Transcript BCIRG006 - A randomized Phase III Trial Comparing AC

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 Registration
9/26/98
Trastuzumab in Combination
with Chemotherapy
Objective - Combination Compared to Chemotherapy Alone
• Primary
– Time to disease progression
(REC)
– Safety
• Secondary
– Overall response rates
– Durations of response
– Time to treatment failure
– 1-year survival
– Quality of life
Trastuzumab in Combination
with Chemotherapy
Design - Stratification to Chemotherapy
No prior
anthracyclines
Prior
anthracyclines
AC = doxorubicin (60 mg/m2)
or epirubicin (75 mg/m2) +
cyclophosphamide (600
mg/m2)
q 3 wks x 6 cycles
T = paclitaxel (175 mg/m2 x 3
hr)
q 3 wks x 6 cycles
Trastuzumab in Combination
with Chemotherapy
Enrollment
Total enrolled
Randomization
469
H + CT
235
CT
234
Subgroups
H + AC
143
AC
138
H+T
92
T
96
Summary: Phase III Clinical Trial
Comparing Best Available Chemotherapy
to Same Therapy + Trastuzumab
Enrolled
R.R. (%)
Dur. Res.
H + CT
CT
235
234
49 (53%)
32
9.3M (58%)
5.9M
7.6M (65%)
4.6M
H + AC
AC
138
145
52 (20%)
43
9.1M (40%)
6.5M
8.1M (33%)
6.1M
H+T
92
42 (163%)
11.0M (150%
6.9M (130%)
T
96
16
4.4M
3.0M
T.T.P
Trastuzumab in Combination
with Chemotherapy
Survival Time
• 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
Clinical Safety
Summary of Trastuzumab 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
Trastuzumab in Combination
with Chemotherapy
Cardiac Dysfunction Outcomes (CREC)
H+AC
AC
H+T
T
39
9
11
2
14
5*
6
1*
4
1
1
2
MBC
4
0
0
2
Cardiac
0
1
0
0
Pneumonia
0
0
1
0
Cardiac Dysfunction
Events
Trastuzumab
Death
*Trastuzumab extension protocol
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 006
Adjuvant Treatment of Breast Cancer
Node Positive and High Risk Node Negative
4 x AC
4 x Docetaxel
60/600 mg/m2
100 mg/m2
ACT
HER2 +
ACTH
FISH
1 Year Trastuzumab
N=3150
6 x Docetaxel and Platinum salts
75 mg/m2
75 mg/m2 or AUC 6
TCH
1 Year Trastuzumab
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
Protocol stopping rule for
excessive cardiac toxicity
– Incidence of cardiac events in the ACT 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 (ACTH and TCH)
considered unacceptable
– Power to detect an absolute increase of 4% :
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
29
2
18
1072
1076
1074
Did not receive study treatment
Total
Overall Follow-up: Date of Randomization to
Last Follow-up Evaluation
100
90
% patients still followed
80
Median follow-up time = 17.6 months
70
AC->T
AC->TH
TCH
60
50
40
30
20
10
0
0
3
6
9
12
15
18
21
Months of Follow-up
24
27
30
33
36
39
42
45
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 administration
Median
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 factors
AC-T
Age
Median
Range
AC-TH
TCH
49 yrs
49 yrs
49yrs
(23 - 74 yrs) (22 - 74 yrs) (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
0
2
Did not start Trastuzumab
23
0
Trastuzumab Therapy Continues
Completed Trastuzumab Treatment
Discontinued During Chemotherapy
Death
Breast Cancer Relapse
Adverse Event (Non-Cardiac)
Adverse Event (Cardiac)
477
403
403
543
0
1
9
10
2
2
6
9
12
3
23
15
16
7
2
24
3
6
19
9
6
14
1
3
5
8
2
1
Did not start chemotherapy
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
Clinically significant cardiac events
AC-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 underestimated
by the non-compliance with the protocol requirement of
a 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 decline
and 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 decline
and 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
0.03
P-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:
• Revlon Foundation:
Axel Ullrich
H. Michael Shepard,
Hank Fuchs,
Bob Mass,
Gwen Fyfe,
Mark Sliwkowski
• Sanofi-Aventis:
Ronald Perlman
Jim Conroy
Terry
• Trastuzumab Clinical
Investigators Network
Rugg
• Nat. Br. Ca. Coalition
• Communitybased/UCLA Clinical
Research Network