Phase III Trial Comparing AC-T with AC-TH and with TCH in ... · 52 AC-TH n=1,074 Hormonotherapy 50 51 Age < 50 years 52 54 KPS = 100 80 80 Radiotherapy 63 63 Mastectomy 60 60 TCH

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


Global Project Coordinator

Valerie Bee

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


Endpoints

Primaryà Disease-free Survival

Secondaryà Overall Survivalà Toxicityà Pathologic & Molecular Markers


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


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



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


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


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


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


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


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


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


97%

99%98%

93%

97%

95% 92%

91%

86%



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


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%




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


99%

100%

98% 96%

100%

98%

93%

97%

98%




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


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


Safety Results


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


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

%

*

*

*

*



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 (%)

**

*

*



CARDIAC TOXICITY

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


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


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


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


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


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


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


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.


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


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


HR (Co-Amp vs Non Co-Amp) = 1.44 [1.16;1.78] P<0.001Co-AmplifiedNon Co-amplified


DFS Co-Amplified Topo II by Arm (1st Interim Analysis)


% D

isea

se F

ree

0.5

0.6

0.8

1.0

0 1 2 3 4 5


Logrank P= 0.24

TCH

AC->TH

AC->T


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


92%

95%

94%

87%

89%87%

85%

83%83%


P=0.336P=0.648


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


Logrank P= <0.001

TCHAC->TH

AC->T

0.5



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


83%

91%

90%

78%

85%

84%

71%

83%

81%


P<0.001P<0.001


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


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…


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


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Principal Investigators involved in the study (I)

* Highest recruiters


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Principal Investigators involved in the study (II)

* Highest recruiters

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Documents

Phase III Trial Comparing AC-T with AC-TH and with TCH in ... · 52 AC-TH n=1,074 Hormonotherapy 50 51 Age < 50 years 52 54 KPS = 100 80 80 Radiotherapy 63 63 Mastectomy 60 60 TCH