Taxotere in the Management of Early-Stage Breast Cancer: Improving Outcomes

1. Taxotere in the Management of Early-Stage Breast Cancer: Improving Outcomes Maureen Trudeau, MD Sunnybrook and Women’s College Health Sciences Centre Toronto, Ontario, Canada

2. Taxotere in the Management of Early-Stage Breast Cancer: Outline • Adjuvant trials • BCIRG001/TAX316 • USO 9735 • PACS 01 • Neoadjuvant trials • Aberdeen/TAX301 • NSABP B-27

3. F A C T A C BCIRG 001: Study Design 5-FU 500 mg/m2Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 R Every 3 weeks x 6 cycles • Stratification • Nodes 1-3 4+ • Center Taxotere 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 Martin M. et al. SABCS 2003, Abstract 43.

4. 1.0 TAC 87% 0.8 FAC 81% 0.6 Cumulative Probability P value N Events HR Stratified Log-Rank TAC745 910.70.0080 FAC746130 0.4 0.2 0.0 12 48 0 24 36 60 6 18 30 42 54 66 Survival Time (months) BCIRG 001: OS (ITT)Median follow-up: 55 months Martin M. et al. SABCS 2003, Abstract 43.

5. BCIRG 001: DFS (ITT)Median follow-up: 55 months 1.0 TAC 75% 0.8 FAC 68% 0.6 Cumulative probability P value N Events HR Stratified Log Rank TAC7451720.72.0010 FAC746227 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 DFS Time(months) Martin M. et al. SABCS 2003, Abstract 43.

6. BCIRG 001: DFS by Hormone Receptor Status 100 100 Positive Negative 90 90 TAC 80 80 % Alive and Disease-Free 70 70 FAC TAC 60 60 HR = 0.72 P = 0.0076 HR = 0.69 P = 0.0297 FAC 50 50 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Time to First Event Time to First Event (Centrally reviewed) Ratio of HRs 1.08 P = 0.7216 Martin M. et al. SABCS 2003, Abstract 43.

7. 100 100 1-3 Nodes 4+ Nodes 90 90 TAC 80 80 % Alive and Disease-Free FAC 70 70 TAC HR = 0.83 P = 0.17 HR = 0.61 P = 0.0009 60 60 FAC 50 50 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Time to First Event Time to First Event BCIRG 001: DFS by Nodal Involvement Ratio of HRs 1.34 P = 0.1457 Martin M. et al. SABCS 2003, Abstract 43.

8. 100 100 Positive Negative 90 90 80 80 TAC TAC % Alive and Disease-Free FAC 70 70 60 60 HR = 0.60 P = 0.0088 HR = 0.76 P = 0.046 FAC 50 50 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Time to First Event Time to First Event (FISH performed centrally) BCIRG 001: DFS by HER2 Status Ratio of HRs 0.85 P = 0.4122 Martin M. et al. SABCS 2003, Abstract 43.

9. BCIRG 001: Hematologic Toxicity *P 0.05 Martin M. et al. SABCS 2003, Abstract 43.

10. Best Status 100 90 80 70 60 50 Mean Scale Scores 40 30 20 10 Worst Status 0 0 656 650 6 634 636 12 602 606 18 549 554 42 520 498 66 490 460 114 408 353 Weeks TAC (N=745) FAC (N=746) BCIRG 001: Global Health Status/QoL Martin M. et al. Eur J Cancer. 2004; 3(2):70,Abstract 50.

11. Adjuvant Taxane and Anthracycline Based Studies Absolute Differences in Overall DFS and OS at 5 Years 8% DFS OS 7% 6% 6% 5% 4% 4% 3% 2% CMF vs Anthra1 0% 3.2% 2.7% CALGB 93442 NSABP B-283 BCIRG 0014 2% 4% 1EBCTCG. Lancet. 1998;352:930-942. 2Henderson C et al. J Clin Oncol. 2003;21:976-983. 3Mamounas E et al. Proc ASCO. 2003;22:4. Abstract 12. 4Martin M et al.Breast Cancer Res Treat. 2003. Abstract 43.

12. USO 9735 Phase III TrialStudy Design TC Taxotere 75 mg/m2 IV d 1 Cyclophosphamide600 mg/m2 IV d 1 Repeat q 3 wks  4 R A N D O M IZ E • N=1016 • Stage I-III BC • Post-mastectomy or breast-conserving therapy • KPS 80 Radiationtherapy Tamoxifenif indicated* AC Doxorubicin 60 mg/m2 IV + Cyclophosphamide 600 mg/m2 IV Repeat q 3 wks  4 *Administered to all patients with hormone receptor-positive BC. Jones SE, et al. Proc Am Soc Clin Oncol 2003;22:15, Abstract 59

13. PACS 01: Study Design RANDOMIZE • Patient Population: • Node-positive • Stage II FEC (500/100/500 mg/m2) q 3 wk x 3 ↓ Taxotere 100 mg/m2 q 3 wk x 3 FEC (500/100/500 mg/m2) q 3 wk x 6 N = 2,000

14. Supportive Care • Prophylactic corticotherapy(méthylprednisolone) for each cycle of docetaxel: 48 mg for 6 doses from D-1 to D+1 • Antiemetic prophylaxis with 5 anti-HT3 • Primary prophylaxis with G-CSF and antibiotics not allowed • G-CSF (filgrastim 5 µg/kg/d) prescribed in case of febrile neutropenia or delay in initiation at day 21, for all subsequent courses. Filgrastim was not allowed for the 1st cycle of docetaxel.

15. 1,999 randomized patients between June 1997 and March 2000 in France (n = 1,621) and Belgium (n = 378) Median follow-up: 59.7 months ITT sample 996 1,003 Safety sample 995 1,001 Eligible sample 977 968 Per Protocol sample 929 899 6FEC100 3FEC100-3Docetaxel Study Population

16. Patient Characteristics

17. Treatment Characteristics

18. Hematologic Toxicity

19. Non Hematologic Toxicity

20. Cardiac Toxicity § myocardial infarct, dyspnea / pericarditis, menace syndrome * cardiogenic shock / sudden death

21. 5-YEAR EFFICACY RESULTS

22. 1.00 3FEC100-3Docetaxel: 78.3% Relapses = 482 218 (21.7%) 264 (26.5%) 0.75 6FEC100: 73.2% 0.50 Probability Log-rank unadjusted P-value = 0.012 Log-rank adjusted P-value = 0.014 0.25 HR (Cox model) = 0.83[0.69-0.99], P-value = 0.041 0.00 0 1 2 3 4 5 6 7 8 Time (years) DFS at 5 years, ITT

23. N 1-3 N > 4 1.00 1.00 3FEC100-3Docetaxel 3FEC100-3Docetaxel 0.75 0.75 6FEC100 Kaplan-Meier Estimate Kaplan-Meier Estimate 0.50 0.50 6FEC100 0.25 Log-rank P-Value = 0.042 HR (Cox model) = 0.76 [0.58-1.00] Log-rank P-Value = 0.120 HR (Cox model) = 0.87 [0.68-1.11] 0.25 0.00 0.00 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Survival Time (years) Survival Time (years) DFS by Nodal Status, ITT

24. Events, ITT * log-rank adjusted

25. Log-rank unadjusted P-value = 0.013 Log-rank adjusted P-value = 0.017 HR (Cox model) = 0.77 [0.59-1.00], P-value = 0.050 OS by Treatment Arm, ITT 1.00 Death = 235 100 (10.0%) 135 (13.5%) 0.75 3FEC100-3Docetaxel: 5-year OS = 90.7% 6FEC100: 5-year OS = 86.7% 0.50 Probability 0.25 0.00 0 1 2 3 4 5 6 7 8 Time (years)

26. Conclusion: Efficacy Results • Substituting 3 cycles of docetaxel for 3 cycles of FEC 100 following 3FEC100 significantly improves DFS and OS in N+ breast cancer patients • This benefit was significant for patients older than 50 years • There was a significant interaction between age and treatment effect and both age groups might be considered separately • For younger women, this schedule of docetaxel offers no advantage compared to 6 FEC100

27. Conclusions: Safety Results • Treatment compliance to docetaxel was good • This sequential schedule demonstrated significantly less cardiac events, less neutropenia at day 21, cycle delay and use of G-CSF in spite of a higher rate of febrile neutropenia • Edema and nail disorders were significantly more frequent than with FEC 100 alone

28. TAX 301: Aberdeen Study Design First Phase Second Phase 4 cycles of Taxotere (n=55) No Response All Patients 4 cycles of CVAP (n=162) Final Assessment / Surgery Response 4 cycles of Taxotere (n=52) Randomize 4 cycles of CVAP (n=52) > 3 cm or T3, T4, TxN2 Smith et al. J Clin Oncol. 2002;20:1456-1466.

29. TAX 301: Results • Patients who respond to primary CVAP chemotherapy and are randomized to further sequential docetaxel vs CVAP achieve: • Higher pCR rates –31% vs 15%, p=0.06 • Higher 5 year OS –97% vs 78%, p=0.04 • Higher rates of Breast Conserving Surgery –67% vs 48%, p=0.01 Hutcheon et al. Breast Cancer Res Treat. 2003;82(suppl 1): S9. Abstract 11.

30. 1.0 Docetaxel 97% CVAP 0.9 Survival (%) 78% 0.8 Log rank p=0.04 0.7 20 40 60 80 100 Time (months) TAX 301: Overall Survival Median Follow-up: 60 months Hutcheon et al. Breast Cancer Res Treat. 2003;82(suppl 1): S9. Abstract 11.

31. A Randomized Trial Comparing Preoperative Doxorubicin/Cyclophosphamide (AC) to Preoperative AC Followed by Preoperative Docetaxel (T) and to Preoperative AC Followed by Postoperative T in Patients with Operable Carcinoma of the Breast: Results of NSABP B-27 HD Bear, S Anderson, RE Smith, A Robidoux, MS Kahlenberg, RG Margolese, SR Dakhil, ER Pajon, JL Hoehn, EP Mamounas, CE Geyer, T Julian, N Wolmark San Antonio Breast Cancer Symposium, December 10, 2004 National Surgical AdjuvantBreast and Bowel Project

32. NSABP B-27 Schema Operable Breast Cancer Randomization AC x 4 Tam x 5 Yrs AC x 4 Tam x 5 Yrs AC x 4 Tam x 5 Yrs Docetaxel x 4 Surgery Surgery Surgery Docetaxel x 4 I II III

33. B-27PRIMARY AIM • To determine whether four courses of Preop or Postop Docetaxel given after four courses of Preop AC will more effectively prolong DFS and OS than four courses of Preop AC alone.

34. B-27Secondary Aims AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs vs Docetaxel x 4 Surgery Surgery I & III II •  Clinical Response •  Pathologic Response •  Nodal Downstaging •  Lumpectomies

35. B-27Secondary Aims AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs vs Surgery Surgery Docetaxel x 4 I III •  DFS and S in Subgroups of patient (i.e. according to nodes, or breast response)

36. B-27Eligibility • Operable Breast Carcinoma • Diagnosis by FNA or core biopsy • Palpable on physical exam (T1c-3 N 0, M 0 , / T 1-3, N 1, M 0 ). • NOT locally or regionally advanced • No T4 or N2 disease

37. NSABP B-27 Opened Closed Total Randomized Dec. 20, 1995 Dec. 31, 2000 2,411 pts. Median time on study: 68.8 months Analysis triggered by crossing the protocol defined threshold of 430 deaths

38. NSABP B-27: Pathologic Complete Responses in Breast 26.1%* 14.3%* 12.8%* % *p<0.001 for test of heterogeneity across groups n=764 n=767 n=775

39. NSABP Protocol B-27Endpoints Considered for this analysis • Survival • All deaths, breast cancer related or not • Disease-Free Survival (DFS) • Events include all local, regional or distant recurrences, residual disease, clinically inoperable disease, all 2nd cancers and all deaths • Relapse-Free Survival (RFS) • Events include all local, regional or distant recurrences, residual disease, clinically inoperable disease, and all deaths (similar to “DFS” in CALGB 9344) Results shown based on Intention to Treat

40. NSABP Protocol B-27Deaths and Events Reported as of 3/31/2004

41. NSABP B-27Overall Survival % Surviving TRTNDeaths Group I 801 150 Group II 803 143 HR=0.94 p=0.57 Group III 799 163 HR=1.07 p=0.53 Years after Surgery 3-31-04

42. NSABP B-27Disease-Free Survival % Disease-free TRTNEvents Group I 801 264 Group II 803 239 HR=0.86 p=0.10 Group III 799 244 HR=0.91 p=0.27 Years after Surgery 3-31-04

43. NSABP B-27Relapse-Free Survival % Relapse-free TRTNEvents Group I 801 247 Group II 803 210 HR=0.81 p=0.03 Group III 799 230 HR=0.91 p=0.32 Years after Surgery 3-31-04

44. NSABP B-27: Relapse-Free SurvivalAC vs. AC + Taxotere % Relapse-free TRTNEvents Group I 801 247 Group II & III 1602 440 HR=0.86 p=0.06 Years after Surgery 3-31-04

45. NSABP B-27: Cumulative IncidenceFirst Events at All Local Sites 0.15 TRTNEvents Group I 801 67 Group II 803 34 Group III 799 44 0.10 Probability of Event p= 0.0014 0.05 3-31-04 0.0 0 1 2 3 4 5 Years

46. Conclusions: Adjuvant Trials • The addition of Taxotere to conventional anthracycline-containing chemo increasesDFS and OS in node-positive early-stagebreast cancer • Taxane-containing combinations (ie, TAC) isa valid treatment option for appropriately selected women with early-stage breast cancer • Optimal way of administering taxanes and identification of subsets most likely to benefit will remain open questions for 3 to 4 years

47. Conclusions: Neoadjuvant Trials • Neoadjuvant chemo can increase operability in operable and locally advanced breast cancer • Clinical and pathologic response predict outcome • Optimal chemotherapy regimens at present incorporate the use of a taxane