Cardiac Toxicity on NSABP B-31 Charles E. Geyer, Jr. MD Director of Medical Affairs NSABP Pittsburgh, PA September 17, 2005

B-31 Cardiac Monitoring Program Development Group John Bryant, PhD Edward Romond, MD Elizabeth Tan-Chiu, MD Sandra Swain, MD

B-31 Cardiac Monitoring Program Data Management Priya Rastogi, MD Greg Yothers, PhD Ann Brown, ScD Cheryl Butch, RN, BA Carole Donnelly Steve Zieger

Operable Breast Cancer Path Positive Axillary Nodes 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* AC q3wk x 4 Paclitaxel q3wk x 4* or Paclitaxel qwk x 12* + Trastuzumab qwk x 52 * Choice of Taxol schedule and hormonal therapy at discretion of investigator – stratification factors

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%

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

B-31 LVEF Evaluation Schedule Arm 1 AC x 4 Paclitaxel mo. 3 mos. 6 mos. 9 mos. 18 mos. Arm 2 AC x 4 Trastuzumab + Paclitaxel mo. 3 mos. 6 mos. 9 mos. 18 mos.

NSABP B-31 Criteria 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%)

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 institution’s LLN Absolute difference of ≤ 4% in CE between arms in patients with good post AC LVEFs considered acceptable .

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

NSABP B-31 Cardiac Event Rates Romond et al. ASCO 2005

Trastuzumab Associated CHF Risk Factors 9/48 3 Year cumulative incidence of CHF: Arm 2 evaluable cohort 3-Yr Cum Inc of CHF (%) 20.0% 3/48 11/196 1/160 2/160 6.8% 5/229 6.1% 2.5% 1.1% 1.5 % Age ≤49 ≥50 ≤49 ≥50 ≤49 ≥50 Post AC 50-54 55-64 65+ LVEF

Recovery of Patients Reporting Symptoms of Possible CHF ACPTX AC PTX+H 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

Histograms of Left Ventricular Ejection Fraction Arm 2 patients with symptoms meeting criteria for CHF (a) (N=30) (N=25) (b) Arm 2 patients with symptoms not meeting criteria for CHF (N=35) (c) (N=44) (d) Proportion Arm 2 patients discontinuing H due to asymptomatic decline in LVEF (e) (N=80) (f) (N=56) < 30 70+ < 30 70+ 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 Nadir LVEF Current LVEF, 18+ Months

B-31 LVEF Evaluation Schedule Arm 1 AC x 4 Paclitaxel mo. 3 mos. 6 mos. 9 mos. 18 mos. Arm 2 AC x 4 Trastuzumab + Paclitaxel mo. 3 mos. 6 mos. 9 mos. 18 mos.

Asymptomatic Patients Criteria for Continuing Trastuzumab Absolute Decrease of < 10% Absolute Decrease of 10 - 15% Absolute Decrease of  15% Relationship of 6 and 9 mo. LVEF to LLN Within Normal Limits 1- 5% below LLN  6% below LLN Cont. Cont.* Cont. Hold * Hold * Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses. * 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

NSABP B-31 Trastuzumab Discontinuation Due to Asymptomatic or Symptomatic Cardiac Dysfunction by Quarter