Memorial Sloan-Kettering Cancer Center TAXOL® (paclitaxel) for Adjuvant Treatment of Node Positive Breast Cancer Oncologic Drug Advisory Committee Adjuvant Chemotherapy of Breast Cancer Larry Norton, M.D. Memorial Sloan-Kettering Cancer Center New York, New York

Adjuvant Chemotherapy of Primary Breast Cancer: What We Know Chemotherapy Improves Disease-Free and Overall Survival Polychemotherapy > Monochemotherapy Multiple Cycles > Single Exposure No Major Advantage to Durations > 3 Months Anthracycline Combinations > CMF

Early Breast Cancer Trialists’ Collaborative Group Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of... Comparison (N) CMF vs. Nil (8,150) CMF+ vs. Nil (3,218) Anthracyclines+ vs. CMF (6,950) Longer vs. Shorter (6,104) Recurrence +24 ± 3 +20 ± 5 +12 ± 4 +7 ± 4 Death +14 ± 4 +15 ± 5 +11 ± 5 -1 ± 5 Lancet Vol. 352, 9/98

Simulation of Impact of Chemotherapy Annual Odds of Recurrence: Nil = 15%/Yr CMF = 11.4%/Yr (Reduced by 24%) AC = 10%/Yr (Reduced by 12%) 100 80 60 % Free of Recurrence 40 AC CMF 20 Nil 2 4 6 8 10 Years

Adjuvant Chemotherapy of Primary Breast Cancer: What Else We Know Adriamycin Doses < 40mg/m2 are Inferior to 60 mg/m2 (CALGB 8541) Cyclophosphamide Doses > 600 mg/m2 are not Superior (NSABP B-22) Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG)

Early Breast Cancer Trialists’ Collaborative Group Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of... Subgroup (N) Age < 50, ER- (1398) Age < 50, ER+ (1115) Age  50, ER- (3240) Age  50, ER+ (6793) Recurrence +40 ± 7 +33 ± 8 +30 ± 5 +18 ± 4 Death +35 ± 9 +20 ± 10 +17 ± 6 +9 ± 5 Lancet Vol. 352, 9/98

Adjuvant Chemotherapy of Primary Breast Cancer: How To Improve Dose-Escalate Anthracycline? Integrate New Agents? Chemotherapy? Biological Agents? Improve Drug Scheduling? Dose-Density, Sequential?

Recently Approved New Drugs for the Treatment of (Advanced) Breast Cancer: Paclitaxel Docetaxel Capecitabine Trastuzumab

Adjuvant Chemotherapy of Primary Breast Cancer: Why Paclitaxel? Active as First Chemotherapy for Stage IV: 52-59% Response Rates (M.D. Anderson, MSKCC et al.) Active after Extensive Prior Chemotherapy, Including Anthracycline-Resistant Disease: 22-30% Response Rates (NCI, MSKCC et al.)

“Normal” Dose Intensity & Dose Escalation 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

“Normal” Dose Intensity & Dose Escalation 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

“Normal” Dose Intensity & Increased Dose Density B1&3 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

“Normal” Dose Intensity & Increased Dose Density 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

Alternating Therapy is Not Dose Dense C4&5 Alternating Therapy is Not Dose Dense 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

Sequential Therapy is Dose Dense 3&6 1 102 104 106 108 1010 1012 7 6 5 4 3 2 Months Cell Number

Stage II Breast Cancer with 4 Involved Axillary Lymph Nodes Doxorubicin CMF Bonadonna et al., JAMA, 1995

Stage II Breast Cancer with >4 Involved Axillary Lymph Nodes % at 10 Years p = .002 Bonadonna et al., JAMA, 1995

CALGB 9141 (Pilot) Node-Positive Stage II-IIIA (N=172) Cyclophosphamide 2000 mg/m2 Paclitaxel 175 mg/m2 + G-CSF Doxorubicin 75 mg/m2 130/145 (89.7%)of Patients Starting Paclitaxel Completed Rx. On Paclitaxel: 25% Grade IV Leukopenia 4% Grade IV Thrombocytopenia Demetri et al., ASCO-1997

Intergroup 0148/CALGB 9344 Node-Positive Stage II-IIIA Cyclophosphamide Paclitaxel 175 mg/m2 600 mg/m2 Tamoxifen forHR(+) 60 Randomize Doxorubicin mg/m2 75 No Further Chemotherapy 90 G-CSF

Relationship of CALGB 9344 (Int 0148) to Current U. S Relationship of CALGB 9344 (Int 0148) to Current U.S. Cooperative Group Trials

NSABP B-28 Node-Positive Stage II-IIIA Paclitaxel 225 mg/m2 Doxorubicin Cyclophosphamide 600 mg/m2 60 mg/m2 (Survival) No Further Chemotherapy Concomitant Tamoxifen x 5 Years for HR(+) or Postmenopausal (Age  50)

Intergroup/CALGB 9741 Node-Positive Stage II-IIIA 3-Week Cycles 2-Week Cycles (w/ G-CSF) Doxorubicin (A) 60 mg/m2 Paclitaxel (T) 175 mg/m2 Cyclophosphamide (C) 600 mg/m2

Intergroup/SWOG 4-9 LN+ Trial C T A Randomize STAMP I or STAMP V C A

Intergroup/ECOG Stage II Trial HER2 (-) Paclitaxel Tamoxifen if HR(+) Cyclophosphamide 600 mg/m2 Doxorubicin 60 mg/m2 Docetaxel

Integration of Biological Agent: Trastuzumab (Herceptin)

NSABP Stage II Trial HER2 (+) Paclitaxel Cyclophosphamide 600 mg/m2 Tamoxifen if HR(+) Doxorubicin 60 mg/m2 Etc. Herceptin

Intergroup/NCCTG Stage II Trial HER2 (+) Paclitaxel Cyclophosphamide 600 mg/m2 Tamoxifen if HR(+) 52 wks Doxorubicin 60 mg/m2 52 wks Herceptin

CALGB Stage IIIB Trial (HER2+) Cyclophosphamide 600 mg/m2 Paclitaxel 90 mg/m2 Surgery & RT Tamoxifen if HR(+) Doxorubicin 60 mg/m2 Herceptin for a Year or Not Dexrazoxane or Not Herceptin or Not

Summary of Advantages of This Approach Integrates Paclitaxel Active as a Single Agent Active Post-Anthracycline Minimizes Incremental Toxicity Allows Integration of Biological Therapy