European Cooperative Trial in Operable Breast Cancer(ECTO): Improved freedom from progression from adding paclitaxel(T) to doxorubicin(A) followed by CMF Luca Gianni Abstract 513

ECTO: Schema Tumors > 2 cm randomized to : SURG ->A 75 mg/m2 x 4 -> CMF x 4 SURG ->AT 60/ 200 x 4 -> CMF x 4 AT 60/ 200 x 4 -> CMF x 4 -> SURG Tam for HR + Analysis: FFP A vs B B vs C

ECTO at 5 years Analysis A vs. B Pts. Events HR p A-CMF 453 91 .66 0.01* AT-CMF 451 63 Analysis B vs. C S-AT-CMF 451 63 1.22 0.24 AT-CMF-S 451 78 Data super imposable so far, no significant difference, however pCR had improved FFP.

ECTO: Main Treatment Outcomes A(%) B(%) C(%) Total FFP pCR 89 no pCR 75 N - 81 89 86 N + 1-3 79 86 71 N +>3 58 65 59 OS 82 91 90 No significant difference in OS. No significant difference in cardiac toxicity

Combined Analysis of NSABP-B31/NCCTG-N9831 Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer Romond EH, Perez EA, Bryant J, Suman V, Geyer CE, Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA, Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE, Mamounas E, Abrams J, Wolmark N Combined Analysis of NSABP-B31/NCCTG-N9831

NSABP B-31 NCCTG N9831 Control: ACT Arm 1 Arm 2 Arm A Arm B Arm C Investigational: ACT+H Arm B Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Patient Eligibility HER-2 positive by FISH or +++ by IHC verified centrally (N9831) or by approved reference lab (B-31) 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 LVH Cardiomegaly on CXR

LVEF Evaluation Schedule B-31 Arm 2 / N9831 Arm C AC Paclitaxel + Trastuzumab mo. 3 mos. 6 mos. 9 mos. 18 mos. B-31 Arm 1 / N9831 Arm A AC Paclitaxel mo. 3 mos. 6 mos. 9 mos. 18 mos.

Relationship of LVEF to LLN Asymptomatic Patients Rules for Trastuzumab Continuation Based on Serial LVEFs Relationship of LVEF to LLN Absolute Decrease of < 10% Absolute Decrease of 10 - 15% Absolute Decrease of  16% 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

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

Patient and Tumor Characteristics (%) AC  Paclitaxel + Trastuzumab 872 B-31 807 N9831 864 808 Age <50 50-59 ≥60 52 34 15 51 32 16 50 18 No. Pos Nodes 1-3 4-9 10+ 57 29 14 13 48 25 11 Hormone Receptors ER+ ER- PR+ PR- 53 47 41 58 46 39 60 Tumor Size ≤2.0 cm. 2.1-4.0 cm. >4.0 cm. 43 40 37 44 17 38

Statistical Analysis Median follow-up: 2.0 years (2.4 years on B-31/1.5 years on N9831) Primary endpoint: DFS analyzed by intent-to-treat Secondary endpoints: OS and Time to 1st Distant Recurrence Definitive analysis after 710 DFS events First interim analysis after 355 DFS events Stop trials only if equivalence is rejected at p=0.0005 (2p=0.001)

Disease-Free Survival ACTH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831

Forest Plot For Disease-Free Survival ALL DATA Age ≥60 50-59 40-49 ≤39 Hormone Receptor Positive Negative Tumor Size ≥ 4.1cm 2.1- 4.0 cm <2.0 cm No. Positive Nodes 10+ 4-9 1-3 Protocol N9831 NSABP B-31 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Hazard Ratio

Disease-Free Survival 1 2 3 4 5 50 60 70 80 90 100 B-31 N9831 ACTH ACTH 87% 87% 85% ACT 86% ACT 78% 74% % 68% 66% N Events N Events ACT 807 90 ACT 872 171 ACTH 808 51 ACTH 864 83 HR=0.55, 2P=0.0005 HR=0.45, 2P=1x10-9 Years From Randomization

Time to First Distant Recurrence 100 ACTH AC->T+H 90% 90% 90% 90% 90% 90% 90 ACT AC->T 80 81% 81% 81% % 74% 74% 70 74% N Events N Events ACTH 1672 96 ACT 1679 194 AC->T 1679 194 60 AC->T+H 1672 96 HR=0.47, 2P=8x10-10 HR=0.47, 2P=8x10-10 50 1 2 3 4 5 Years From Randomization B31/N9831

Hazard of Distant Recurrence 120 100 ACT 80 Rate per 1000 Women /Yr 60 40 ACTH 20 1 2 3 4 Years From Randomization B31/N9831

B-31/N9831 Survival ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92 HR=0.67, 2P=0.015 Years From Randomization B31/N9831

B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF P(Age)=0.04 P(LVEF)<0.0001

Conclusions For high risk HER-2 positive breast cancer, trastuzumab given concurrently with paclitaxel following AC chemotherapy, reduces the risk of a first breast cancer event at 3 years by 52%. The relative risk reduction benefit was present and of similar magnitude in all subsets of patients analyzed. There is not, however, statistical power to establish efficacy in the node negative subset. The addition of trastuzumab reduced the probability of distant recurrence by 53% at 3 years, and the hazard of developing distant metastases appears, thus far, to decrease over time.

Conclusions 4. Results at a median follow-up of 2 years show a statistically significant survival advantage with a relative risk reduction of 33%. 5. The combination of trastuzumab and chemotherapy has a notable risk of cardiac toxicity. Careful monitoring of cardiac function is of vital importance if trastuzumab is to be used in the adjuvant setting.