Cardiac Toxicity on NSABP B-31

1
Cardiac Toxicity on NSABP B-31

• Charles E. Geyer, Jr. MD
• Director of Medical Affairs
• NSABP
• Pittsburgh, PA
• September 17, 2005

2
B-31 Cardiac Monitoring ProgramDevelopment Group

• John Bryant, PhD
• Edward Romond, MD
• Elizabeth Tan-Chiu, MD
• Sandra Swain, MD

3
B-31 Cardiac Monitoring ProgramData Management

• Priya Rastogi, MD
• Greg Yothers, PhD
• Ann Brown, ScD
• Cheryl Butch, RN, BA
• Carole Donnelly
• Steve Zieger

4
NSABP B-31
Operable Breast Cancer HER-2 Positive Tumor Path
Positive Axillary Nodes
Randomization
AC q3wk x 4 Paclitaxel q3wk x 4 or Paclitaxel
qwk x 12 Trastuzumab qwk x
52
AC q3wk x 4 Paclitaxel q3wk x 4 or Paclitaxel
qwk x 12
Choice of Taxol schedule and hormonal therapy
at discretion of investigator stratification
factors
5
B-31 Design Assumptions

• A potential 4 incidence of CHF was anticipated
  with concurrent trastuzumab and paclitaxel
  following AC
• This would be acceptable if 25 relative risk
  reduction for death were demonstrated,
  particularly if cardiac effects were largely
  reversible
• 10 year OS improvement projection 62-70

6
B-31 Cardiac Eligibility Criteria

• Normal left ventricular ejection fraction
• No past or active cardiac disease including
• History of myocardial infarction
• History of congestive heart failure
• Angina pectoris requiring medication
• Arrhythmia requiring medication
• Clinically significant valvular disease
• Uncontrolled hypertension
• Left ventricular hypertrophy
• Cardiomegaly on CXR

7
B-31 LVEF Evaluation Schedule
Arm 1 AC x 4 Paclitaxel
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
Arm 2 AC x 4 Trastuzumab
Paclitaxel
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
8
NSABP B-31Criteria for Trastuzumab Initiation

• Trastuzumab only initiated if
• Patient remained free of cardiac symptoms
  AND
• Post AC LVEF LLN AND
• Absolute decline was 15 percentage points from
  pre-entry value
• Patients not meeting post AC criteria
• Trastuzumab arm - 66/974 (6.8)
• Control arm - 82/962 (8.5)
• Combined arms - 148/1936 (7.6)

9
B-31 Cardiac Event Primary Endpoint for Cardiac
Safety

• If either of the following occurred
• Definite or probable Cardiac Death
• Symptomatic CHF confirmed by
  MUGA or Echo
• Dyspnea with normal activity or at rest AND
• Documented absolute drops in LVEF of
• Greater than 10 to below 55, or
• Greater than 5 to below institutions
  LLN
• Absolute difference of 4 in CE between arms in
  patients with good post AC LVEFs considered
  acceptable

.
10
Symptomatic Patients Real Time Blinded
Evaluation

• Symptoms of possible CHF reported within 14 days
  regardless of severity (Form CR)
• Source documents blinded centrally in regards to
  trastuzumab therapy
• Reviewed by each member of external Cardiac
  Advisory Panel (CAP)
• Majority determination of whether or not protocol
  criteria for a Cardiac Event were met

11
NSABP B-31 Cardiac Event Rates
Romond et al. ASCO 2005
12
Trastuzumab Associated CHF Risk Factors
3 Year cumulative incidence of CHF Arm 2
evaluable cohort
9/48
20.0
3-Yr Cum Inc of CHF ()
3/48
11/196
1/160
2/160
5/229
6.8
6.1
2.5
1.1
1.5
Age 49 50 49
50 49 50
Post AC 50-54 55-64
65 LVEF
13
Recovery of Patients Reporting Symptoms of
Possible CHF
AC?PTX AC ?PTXH

• Confirmed CHF (n)
  4 31
• Followed 6 months from CHF 1
  27 Symptoms during
  last 6 months 1/1
  1/27 On meds during last 6 months
  1/1 18/27
• Not confirmed with CHF (n)
  8 43
• Followed 6 months from symptoms 6
  39 Symptoms during
  last 6 months 0/6
  1/39 On meds during last 6 months
  0/6 8/39

14
Histograms of Left Ventricular Ejection Fraction
Arm 2 patients with symptoms meeting criteria for
CHF

(a)
(N25)
(N30)
(b)
Arm 2 patients with symptoms not meeting criteria
for CHF

(N35)
(N44)
(c)
(d)
Proportion
Arm 2 patients discontinuing H due to
asymptomatic decline in LVEF

(e)
(f)
(N80)
(N56)
70
70
lt 30
lt 30
30-34
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
35-39
40-44
45-49
50-54
55-59
60-64
65-69
Current LVEF, 18 Months
Nadir LVEF
15
B-31 LVEF Evaluation Schedule
Arm 1 AC x 4 Paclitaxel
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
Arm 2 AC x 4 Trastuzumab
Paclitaxel
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
16
Asymptomatic PatientsCriteria for Continuing
Trastuzumab
Absolute Decrease of lt 10
Absolute Decrease of 10 - 15
Absolute Decrease of ? 15
Relationship of 6 and 9 mo. LVEF to LLN
Cont. Cont. Cont.

• Within Normal Limits
• 1- 5 below LLN
• ? 6 below LLN

Cont. Hold Hold
Hold Hold Hold
Repeat LVEF assessment after 4 weeks -
If criteria for continuation met resume
trastuzumab

- If 2 consecutive holds, or total of 3 holds
occur discontinue trastuzumab
17
NSABP B-31 Trastuzumab Discontinuation Due to
Asymptomatic or Symptomatic Cardiac Dysfunction
by Quarter