T643 87 AC->TH618 92 TCH
83%
91%
90%
78%
85%
84%
71%
83%
81%
Year from randomization
P<0.001P<0.001
Slamon D., SABCS 2006BCIRG 006
Therapeutic Index – Most Recent Dataà Difference in DFS, OS and BC death events (ITT) between
the 2 Herceptin-containing armsü DFS AC-TH - 128 TCH – 142ü OS AC-TH - 49 TCH – 56ü Br Ca Deaths AC-TH - 44 TCH – 47
à Difference in critical adverse events between anthracyclineand non-anthracycline containing armsü Grade 3/4 CHF
� AC-T - 5 AC-TH - 20 TCH - 4ü Leukemia
� Anthracycline-Based Arms - 4 TCH – 0à Global safety TCH > AC-TH
à In addition, 23 pts with bona fide HER2 amplification who were randomized to the AC-TH arm never got trastuzumabdue to unacceptable declines in LVEF before receiving the antibody
Slamon D., SABCS 2006BCIRG 006
Critical QuestionüConsidering:
ü The recently published data from US Oncology showing a highly statistically significant superiority of docetaxel-cyclophospamide (TC) over adriamycin-cyclophosphamide (AC) in terms of breast cancer efficacy (Jones, S. JCO 24:5381, 2006).
What is the role of anthracyclinesin the adjuvant treatment of breast cancer?
ü The 006 update for HER2 positive malignancies shows the difference in number of DFS events and breast cancer deaths in favor of AC-TH, neither of which are statistically significant, is now exceeded by the number of critical adverse events. These include grade III/IV CHF and AC- related leukemia as well as a small AND sustained loss of LVEF for 18% (189 pts) both of which are highly statistically significant…
Slamon D., SABCS 2006BCIRG 006
Acknowledgements
ØAll participating Investigators and Patients
ØIDMC (Chair, S Swain) and Independent Cardiac Panel
ØCentral laboratories: M Press (USC), G Sauter (Basel)
ØIDDI: M. Buyse
ØNBCC: Fran Visco and Carolina Hinestrosa
ØBCIRG Central Team: V Bee, D Cabaribere, T Kiskartalyi, T Smith, L Lallaoui, H Taupin, K Afenjar, P Drevot, L Andersen, H Fung, J Mortimer, A Riva, MA Lindsay
Slamon D., SABCS 2006BCIRG 006
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Principal Investigators involved in the study (I)
* Highest recruiters
Slamon D., SABCS 2006BCIRG 006
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Principal Investigators involved in the study (II)
* Highest recruiters
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