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Integration of Taxanes in the Management of Breast Cancer Jean-Marc A. Nabholtz, MD, MSc Professor of Medicine, Univ. of California at Los Angeles Director,

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Presentation on theme: "Integration of Taxanes in the Management of Breast Cancer Jean-Marc A. Nabholtz, MD, MSc Professor of Medicine, Univ. of California at Los Angeles Director,"— Presentation transcript:

1 Integration of Taxanes in the Management of Breast Cancer Jean-Marc A. Nabholtz, MD, MSc Professor of Medicine, Univ. of California at Los Angeles Director, Cancer Therapy Development Program Director, Solid Tumor Program, Jonsson Comprehensive Cancer Center, UCLA Chairman, CIRG and BCIRG

2 Development of Chemotherapy Breast Cancer Before anthracyclines CMF, CMFVP With anthracyclines Combinations: AC, FAC, AVCMF, FEC, CEF Sequence and Alternating (Milan A & B) Dose intensity,dose density, HDCT Taxanes (Paclitaxel/Docetaxel) Sequential: A  T  C or AC  T Combinations: TA, TAC Biologic Modifiers (Herceptin) Integration in chemotherapy strategies 1970s 1980s 1990s 2000s

3 Chemotherapy Drug Development NEW SINGLE AGENT 2 nd LINE 1 st LINE ADJUVANT NEW COMBINATIONS

4 Single agents First-line breast cancer Vogel CL, Nabholtz Oncologist 1999; 4: Nabholtz et al. Exp. Opin Pharmacother 2000; 1:

5 Adjuvant Chemotherapy Breast Cancer 1990s-2000s: Emergence of Taxanes Paclitaxel and Docetaxel Differences accounting for existing adjuvant strategies Ratio efficacy / toxicity / practicality Ability to integrate with anthracyclines Synergism with Herceptin

6 Paclitaxel Phase II Metastatic Breast Cancer StudiesPts RR First-Line: 3 Hour-infusion % ( mg/m2) (32-60) 24 Hour-infusion % ( mg/m2) (32-62) Second-line: 3 Hour-infusion % ( mg/m2) (6-42) 24 Hour-infusion % ( mg/m2) (24-33) 96 Hour-infusion % ( mg/m2) (30-48)

7 RANDOMIZED PHASE II TRIALS PACLITAXEL (P) METASTATIC BREAST CANCER TTF or TTP Overall Survival Patients ORR (%) Median Months Median Months Study Design (nb) P value P value P value Nabholtz et al P 135 mg/m /JCO 1996 vs P 175 mg/m Schedule: 3 hr infusion NS.02 NS Peretz et al P as 3-hr infusion No difference NA ECCO 95 vs P as 24-hr infusion 31 NA NS Dose: 175 mg/m 2 Winer et al P 175 mg/m ASCO 98 vs P 210 mg/m vs P 250 mg/m Schedule: 3-hr infusion NS.03 NS

8 RANDOMIZED PHASE II TRIALS PACLITAXEL (P) METASTATIC BREAST CANCER TTF or TTP Overall Survival Patients ORR (%) Median Mos Median Mos Study Design (nb) P value P value P value Smith et al P as 3-hr infusion NA No Difference NSABP B26 vs JCO 1999 P as 24-hr infusion 50 Dose: 250 mg/m Holmes et al P as 3-hr infuson NA 11 ASCO 98 vs P as 96-hr infusion Dose: 3-hr Arm: 250mg/m 2 NS NS 96-hr Arm: 140 mg/m 2

9 Paclitaxel Schedule and Dose are important High Dose and Long Schedule (250 mg/m2, 24 Hours), : Efficacy (RR=50%) but Toxicity and Practicality… Low Dose and Short Schedule (175 mg/m2, 3 Hours): Low Efficacy (RR=25-30%), but good toxicity profile and practicality. Weekly: Phase II data

10 Paclitaxel Neoadjuvant Studies Nabholtz; May, 2002

11 Docetaxel Worldwide: 8 Phase I Dose and schedule for Phase II,III Dose: 100mg/m 2 One hour infusion Every three weeks

12 Phase II Studies: Breast

13 Pivotal Phase III Trials Monochemotherapy Nabholtz, May, 2001.

14 Paclitaxel Phase III trial Monochemotherapy Second line chemotherapy after Failure of Doxorubicin No self standing trial Cross Over only Paclitaxel 3 Hours: RR: 13-14% (EORTC JCO 2000) Paclitaxel 24 Hours: RR: 20% (Intergroup ASCO 97) First Line Chemotherapy 3 Hours: Worse than Doxo 75 mg/m 2 Gamucci, EORTC JCO Hours: Equal to Doxo 60 mg/m 2 Sledge,Intergroup ASCO 97

15 Paclitaxel: 3 hour schedule: efficacious, but pharmacokinetic Interaction with potential cardiac toxicity interval between paclitaxel and doxorurubicin Maximum cumulative dose of doxorubicin 360 mg/m2 24 hour schedule: no cardiac toxicity, but low efficacy (ECOG) Use of epirubicin in Europe: ITALY: EC vs ET, N+ Docetaxel: 1 hour infusion (AT/TAC): No added cardiac toxicity to doxorubicin (No pharmacokinetic interaction) Recommended doses: 75/50 or 60/60 mg/m2 Efficacious Ability to integrate Taxanes and Anthracyclines

16 Randomized Trials of Taxane-Anthracycline Combinations vs Polychemotherapy Docetaxel Paclitaxel * ASCO 2000 in all pts. ** ASCO 2001 in HER2 positive pts. *** ASCO 2002

17 Development of Adjuvant Chemotherapy Breast Cancer Before anthracyclines CMF, CMFVP With anthracyclines Combinations: AC, FAC, AVCMF, FEC, CEF Sequence and Alternating (Milan A & B) Dose intensity,dose density, HDCT Taxanes (Paclitaxel/Docetaxel) Sequential: A  T  C or AC  T Combinations: TA, TAC Biologic Modifiers (Herceptin) Integration in chemotherapy strategies 1970s 1980s 1990s 2000s

18 Treatment of Adjuvant Breast Cancer First Generation Trials: comparing taxane / anthracycline to non-taxane / anthracycline  polychemotherapy  sequential Second Generation Trials: comparing taxanes in both arms  polychemotherapy  sequential

19 Taxane Adjuvant Trials Number of patients First Generation31,000 Paclitaxel10,000 Docetaxel21,000 Second Generation25,000 Paclitaxel12,000 Docetaxel13,000 Total56,000

20 Paclitaxel Adjuvant Studies Nabholtz; May, 2002

21 CALGB 9344 Update ASCOsNDANIH CDC 5/984/9911/00 Median F/U (mos) Number of Events Recurrences Deaths Reduction in Hazard of recurrence22%*22%*13%* Hazard of death26%*26%*14% *p<0.05

22 CALGB 9344: Disease Free Survival by Subgroup Receptor Status Positive Receptor Status Negative / Unknown Proportion Disease-Free AC  T AC Years AC  T AC Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer

23 NSABP B-28 Disease-free Survival and Survival All Patients ACAC  TRR*P n=1525n=1528(95%CI)value Events ( ) Deaths ( ) *RR adjusted for # (+) nodes, operation, and TAM use

24 Large Taxane Trials Reported as of 11/2000 CALGB 9344 NSABP-B28 T x 4 Nil  4 N+ 1-3 N+  4 N+ 1-3 N+ A (↑ doses) C x 4 N=3170 N=3060 Premenopausal:62 % ER+: 58% < 50 y of age:51 % ER+: 66 % 54 % 30 % ± Tamoxifen X 5 Y (given to 70%) Delayed Administration ± Tamoxifen X 5 Y (given to 85%) Concomitant Administration A (fixed dose) C x 4 T x 4 Nil

25 Deaths ( ) AC n=237 Survival Patients Not Receiving Tamoxifen AC T n=237 RR (95%CI) p- value * RR Adjusted for # (+) nodes and operation B-28

26 B-27 Schema Operable Breast Cancer Randomization IIIIII AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Docetaxel x 4 Surgery Surgery Mamounas, Dec 2001

27 B-27 Pathologic Response (pCR) in Breast P < AC Taxotere (718 pts) AC (1,492 pts) 3.9% 9.8% No Tumor Non-Invasive 6.9% 18.7% 13.7% 25.6% 20% 10% 0 30% Mamounas, Dec 2001

28 All Patients 4 cycles of CVAP 4 cycles of docetaxel 4 cycles of CVAP No Response Response Randomise First PhaseSecond Phase Final Assessment / Surgery Tax301 Study Conducted by the Aberdeen Breast Group Final Assessment / Surgery Hutcheon et al. SABCS 2001, abs 506

29 34%18% 2% 5 19%16%13%4 23%26%29%3 20%18%31%2 4%22%25%1 Docetaxel n = 47 CVAP n = 50 No Initial Response Docetaxel n = 45 Miller & Payne Grade of Pathological Response Initial Response pNR pCR Tax301 Pathological Response Rates Hutcheon et al. SABCS 2001, abs 506

30 Taxotere First Generation Trials: Polychemotherapy BCIRG 001 N+ 6 x FAC 6 x TAC North American Intergroup N+ 1-3/N 0 4 x AC 4 x AT (75,50,500) (500,50,500) (60,600) (60,60) 1500 patients 3200 patients

31 Design Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 F A C T A C R Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14 Every 3 weeks x 6 cycles Stratification: Nodes: Center Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

32 TAC FAC Months Number at Risk TAC FAC % Alive and Disease Free # EventsRRp-value TAC FAC170 Total289 Disease Free Survival (ITT) BCIRG 001 Median follow-up: 33 months / n=1,491 82% 74% Nabholtz et al, ASCO 2002 (Abs 141)

33 Confirmatory Analyses: DFS AnalysisCohortRR p Main Analysis (Stratified by nodes) ITT 0.68 (0.54 – 0.86) UnadjustedITT 0.67 (0.53 – 0.85) Cox Model*ITT 0.64 (0.50 – 0.81) *Controls for nodes, age, tumor size, histology, ER/PR, HER2 Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

34 Sites of First Events TAC n= 745 FAC n= 746 number of events Metastatic80119 Local/Regional23 31 Contralateral 3 6 Other 2 nd Primary 6 10 Death NED Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

35 Planned Additional Analyses Disease Free Survival and Overall Survival Prospectively defined and powered at 5 years By nodal status Prospectively defined but not powered By Hormonal Receptor By HER2 status (FISH) Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

36 Disease Free Survival by Nodal Status Prospectively defined and powered at 5 years RRp-value 1-3 Nodes TAC FAC Months Number at Risk TAC FAC % Alive and Disease Free % 79% TAC FAC TAC FAC Nodes 4+ 69% 67% Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

37 TAC FAC Months Number at Risk TAC FAC % Alive Overall Survival by Nodal Status Prospectively defined and powered at 5 years 96% 89% RRp-value 1-3 Nodes TAC TAC FAC Nodes 4+ 86% 84% Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

38 Hazard Ratio TAC BetterFAC Better All Number of Positive Nodes (N=149) (N=420) (N=922) (N=1491) BCIRG001 - DFS: Comparison by Nodal Status Original Analysis: 1-3 versus 4+ Nodes DFS Relative Risk Reduction by Nodal Status

39 5 Year Recurrence and Survival by number of Lymph Nodes Number of Pathologically Positive Axillary Lymph Nodes 0% 20% 40% 60% 80% 100% > = survival = recurrence Results of a national survey by the ACS. Cancer 1980;45:2917 Nabholtz; May, 2002

40 Disease Free Survival by Hormonal Status TAC FAC Months N at Risk TAC FAC % Alive and Disease Free TAC FAC Months N at Risk TAC FAC NegativePositive RR = 0.62 p = RR = 0.68 p = 0.02 Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

41 TAC FAC Months N at Risk TAC FAC % Alive and Disease Free TAC FAC Months N at Risk TAC FAC Disease Free Survival by HER2 status Negative (FISH)Positive (FISH) RR = 0.74 p = 0.06 RR = 0.59 p = 0.02 Nabholtz et al, ASCO 2002 (Abs 141) BCIRG 001

42 StudyDesign Intergroup (led by ECOG) AC (x4)  P 175/3h/d1 q3wks (x4) vs AC (x4)  P 90 weekly (x12) vs AC (x4)  T 100/1h/d1 q3wks (x4) vs AC (x4)  T 35 weekly (x12) NSABP-B30 AC (x4)  T 100 (x4) vs AT 50/75* (x4) vs TAC 75/50/500* (x4) BCIRG 005 AC (x4)  T 100 (x4) vs TAC 75/50/500 (x6) Taxanes Second Generation Pivotal Adjuvant Trials A = Adriamycin; C = Cyclophosphamide; T = Taxotere; P = paclitaxel; A = Adriamycin; C = Cyclophosphamide; T = Taxotere; P = paclitaxel; *recent change

43 Current BCIRG Adjuvant Program Adjuvant Setting Screen by FISH ~15-18,000 patients Her 2 negative ~12,000 pts N+ Her 2 positive N+/High risk N- BCIRG 006 3,150 pts BCIRG 005 3,130 pts Her 2 negative ~9,000 pts N- Pilot Phase II (TCH) BCIRG 101 BCIRG 102 BCIRG 0XX Nabholtz; May, 2002

44 BCIRG 005 Adjuvant Breast Cancer Node Positive Her2 – FISH 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 6 x TAC 75 75/50/500 mg/m 2 N= centres

45 BCIRG 006 Adjuvant 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= centres 1 Year Trastuzumab AC  T AC  TH TCH

46 Conclusion Taxanes: chemotherapies of the 1990’s for breast cancer Established role in advanced breast cancer Entering adjuvant setting…


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