1. 1 (Epirubicin Hydrochloride) Oncologic Drugs Advisory Committee Review June 7, 1999 EPIRUBICIN Pharmacia & Upjohn

2. 2 Presentation Agenda  Regulatory History and Pharmacology  Early Breast Cancer Adjuvant Therapy  Advanced Breast Cancer Therapy  Conclusions  Q & A

3. 3 Epirubicin Presentation Team FunctionNameAffiliation MedicalLangdon Miller, MDP&U Elena Colajori, MDP&U BiostatisticalAnna Petroccione, MD, PhDP&U Clinical PharmacologyItalo Poggesi, PhDP&U PharmacovigilanceClaudio Praga, MDP&U InvestigatorsMark Levine, MDNCIC Kathleen Pritchard, MDNCIC Dongsheng Tu, PhDNCIC Jacques Bonneterre, MDFESG

4. 4 Regulatory History  Registered in >80 countries worldwide –First approved in France in 1982 –Registered in most countries since 1984  Originally approved doses –Single-agent therapy: 60-90 mg/m 2 –Combination therapy: 50-75 mg/m 2  US NDA submitted in 1984 –Small sample sizes –Limited survival data

5. 5 Worldwide Clinical Development and Use (1984 to 1999)  Extensively studied in clinical trials –Breast cancer –Other tumor types  Subject of >2000 publications  Millions of patients have received the drug worldwide  Efficacy and safety thoroughly characterized through clinical trials and postmarketing surveillance

6. 6 Epirubicin Structure and Mechanism of Action OH NH 2 Cl OO CH 3 O O OOH O  Anthracycline  4’ epimer of doxorubicin  Mechanism of action –DNA intercalation –Topoisomerase II inhibition –Helicase inhibition –Free-radical formation  Metabolites relatively noncytotoxic HO Epirubicin

7. 7  Increased lipophilicity –Increased cell penetration Pharmacologic Implications of Epirubicin Structure 0.1 1.0 10.0 100.0 1000.0 10000.0 050100150 Time (hours) Mean Plasma Concentration + SD (ng/mL) Doxorubicin 60 mg/m 2 (N=8) Epirubicin 60 mg/m 2 (N=8) Camaggi, Cancer Chemother Pharmacol 21:221-8, 1988  Additional glucuronidation pathway –More rapid clearance –Shorter terminal half-life  MTD redefined –Dose can be escalated up to 180 mg/m 2

8. 8 Clinical Dose Response in Advanced Breast Cancer 0% 25% 50% 75% 100% 0100200 Epirubicin Starting Dose (mg/m 2 ) Response Rate Single-agent Response Rate Sledge G, personal communication

9. 9 Basis for Approval  Early Breast Cancer -- 3 Randomized Controlled Trials – Pivotal Study: CEF vs CMF (EBC-1/MA-5) – Supportive Study: Epirubicin Dose-Response (EBC-2/GFEA05) – Other Supportive Study: Epirubicin Plus Tamoxifen (EBC-3/C-4-87)  Advanced Breast Cancer -- 4 Randomized Controlled Trials –Pivotal Study: CEF vs CMF (ABC-1/HEPI 013) –Supportive Study: Epirubicin Dose-Response (ABC-2/HEPI 010) –Other Supportive Studies: Epirubicin Dose-Response (ABC-3, 4)

10. 10 Basis for Selection of Studies  Studies were selected in consultation with the FDA: –Trials were conducted in women with breast cancer –All studies were completed, well-controlled, randomized, phase III trials –Symmetrical designs allowed for a specific evaluation of epirubicin effect –Epirubicin was tested at starting doses of  100 mg/m 2 –Full study reports were available –Data were available electronically or could be provided on request by the study group

11. 11 Proposed Indications  Indicated as a component of adjuvant therapy in patients with evidence of axillary-node tumor involvement following resection of primary breast cancer (Stage II & III) –Starting doses of 100 to 120 mg/m 2  Indicated for the therapy of patients with locally advanced or metastatic breast cancer –Starting doses of 100 to 135 mg/m 2

12. 12 Adjuvant Therapy of Early Breast Cancer

13. 13 Overview of Epirubicin Studies in Early Breast Cancer (N=1885) MenopausalIntensive StudyStatusEpirubicin (N)Control (N) Pivotal EBC-1Pre/PeriCEF-120CMF (MA-5)(356)(360) Supportive EBC-2Pre/PostCEF-100CEF-50 (GFEA05)(276)(289) Other Supportive EBC-3PostE-100 + TT (C-4-87) (303)(301) C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate, T=tamoxifen

14. 14 Intensive CEF vs CMF as Adjuvant Therapy for Premenopausal Patients With Axillary Node-Positive Breast Cancer Results of an NCIC-CTG-Sponsored Phase III Multicenter Randomized Controlled Trial (EBC-1/MA-5) NCIC-CTG=National Cancer Institute of Canada Clinical Trials Group Number of sites: 37 Enrollment dates: 1989-1993

15. 15 Study Schema (EBC-1/MA-5) *Women with partial mastectomy underwent radiotherapy after chemotherapy C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate RANDOMIZATION CEF-120 q 4 wk for 6 cycles* C, 75 mg/m 2 orally, d 1-14 C, 75 mg/m 2 orally, d 1-14 E, 60 mg/m 2 IV, d 1 + 8 E, 60 mg/m 2 IV, d 1 + 8 F, 500 mg/m 2 IV, d 1 + 8 F, 500 mg/m 2 IV, d 1 + 8 (plus antibiotic prophylaxis) (plus antibiotic prophylaxis) Stratification: Total vs partial mastectomy Total vs partial mastectomy Receptor status Receptor status Number of positive nodes Number of positive nodes CMF q 4 wk for 6 cycles* C, 100 mg/m 2 orally, d 1-14 C, 100 mg/m 2 orally, d 1-14 M, 40 mg/m 2 IV, d 1 + 8 M, 40 mg/m 2 IV, d 1 + 8 F, 600 mg/m 2 IV, d 1 + 8 F, 600 mg/m 2 IV, d 1 + 8

16. 16 CMF q 4 wk for 6 cycles C, 100 mg/m 2 orally, d 1-14 C, 100 mg/m 2 orally, d 1-14 M, 40 mg/m 2 IV, d 1 + 8 M, 40 mg/m 2 IV, d 1 + 8 F, 600 mg/m 2 IV, d 1 + 8 F, 600 mg/m 2 IV, d 1 + 8 CMF An Adjuvant Standard  CEF vs CMF comparison allowed isolation of epirubicin effect against a standard regimen  CMF -- an adjuvant standard –Prior to start of EBC-1 in 1989 –Currently in 1999  Current CMF usage in US –  23,600 patients with Stage II early breast cancer on treatment –  39% are receiving adjuvant CMF

17. 17  Primary –Relapse-free survival  Secondary –Overall survival –Safety –Quality of life (Breast Cancer Chemotherapy Questionnaire [BCQ], McMaster University) Study Endpoints (EBC-1/MA-5)

18. 18  Hypothesis – 10% absolute improvement in 5-year relapse-free survival  Assumed rate in CMF arm: 55%  Expected rate in CEF arm: 65%  Statistical test – Stratified 2-tailed log-rank test with  =0.05 Statistical Considerations (EBC-1/MA-5)

19. 19  Pre- or perimenopausal  Histologically proven breast cancer treated with total or partial mastectomy  Histologically positive axillary nodes  No distant metastases  No prior hormonal or cytotoxic therapy  LVEF  45%  Adequate hematological, renal, and liver function Eligibility Criteria (EBC-1/MA-5)

20. 20  Assessments at baseline and during chemotherapy – CXR, bone scan (baseline) – CBC (baseline, weekly) – PE, AEs, QoL (baseline and monthly) – LFTs (baseline, 3 and 6 months) – Echocardiogram or MUGA scan (baseline, 6 months)  Follow-up assessments –PE, CBC, LFTs, survival (every 3 months x 2 years, every 6 months x 5 years, yearly thereafter) –Mammogram, CXR (yearly) –Echocardiogram or MUGA scan (6, 12, 36, and 60 months) –QoL (every 3 months x 2 years) Patient Evaluation (EBC-1/MA-5)

21. 21 Patients randomized N=716 CEFN=356*‡CMFN=360* * Includes 1 patient who never received treatment ‡ Includes 1 patient who was erroneously treated with CMF Intent-to-Treat Study Population (EBC-1/MA-5)

22. 22 CEFCMF N=356N=360 Median age (yr)44.544.5 [range][26-56] [23-57] ECOG performance status (%) 07883 1 21 17 211 Menopausal status (%) Premenopausal7879 Perimenopausal2221 Clinical stage (%) I3840 II5048 III46 Unknown86 Patient Characteristics (EBC-1/MA-5)

23. 23 % of Patients % of Patients CEFCMF N=356N=360 Surgery type Partial mastectomy4949 Total mastectomy5151 Nodes examined 1-589 6-103638 >105654 >105654 Positive nodes at surgery 1-36161 4-103233 >1067 Surgical Findings (EBC-1/MA-5)

24. 24 % of Patients % of Patients CEFCMF N=356N=360 Estrogen ER positive*6060 ER negative2927 Unknown1113 Progesterone PR positive*6359 PR negative2528 Unknown1214 *  10 fmol/mg Receptor Status (EBC-1/MA-5)

25. 25 CEFCMF N=354N=360 Patients completing 6 cycles (%)9697 Median dose intensity, mg/m 2 /wk (Median relative dose intensity, %) Cyclophosphamide219 (83)325 (96) Epirubicin/Methotrexate 24 (80) 19 (96) Fluorouracil199 (80)282 (96) Radiotherapy (%)4546 Treatment Administration (EBC-1/MA-5)

26. 26 CMF 0.4 0.5 0.6 0.7 0.8 0.9 1 12345670 0 CEF 0.1 0.1 0.2 0.2 0.3 0.3 Years Probability CEFCMF No. of patients356360 5-year RFS62%53% Log-rank probability p=0.013 Relapse-Free Survival (EBC-1/MA-5)

27. 27 Multivariate Analysis: Treatment Effect on Relapse-Free Survival Adjusted for Prognostic Factors (EBC-1/MA-5) Conditional Factors*Risk Ratiop-value Baseline characteristics Tumor Size  T 3 2.5<0.001 Tumor Size  T 3 2.5<0.001 Nodal Status  41.7<0.001 Nodal Status  41.7<0.001 Treatment CEF/CMF 0.76 0.021 * Factors evaluated in the modeling process were menopausal status, type of surgery, tumor size, receptor status, and nodal status

28. 28 CEF CMF 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 01234567 Years Probability CEFCMF No. of patients356360 5-year survival77%70% Log-rank probability p=0.043 Overall Survival (EBC-1/MA-5)

29. 29 Conditional Factors*Risk Ratiop-value Baseline characteristics Tumor size  T 3 2.5<0.001 Tumor size  T 3 2.5<0.001 Receptor statusNegative2.0<0.001 Receptor statusNegative2.0<0.001 Nodal status  41.7<0.001 Nodal status  41.7<0.001 Treatment CEF/CMF 0.71 0.034 Multivariate Analysis: Treatment Effect on Overall Survival Adjusted for Prognostic Factors (EBC-1/MA-5) * Factors evaluated in the modeling process were menopausal status, type of surgery, tumor size, receptor status, and nodal status

30. 30 CEFCMF Grade 3/4 EventsN=354N=360 Hematologic Events (%) Neutropenia 9560 + fever or infection 11 2 + fever or infection 11 2 Anemia10 1 Thrombocytopenia 9 4 Hemorrhage 1 0 Non-hematological Events (%) Alopecia 42 7 Stomatitis 13 2 Vomiting 12 5 Asthenia 3 0 Diarrhea 1 3 Cutaneous 1 0 Discontinuations (N [%]) 6 [1.7] 2 [0.6] Drug-related deaths (N [%]) 0 0 On-Treatment Adverse Events (EBC-1/MA-5)

31. 31 CEFCMF Event N=354N=360 Cardiac toxicity (N [%])12 [3.4]4 [1.1] Asymptomatic  LVEF (  40%) 7 [2.0]3 [0.8] Congestive heart failure (CHF) 5 [1.4]1 [0.3] Acute leukemia (N [%]) Asymptomatic  LVEF (  40%) 7 [2.0]3 [0.8] Congestive heart failure (CHF) 5 [1.4]1 [0.3] Acute leukemia (N [%]) Acute myelogenous leukemia (AML)4 [1.1]1 [0.3] Acute myelogenous leukemia (AML)4 [1.1]1 [0.3] Acute lymphocytic leukemia (ALL)1 [0.3]0 Acute lymphocytic leukemia (ALL)1 [0.3]0 Late Adverse Events (EBC-1/MA-5)

32. 32 Overall Survival AML-Free Survival Life-Table Analysis of AML-Free and Overall Survival (EBC-1) CEF CMF

33. 33  Breast Cancer Chemotherapy Questionnaire (BCQ) – Designed to assess quality of life during adjuvant therapy  30 questions – Focus on emotional and physical symptoms – 7-point scale for each question  Mean summary score computed using information from all scales  <0.5 change is considered clinically inconsequential Quality of Life (BCQ) (EBC-1/MA-5) Levine et al. J Clin Oncol 1988;6:1798-1810

34. 34 Time (mo)012345691215182124 CMF (N)276322324322326324251270277268256227220 CEF (N)270322325321315316252288265244239233217 0 1 2 3 4 5 6 7 03691215182124 Months From Randomization BCQ Mean Summary Score + S.E. CEF CMF Quality of Life (BCQ) (EBC-1/MA-5)

35. 35  Compared to CMF, CEF-120 improved: –Relapse-free survival –Overall survival  Toxicities were manageable and outweighed by benefits – 96% of patients completed CEF-120 therapy –No on-treatment CEF-120-related deaths occurred –QoL was clinically similar between the 2 treatments  Epirubicin was the critical component of the CEF regimen Conclusions (EBC-1/MA-5)

36. 36 Results of an FESG-Sponsored Phase III Multicenter Randomized Controlled Trial (EBC-2/GFEA05) FESG=French Epirubicin Study Group Number of sites: 20 Enrollment dates: 1990-1993 Randomized Dose-Response Study of CEF-100 vs CEF-50 as Adjuvant Therapy for Patients With Axillary Node-Positive Breast Cancer

37. 37 * Tamoxifen was administered to postmenopausal women Radiotherapy was administered at the completion of chemotherapy Radiotherapy was administered at the completion of chemotherapy C=cyclophosphamide, E=epirubicin, F=fluorouracil C=cyclophosphamide, E=epirubicin, F=fluorouracil RANDOMIZATION CEF-100 q 3 wk for 6 cycles* C, 500 mg/m 2 IV, d 1 C, 500 mg/m 2 IV, d 1 E, 100 mg/m 2 IV, d 1 E, 100 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 Patient Population: Pre-/post- menopausal Pre-/post- menopausal Positive axillary nodes Positive axillary nodesStratification: Study center Study center Number of positive nodes Number of positive nodes CEF-50 q 3 wk for 6 cycles* C, 500 mg/m 2 IV, d 1 C, 500 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 N=565 Study Schema (EBC-2/GFEA05)

38. 38 Treatment Administration (EBC-2/GFEA05) CEF-100CEF-50 N=266N=280 Patients completing 6 cycles (%)9495 Median dose intensity, mg/m 2 /wk (Median relative dose intensity, %) Cyclophosphamide153 (92)157 (94) Epirubicin 31 (92) 16 (94) Fluorouracil153 (92)157 (94) Radiotherapy (%)9794

39. 39 CEF-100CEF-50 No. of patients276289 5-year RFS65%52% Log-rank probability p=0.007 CEF-50 CEF-100 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years Probability 012345678 Relapse-Free Survival (EBC-2/GFEA05)

40. 40 012345678 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years Probability CEF-100CEF-50 No. of patients276289 5-year survival76%65% Log-rank probability p=0.007 CEF-50 CEF-100 Overall Survival (EBC-2/GFEA05)

41. 41 CEF-100CEF-50 Grade 3/4 EventsN=266N=280 Hematologic Events (%) Neutropenia 25 11 + fever or infection 4 0 + fever or infection 4 0 Anemia 1 0 Thrombocytopenia 0 0 Non-hematologic Events (%) Alopecia 76 19 Nausea/Vomiting 34 22 Stomatitis 4 0 Diarrhea 0 0 Cutaneous 0 0 Discontinuations (N [%]) 11 [4.1] 5 [1.8] Drug-related deaths (N [%]) 0 0 On-Treatment Adverse Events (EBC-2/GFEA05)

42. 42 CEF-100CEF-50 Event N=266N=280 Cardiac events (N [%])8 [3.0]5 [1.7] Congestive heart failure (CHF)4 [1.5]1 [0.3] Congestive heart failure (CHF)4 [1.5]1 [0.3] Other events4 [1.5]4 [1.4] Other events4 [1.5]4 [1.4] Acute leukemia (N [%]) Acute myelogenous leukemia1 [0.4]0 Acute myelogenous leukemia1 [0.4]0 Acute lymphocytic leukemia 0 1 [0.4] Acute lymphocytic leukemia 0 1 [0.4] Late Adverse Events (EBC-2/GFEA05)

43. 43  Compared with CEF-50, CEF-100 significantly: – Improved relapse-free survival – Improved overall survival  Toxicities were manageable – 94% of patients completed CEF-100 therapy – Relative dose intensity was 90% – No on-treatment CEF-100-related deaths occurred  EBC-2 strongly corroborates EBC-1, confirming the clinical benefits of epirubicin-based therapy Conclusions (EBC-2/GFEA05)

44. 44 Results of an ICCG-Sponsored Phase III Multicenter Randomized Controlled Trial (EBC-3/C-4-87) ICCG=International Collaborative Cancer Group Number of sites: 13 Enrollment dates: 1988-1995 Randomized Study of Epirubicin-100 Plus Tamoxifen vs Tamoxifen Alone as Adjuvant Therapy for Postmenopausal Patients With Axillary Node-Positive Breast Cancer

45. 45 Study Schema (EBC-3/C-4-87) * Women with partial mastectomy underwent radiotherapy after chemotherapy E=epirubicin, T=tamoxifen RANDOMIZATION E + T E, 50 mg/m 2 IV, d 1 + 8 every 4 wks x 6 cycles E, 50 mg/m 2 IV, d 1 + 8 every 4 wks x 6 cycles T, 20 mg/day orally for 4 years T, 20 mg/day orally for 4 years Patient Population: Post- menopausal Post- menopausal Positive axillary nodes Positive axillary nodesStratification: Study center Study center T alone T, 20 mg/day orally for 4 years T, 20 mg/day orally for 4 years N=604

46. 46 0 10 20 30 40 50 60 70 80 90 100 012345678 % Probability E-100 + T T alone E-100 + TT alone No. of patients303301 5-year survival74%62% Log-rank probability p=0.023 Years Relapse-Free Survival (EBC-3/C-4-87)

47. 47 T alone E-100 + T E-100 + TT alone No. of patients303301 5-year survival81%77% Log-rank probability p=0.46 2345678 Years % Probability 0 10 20 30 40 50 60 70 80 90 100 01 Overall Survival (EBC-3/C-4-87)

48. 48 E+TT Grade 3/4 Events N=298*N=292* Hematologic Events (%)Leukopenia 2 0 + fever or infection 0 0 Thrombocytopenia 1 0 Anemia 0 0 Non-hematologic Events (%) Alopecia 46 0Nausea/Vomiting 15 1 Stomatitis 2 0 Discontinuations (N [%]) 18 [5.9] -- Drug-related deaths (N [%]) 1 [0.3] 0 * Patients with at least 1 on-treatment follow-up assessment On-Treatment Adverse Events (EBC-3/C-4-87)

49. 49 E+TT Event N=303N=301 Congestive heart failure (N [%])4 [1.3]0 Acute leukemia (N [%]) Acute myelogenous leukemia2 [0.7]0 Acute myelogenous leukemia2 [0.7]0 Acute lymphocytic leukemia 00 Acute lymphocytic leukemia 00 Late Adverse Events (EBC-3/C-4-87)

50. 50  Combination therapy with epirubicin and tamoxifen significantly improved relapse-free survival over tamoxifen therapy alone  On-treatment toxicities of epirubicin were modest  Benefits of epirubicin in postmenopausal patients were further documented Conclusions (EBC-3/C-4-87)

51. 51 5-Year Relapse-Free Survival in Early Breast Cancer Studies TreatmentControl Study Therapy(%) (%) CEF combination: EBC-1/MA-5 62%53%p=0.013* EBC-2/GFEA05 65%52%p=0.007‡ Chemo-hormonal EBC-3/C-4-8774%62%p=0.023‡ * Stratified log-rank test ‡ Unstratified log-rank test

52. 52 5-Year Overall Survival in Early Breast Cancer Studies TreatmentControl Study Therapy(%) (%) CEF combination: EBC-1/MA-5 77%70%p=0.043* EBC-2/GFEA05 76%65%p=0.007‡ Chemo-hormonal: EBC-3/C-4-8781%77%p=0.46‡ * Stratified log-rank test ‡ Unstratified log-rank test

53. 53 Therapy of Advanced Breast Cancer

54. 54 Overview of Studies in Advanced Breast Cancer (N=1231) Prior StudyTherapyTreatment (N)Control (N) Pivotal ABC-1AdjuvantCEF-100CMF (HEPI 013)permitted(223)(237) Supportive ABC-2AdjuvantCEF-100CEF- 50(HEPI 010) permitted (214)(242) Other Supportive ABC-3Adjuvant CEF-100 CEF-50 permitted (84)(80) ABC-4CMF for E-135E-75 metastatic disease(74) (77) C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate

55. 55 C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate RANDOMIZATION CEF-100 q 3 wk C, 400 mg/m 2 IV, d 1 + 8 C, 400 mg/m 2 IV, d 1 + 8 E, 50 mg/m 2 IV, d 1 + 8 E, 50 mg/m 2 IV, d 1 + 8 F, 500 mg/m 2 IV, d 1 + 8 F, 500 mg/m 2 IV, d 1 + 8 Patient Population: First-line therapy First-line therapy Metastatic disease Metastatic diseaseStratification: Study center Study center Presence of visceral metastases Presence of visceral metastases Number of organs with metastases Number of organs with metastases Prior adjuvant chemotherapy Prior adjuvant chemotherapy CMF q 3 wk C,500 mg/m 2 IV, d 1 + 8 C,500 mg/m 2 IV, d 1 + 8 M, 40 mg/m 2 IV, d 1 + 8 M, 40 mg/m 2 IV, d 1 + 8 F,600 mg/m 2 IV, d 1 + 8 F,600 mg/m 2 IV, d 1 + 8 N=460 Study Schema (ABC-1/HEPI 013)

56. 56 Overview of Efficacy Results* (ABC-1/HEPI 013) CEF-100CMF N=223N=237 Response rate (%)57.444.7p=0.007 Median response duration (mo)8.87.2p=0.07 Median time to tumor progression (mo)8.76.3p=0.01 Median time to treatment failure (mo)6.25.0p=0.01 Median survival (mo)20.118.2p=NS * Based on intent-to-treat population

57. 57 CEF-100CMF AgentN=223N=237 Epirubicin 16 (7%) 44 (19%) Doxorubicin 5 (2%) 41 (17%) Mitoxantrone 19 (9%)20 (8%) Total40 (18%)105 (44%) Subsequent Anthracycline or Anthracenedione Use (ABC-1/HEPI 013)

58. 58 C=cyclophosphamide, E=epirubicin, F=fluorouracil RANDOMIZATION CEF-100 q 3 wk C, 500 mg/m 2 IV, d 1 C, 500 mg/m 2 IV, d 1 E, 100 mg/m 2 IV, d 1 E, 100 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 Patient Population: First-line therapy First-line therapy Metastatic disease Metastatic diseaseStratification: Study center Study center Presence of visceral metastases Presence of visceral metastases Number of organs with metastases Number of organs with metastases CEF-50 q 3 wk C,500 mg/m 2 IV, d 1 C,500 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 F,500 mg/m 2 IV, d 1 F,500 mg/m 2 IV, d 1 N=456 Study Schema (ABC-2/HEPI 010)

59. 59 Overview of Efficacy Results* (ABC-2/HEPI 010) CEF-100CEF-50 N=214N=242 Response rate (%)48.136.0p=0.009 Median response duration (mo)9.19.3p=NS Median time to tumor progression (mo)7.57.0p=NS Median time to treatment failure (mo)5.75.3p=NS Median survival (mo)18.017.0p=NS * Based on intent-to-treat population

60. 60 C=cyclophosphamide, E=epirubicin, F=fluorouracil RANDOMIZATION CEF-100 q 3 wk C, 500 mg/m 2 IV, d 1 C, 500 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1+ 8 E, 50 mg/m 2 IV, d 1+ 8 F, 500 mg/m 2 IV, d 1 F, 500 mg/m 2 IV, d 1 Patient Population: First-line therapy First-line therapy Locally advanced or metastatic disease Locally advanced or metastatic diseaseStratification: Study center Study center Menopausal status Menopausal status Locally advanced or metastatic disease Locally advanced or metastatic disease CEF-50 q 3 wk C,500 mg/m 2 IV, d 1 C,500 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 E, 50 mg/m 2 IV, d 1 F,500 mg/m 2 IV, d 1 F,500 mg/m 2 IV, d 1 N=164 Study Schema (ABC-3)

61. 61 Overview of Efficacy Results* (ABC-3) CEF-100CEF-50 N=84N=80 Response rate (%)57.136.3p=0.008 Median response duration (mo)22.114.0p<0.01 Median time to tumor progression (mo)---- -- Median time to treatment failure (mo)19.28.0p<0.02 Median survival (mo)27.120.8p=NS * Based on intent-to-treat population -- Not reported

62. 62 RANDOMIZATION Epirubicin, 135 mg/m 2 IV q 3 wk Patient Population: Prior CMF therapy Prior CMF therapy Metastatic disease Metastatic diseaseStratification: Site of metastases Site of metastases Response to prior CMF Response to prior CMF N=151 Epirubicin, 75 mg/m 2 IV q 3 wk Study Schema (ABC-4)

63. 63 Overview of Efficacy Results* (ABC-4) E-135E-75 N=74N=77 Response rate (%)27.07.8p=0.002 Median response duration (mo) 6.13.7p=NS Median time to tumor progression (mo) 4.42.5p=0.003 Median time to treatment failure (mo)---- -- Median survival (mo)10.97.9p=0.065 * Based on intent-to-treat population -- Not reported

64. 64 CEF-100CMFCEF-50 CEF-100CMFCEF-50 ABC-1ABC-2ABC-1ABC-2 Grade 3/4 EventsN=220N=209N=234N=238 Hematologic events (%) Neutropenia 78866831 + fever or infection151112 1Anemia12 7 9 1 + fever or infection151112 1Anemia12 7 9 1 Thrombocytopenia7 6 6 2 Non-hematological events (%) Alopecia 6671 1455 Nausea/Vomiting 2130 14 26 Stomatitis12 10 15 0 Diarrhea 1 0 2 1 Cutaneous 0 1 0.4 0 Congestive heart failure 6 [2.7%] 1 [0.5%]0 2 [0.8%] Drug-related deaths 3 [1.4%] 2 [1.0%] 3 [1.2%] 2 [0.8%] Summary of Adverse Events (ABC-1/HEPI 013 & ABC-2/HEPI 010)

65. 65 Overall Response Rates in Studies in Advanced Breast Cancer TreatmentControl Study(%) (%) TreatmentControl Study(%) (%) ABC-1 57.444.7p=0.007 ABC-2 48.136.0p=0.009 ABC-3 57.136.3p=0.008 ABC-4 27.0 7.8p=0.002

66. 66 Complete Response Rates in Studies in Advanced Breast Cancer TreatmentControl Study (%)(%) ABC-113.510.5 ABC-210.35.8 ABC-310.76.3 ABC-4 5.40

67. 67 Time to Tumor Progression or Treatment Failure in Studies in Advanced Breast Cancer TreatmentControl Study Endpoint (mo)(mo) ABC-1 TTP8.76.3p=0.01 TTF6.25.0p=0.01 ABC-2TTP 7.57.0p=NS ABC-3TTF 19.28.0p<0.02 ABC-4TTP 4.42.5p=0.003

68. 68 Conclusions  Indicated as a component of adjuvant therapy in patients with evidence of axillary-node tumor involvement following resection of primary breast cancer (Stage II & III) –Improves relapse-free survival –Improves overall survival  Indicated for the therapy of patients with locally advanced or metastatic breast cancer –Improves time to tumor progression –Increases overall and complete response rates

69. 69 Q & A