BCIRG006 - Randomized Phase III Trial Comparing AC-T vs AC-TH vs TCH in

HER2 Positive Node Positive or High Risk Node Negative Breast Cancer

Initial efficacy from 1st planned analysis as of 6/30/05 (to be presented at SABCS-12/05) and

Summary of cardiac data as of 4th Planned Analysis - 3222 patients from 12/31/04

Prepared by Marc Buyse and Valentine Jehl, IDDI

Valerie Bee and Veronique Wilson, BCIRG

10 May 2005

Trastuzumab Registration9/26/98

Trastuzumab in Combination with Chemotherapy

• Primary– Time to disease progression

(REC)– Safety

• Secondary– Overall response rates– Durations of response– Time to treatment failure– 1-year survival– Quality of life

Objective - Combination Compared to Chemotherapy Alone

Trastuzumab in Combination with Chemotherapy

No prior anthracyclines

Design - Stratification to Chemotherapy

AC = doxorubicin (60 mg/m2)or epirubicin (75 mg/m2) +

cyclophosphamide (600 mg/m2)q 3 wks x 6 cycles

Prior anthracyclines

T = paclitaxel (175 mg/m2 x 3 hr) q 3 wks x 6 cycles

Trastuzumab in Combination with Chemotherapy

Total enrolled 469

Enrollment

Randomization H + CT CT235 234

Subgroups

H + AC AC H + T T143 138 92 96

Summary: Phase III Clinical Trial Comparing Best Available Chemotherapy

to Same Therapy + Trastuzumab

Enrolled

H + CT 235 49 (53%) 9.3M (58%) 7.6M (65%)

CT 234 32 5.9M 4.6M

H + AC 138 52 (20%) 9.1M (40%) 8.1M (33%)

AC 145 43 6.5M 6.1M

H + T 92 42 (163%) 11.0M (150% 6.9M (130%)

T 96 16 4.4M 3.0M

R.R. (%) Dur. Res. T.T.P

Trastuzumab in Combination with Chemotherapy

• Overall Trastuzumab impact on survival uncertain

– Limited duration of follow-up (12 months)

– CT alone patients allowed to enter Trastuzumab extension protocol

• Preliminary analysis - improved 1-yr survival

– H + CT = 78% alive

– CT alone = 67% alive

Survival Time

Clinical Safety

• Trastuzumab is generally well tolerated

– Single agent

– Combined with chemotherapy

• Most adverse events mild to moderate in severity

– Infusion associated symptoms, including fever and chills primarily with first dose

• Serious adverse events infrequent

• Increased incidence of cardiac dysfunction, particularly when administered with anthracycline based therapy

Summary of Trastuzumab Safety

Trastuzumab in Combination with Chemotherapy

Cardiac Dysfunction Outcomes (CREC)

*Trastuzumab extension protocol

H+AC AC H+T T

Cardiac Dysfunction Events

39 9 11 2

Trastuzumab 14 5* 6 1*

Death 4 1 1 2

MBC 4 0 0 2

Cardiac 0 1 0 0

Pneumonia 0 0 1 0

Conclusion

• The results of this study indicate that Trastuzumab in combination with chemotherapy is well-tolerated and provides substantial clinical benefit in first-line treatment of HER-2 overexpressing metastatic breast cancer

• Future studies of Trastuzumab will be important– Adjuvant breast cancer– Other combinations– Other tumors

Adjuvant use of Trastuzumab must be evaluated in a randomized-controlled trial

BCIRG 006Adjuvant Treatment of Breast Cancer

Node Positive and High Risk Node Negative

HER2 +FISH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 Year Trastuzumab

N=31501 Year Trastuzumab

ACT

ACTH

TCH

Protocol definition of “clinically significant cardiac events”

Occurrence of one or more of the following:– cardiac death – grade 3 or 4 cardiac left ventricular ejection

fraction (congestive heart failure) – *grade 3 or 4 arrhythmias – *grade 3 or 4 cardiac ischemia / infarction

– * Defined as events - unique to 006 Trial

Adverse Events graded according to NCI-CTC Version 2.0

– Incidence of cardiac events in the ACT arm expected to be approximately 1%

– Absolute increase in the observed incidence of cardiac events of more than 4% in either of the Trastuzumab containing arms (ACTH and TCH) considered unacceptable

– Power to detect an absolute increase of 4% :

Protocol stopping rule for excessive cardiac toxicity

Analysis # Number of patients

Approximate power

1 300 40%

2 900 80%

3 1500 95%

4 3222 >99%

Protocol definition of “clinically significant asymptomatic LVEF decline”

– Any absolute LVEF decline of more than 15% from baseline that is also below the lower limit of normal (LLN)

– Analyses were carried out on maximum absolute and relative LVEF declines from baseline >10% and >15% and below LLN, confirmed on two consecutive occasions within 28 days, within 42 days, or at any time, using the same or any assessment method

BCIRG 006 Study Status

• 3,222 patients randomized between April 2001 and March 2004

Treatment AC-T AC-TH TCH

Started treatment as per protocol 1043 1074 1056

Did not receive study treatment 29 2 18

Total 1072 1076 1074

Overall Follow-up: Date of Randomization to Last Follow-up Evaluation

AC->T

AC->TH

TCH

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Months of Follow-up

0

10

20

30

40

50

60

70

80

90

100

% p

atie

nts

stil

l fo

llow

ed

Median follow-up time = 17.6 months

Database Status• Clinical cut-off as of December 31, 2004• Database frozen as of May 6, 2005• Median follow-up of 17.6 months• Few missing data:

– 20 chemotherapy cycles (of 22,628) – 7 end of chemotherapy forms (of 3,222)

• Few outstanding queries (10): – 7 on LVEF at baseline– 2 on ECG at baseline– 1 on grade of sinus bradycardia at baseline

Chemotherapy administration - cycles

Cycles Received

AC-T AC-TH TCH

1 4 3 5

2 6 3 10

3 7 6 9

4 11 14 9

5 28 13 14

6 14 20 1007

(95.5%)

7 22 22 0

8 951

(91.2%)

993

(92.5%)

0

Chemotherapy administrationMedian

Relative Dose Intensity

AC-T AC-TH TCH

Doxorubicin 99% 97% -

Cyclophosphamide 99% 97% -

Docetaxel 99% 100% 99%

Cisplatin - - 98%

Carboplatin - - 94%

Median Cumulative Dose

of Doxorubicin 240 mg/m² 240 mg/m² -

Trastuzumab administration

Median Cumulative Dose

of Trastuzumab

AC-T AC-TH TCH

During Chemotherapy - 26 mg/kg 38 mg/kg

After Chemotherapy - 78 mg/kg 66 mg/kg

Total - 98 mg/kg 104 mg/kg

Potential cardiac risk factorsAC-T AC-TH TCH

Age

Median

Range

49 yrs

(23 - 74 yrs)

49 yrs

(22 - 74 yrs)

49yrs

(23 - 73 yrs)

Risk factors (# of Pts)

Diabetes

Hypercholesterolemia

Hyperlipidemia

Obesity

37

51

16

25

31

44

10

36

31

43

12

35

Radiotherapy (# of Pts)

After chemotherapy

To left chest

584

299

562

270

588

280

Pre-existing cardiac signs and symptoms

AC-T AC-TH TCH

# patients with on-going cardiac event at baseline

223 254 254

# patients with ceased cardiac event at baseline

39 45 47

# patients with ECG abormalities at baseline (of which 4 significant)

201 186 193

No major imbalance with respect to cardiac history at baseline

Discontinuation of Trastuzumab

AC-T AC-TH TCH

Did not start chemotherapy

Did not start TrastuzumabTrastuzumab Therapy Continues

Completed Trastuzumab Treatment

Discontinued During Chemotherapy

Death

Breast Cancer Relapse

Adverse Event (Non-Cardiac)

Adverse Event (Cardiac)

Adverse Event (Asymptomatic LVEF decline)Consent Withdrawn

Other

Discontinued During Follow-up

Adverse Event (Non-Cardiac)

Adverse Event (Cardiac)

Adverse Event (Asymptomatic LVEF decline)Breast Cancer Relapse

Consent Withdrawn

Lost to follow-up

Other

0

23477

403

0

1

9

10

1223

15

2

24

196

14

1

3

2

0403

543

2

2

6

9

316

7

3

6

95

8

2

1

Clinically significant cardiac eventsAC-T AC-TH TCH

Cardiac death 0 0 0

Cardiac ischemia / infarction

Grade 3

Grade 4

1

0

2

2

2

2

Arrhythmias

Grade 3

Grade 4

9

1

6

0

8

0

Cardiac left ventricular function (CHF)

Grade 3

Grade 4

1

0

17

1

1

0

Total events 12 28 13

Total patients 12 25 13

LVEF Declines by NYHA Class

AC-T AC-TH TCH

>10%, <LLN

9 34 7

>15%, <LLN

6 25 4

Grade 3/4 CHF 2 20 1

Clinically significant cardiac events - as defined in the CIRG 006 protocol but not in the

other groups

Treatment AC-T AC-TH TCH

# with events 13 27 13

# patients 1043 1072 1056

Proportion

(95% C.I.)

1.2%

(0.6% - 2.0%)

2.3%

(1.5% - 3.4%)

1.2%

(0.6% - 2.1%)

Fisher’s exact tests:

AC-T vs AC-TH: P=0.046; AC-T vs TCH: P=1.00

Compliance with repeat LVEF assessments

Repeat Assessment Time

AC-T AC-TH TCH

27 days 18% 24% 22%

28 – 42 days 28% 38% 35%

43 – 90 days 25% 21% 27%

91 – 180 days 18% 10% 9%

> 180 days 11% 7% 7%

Notes:

1. The frequency of LVEF declines was likely underestimatedby the non-compliance with the protocol requirement ofa repeat assessment within 28 days

2. The compliance with repeat assessment times was slightly better in the Trastuzumab-containing arms

Patients with >15% absolute LVEF declineand below LLN, using any assessment method

AC-T AC-TH TCH

# confirmed within 28 days

1 12 2

# confirmed within 42 days

3 20 3

# confirmed at any time

6 26 4

# patients 1021 1058 1031

Fisher’s exact tests:

Within 28 days: AC-T vs AC-TH: P=0.003; AC-T vs TCH: P=1.00

Within 42 days: AC-T vs AC-TH: P=0.001; AC-T vs TCH: P=1.00

At any time: AC-T vs AC-TH: P=0.001; AC-T vs TCH: P=0.55

Patients with >15% relative LVEF declineand below LLN, using same assessment method

AC-T AC-TH TCH

# confirmed within 28 days

4 19 6

# confirmed within 42 days

6 32 7

# confirmed at any time

12 39 9

# patients 1003 1042 1019

Fisher’s exact tests:

Within 28 days: AC-T vs AC-TH: P=0.003; AC-T vs TCH: P=0.75

Within 42 days: AC-T vs AC-TH: P<0.001; AC-T vs TCH: P=1.00

At any time: AC-T vs AC-TH: P<0.001; AC-T vs TCH: P=0.52

Conclusions - 1• Data included in these analyses are NOT

final. However, it is unlikely that any of the main results will change qualitatively with further database cleaning and follow-up

• The protocol-defined threshold of a 4% increase in protocol-defined cardiac events was not exceeded for either of the Trastuzumab-containing arms (AC-TH or TCH) as compared to the control (AC-T) arm

Conclusions - 2• There was a clear and statistically significant

excess of patients with protocol-defined cardiac events in the AC-TH arm compared to the AC-T arm

Treatment AC-T AC-TH TCH

# with events 12 25 13

# patients 1043 1072 1056

Proportion 1.2% 2.3% 1.2%

P=0.046 P=0.07

P=1.00

Conclusions - 3• There was a clear and highly statistically

significant excess of patients with >15% absolute LVEF declines in the AC-TH arm compared to the AC-T arm or the TCH arm

Treatment AC-T AC-TH TCH

# with events 6 25 4

# patients 1003 1042 1019

Proportion 0.6% 2.4% 0.4%

P=0.001 P<0.001

P=0.54

Conclusions - 4• Cardiac toxicity was as expected (1.2% of

treated patients) in the AC-T arm• There was convincing statistical evidence of

increased cardiac toxicity in the AC-TH arm as compared to the AC-T arm, with about twice as many patients affected (2.3% of treated patients)

• There was no statistical evidence of cardiac toxicity in the TCH arm as compared to the AC-T arm

Conclusions - 5• Using a mixed model to analyze LVEF declines

over time, the slope of the decline was statistically significant for the AC-TH and AC-T arms, but not for the TCH arm

Treatment AC-T AC-TH TCH

Slope* -0.78 -1.77 0.03P-value 0.0002 <0.0001 0.79

* A slope of –1 represents an average annual decline of 1% in LVEF

Acknowledgements

• The Investigators & Staff

of - CIRG

Acknowledgements • Genentech:

Axel Ullrich H. Michael Shepard, Hank Fuchs, Bob Mass, Gwen Fyfe, Mark Sliwkowski

• Sanofi-Aventis: Terry Rugg

• Nat. Br. Ca. Coalition

• Revlon Foundation: Ronald Perlman Jim Conroy

• Trastuzumab Clinical Investigators Network

• Community-based/UCLA Clinical Research Network