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 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 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/m 2 ) or epirubicin (75 mg/m 2 ) + cyclophosphamide (600 mg/m 2 ) q 3 wks x 6 cycles Prior anthracyclines T = paclitaxel (175 mg/m 2 x 3 hr) q 3 wks x 6 cycles

Trastuzumab in Combination with Chemotherapy Total enrolled469 Enrollment RandomizationH + CTCT Subgroups H + ACACH + TT

Summary: Phase III Clinical Trial Comparing Best Available Chemotherapy to Same Therapy + Trastuzumab Enrolled H + CT23549 (53%)9.3M (58%)7.6M (65%) CT M 4.6M H + AC13852 (20%)9.1M (40%)8.1M (33%) AC M 6.1M H + T9242 (163%)11.0M (150%  6.9M (130%) T M3.0M 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+ACACH+TT Cardiac Dysfunction Events Trastuzumab 14 5*6 1* Death 4112 MBC 4002 Cardiac 0100 Pneumonia 0010

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 HER2 + FISH 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 6 x Docetaxel and Platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6 1 Year Trastuzumab N= Year Trastuzumab AC  T AC  TH 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 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% : Protocol stopping rule for excessive cardiac toxicity Analysis #Number of patients Approximate power % % % 43222>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 TreatmentAC-TAC-THTCH Started treatment as per protocol Did not receive study treatment29218 Total

Overall Follow-up: Date of Randomization to Last Follow-up Evaluation AC->T AC->TH TCH Months of Follow-up % patients still followed 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-TAC-THTCH (95.5%) (91.2%) 993 (92.5%) 0

Chemotherapy administration Median Relative Dose Intensity AC-TAC-THTCH Doxorubicin99%97%- Cyclophosphamide99%97%- Docetaxel99%100%99% Cisplatin--98% Carboplatin--94% Median Cumulative Dose of Doxorubicin240 mg/m² -

Trastuzumab administration Median Cumulative Dose of Trastuzumab AC-TAC-THTCH During Chemotherapy-26 mg/kg38 mg/kg After Chemotherapy-78 mg/kg66 mg/kg Total-98 mg/kg104 mg/kg

Potential cardiac risk factors AC-TAC-THTCH Age Median Range 49 yrs ( yrs) 49 yrs ( yrs) 49yrs ( yrs) Risk factors (# of Pts) Diabetes Hypercholesterolemia Hyperlipidemia Obesity Radiotherapy (# of Pts) After chemotherapy To left chest

Pre-existing cardiac signs and symptoms AC-TAC-THTCH # patients with on-going cardiac event at baseline # patients with ceased cardiac event at baseline # patients with ECG abormalities at baseline (of which 4 significant) 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 Trastuzumab Trastuzumab 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

Clinically significant cardiac events AC-TAC-THTCH Cardiac death000 Cardiac ischemia / infarction Grade 3 Grade Arrhythmias Grade 3 Grade Cardiac left ventricular function (CHF) Grade 3 Grade Total events Total patients122513

LVEF Declines by NYHA Class AC-TAC-THTCH >10%, <LLN 9347 >15%, <LLN 6254 Grade 3/4 CHF 2201

Clinically significant cardiac events - as defined in the CIRG 006 protocol but not in the other groups TreatmentAC-TAC-THTCH # with events # patients 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-TAC-THTCH  27 days 18%24%22% 28 – 42 days28%38%35% 43 – 90 days25%21%27% 91 – 180 days18%10%9% > 180 days11%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-TAC-THTCH # confirmed within 28 days 1122 # confirmed within 42 days 3203 # confirmed at any time 6264 # patients 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-TAC-THTCH # confirmed within 28 days 4196 # confirmed within 42 days 6327 # confirmed at any time # patients 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 TreatmentAC-TAC-THTCH # with events # patients Proportion1.2%2.3%1.2% P=0.046P=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 TreatmentAC-TAC-THTCH # with events6254 # patients Proportion0.6%2.4%0.4% P=0.001P<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 TreatmentAC-TAC-THTCH Slope* P-value0.0002< * 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