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Integration of Taxanes in the Management of Breast Cancer

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.

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Integration of Taxanes in the Management of Breast Cancer

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  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 1970s • 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 1980s 1990s 2000s

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

  4. Single agents First-line breast cancer Vogel CL, Nabholtz Oncologist 1999; 4: 17-33. Nabholtz et al. Exp. Opin Pharmacother 2000; 1: 187-206.

  5. Adjuvant Chemotherapy Breast Cancer1990s-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 Studies Pts RR • First-Line: • 3 Hour-infusion 6 273 46% (175-250 mg/m2) (32-60) • 24 Hour-infusion 3 59 50% (135-250 mg/m2) (32-62) • Second-line: • 3 Hour-infusion 6 202 25% (135-250 mg/m2) (6-42) • 24 Hour-infusion 6 273 46% (175-250 mg/m2) (24-33) • 96 Hour-infusion 2 53 39% (125-140 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 alP 135 mg/m2 47122 3 10.5 1993/JCO 1996 vs P 175 mg/m2 29 4.2 11.7 Schedule: 3 hr infusion NS .02 NS Peretz et al P as 3-hr infusion 521 29 No difference NA ECCO 95 vs P as 24-hr infusion 31 NA NS Dose: 175 mg/m2 Winer et al P 175 mg/m2 475 21 3.8 9.8 ASCO 98 vs P 210 mg/m2 28 4.1 11.8 vs P 250 mg/m2 22 4.8 11.9 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 563 40 NA No Difference NSABP B26 vs JCO 1999 P as 24-hr infusion 50 Dose: 250 mg/m2 0.02 Holmes et al P as 3-hr infuson 179 23 NA 11 ASCO 98vs P as 96-hr infusion 29 10 Dose: 3-hr Arm: 250mg/m2 NS NS 96-hr Arm: 140 mg/m2

  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/m2 • 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/m2 Gamucci, EORTC JCO 2000 • 24 Hours: Equal to Doxo 60 mg/m2 Sledge,Intergroup ASCO 97

  15. Ability to integrate Taxanes and Anthracyclines • Paclitaxel: • 3 hour schedule: efficacious, but pharmacokinetic Interaction with potential cardiac toxicity • 16-24 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

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

  17. Development of Adjuvant Chemotherapy Breast Cancer 1970s • 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 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

  20. Paclitaxel Adjuvant Studies Nabholtz; May, 2002

  21. CALGB 9344 Update ASCO sNDA NIH CDC 5/98 4/99 11/00 Median F/U (mos) 18 30 52 Number of Events Recurrences 453 624 901 Deaths 200 342 589 Reduction in Hazard of recurrence 22%* 22%* 13%* Hazard of death 26%* 26%* 14%*p<0.05

  22. CALGB 9344:Disease Free Survival by Subgroup 1.00 AC  T AC Receptor Status Positive 0.75 0.50 Proportion Disease-Free 1.00 AC  T AC Receptor Status Negative / Unknown 0.75 0.50 0 1 2 3 4 5 6 Years 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 AC ACT RR* P n=1525 n=1528 (95%CI) value Events 282 269 0.93 0.38 (0.78-1.10) Deaths 133 136 1.00 0.98 (0.78-1.27) *RR adjusted for # (+) nodes, operation, and TAM use

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

  25. B-28 Survival Patients Not Receiving Tamoxifen p- value AC n=237 AC T n=237 RR (95%CI) Deaths 52 39 0.75 0.20 (0.49-1.16) * RR Adjusted for # (+) nodes and operation

  26. 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 Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4 I II III Mamounas, Dec 2001

  27. B-27 Pathologic Response (pCR) in Breast No Tumor Non-Invasive 30% P < 0.001 20% 18.7% 9.8% 10% 25.6% 13.7% 6.9% 3.9% 0 AC (1,492 pts) AC Taxotere (718 pts) Mamounas, Dec 2001

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

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

  30. Taxotere First Generation Trials: Polychemotherapy 6 x TAC (75,50,500) BCIRG 001 N+ 6 x FAC 1500 patients (500,50,500) 4 x AT (60,60) North American Intergroup N+ 1-3/N0 4 x AC (60,600) 3200 patients

  31. BCIRG 001 F A C T A C 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 Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro500 mg bid, day 5-14 Nabholtz et al, ASCO 2002 (Abs 141)

  32. Disease Free Survival (ITT) 82% 74% BCIRG 001 Median follow-up: 33 months / n=1,491 100 90 TAC 80 % Alive and Disease Free FAC 70 60 50 0 6 12 18 24 30 36 42 48 Months Number at Risk TAC 745 736 710 678 654 373 152 23 1 FAC 746 729 699 656 605 334 150 31 0 Nabholtz et al, ASCO 2002 (Abs 141)

  33. BCIRG 001 Confirmatory Analyses: DFS *Controls for nodes, age, tumor size, histology, ER/PR, HER2 Nabholtz et al, ASCO 2002 (Abs 141)

  34. BCIRG 001 Sites of First Events Nabholtz et al, ASCO 2002 (Abs 141)

  35. BCIRG 001 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)

  36. BCIRG 001 100 100 90% TAC 90 90 79% 80 80 1-3 % Alive and Disease Free TAC 69% FAC FAC 70 70 67% 4+ 60 60 4+ Nodes 0.86 0.33 50 50 0 0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 Months Number at Risk TAC 463 462 452 437 427 250 103 14 1 1-3 FAC 459 454 438 417 393 224 98 26 0 TAC 282 274 258 241 227 123 49 9 0 4+ FAC 287 275 261 239 212 110 52 5 0 Disease Free Survival by Nodal StatusProspectively defined and powered at 5 years Nabholtz et al, ASCO 2002 (Abs 141)

  37. Overall Survival by Nodal StatusProspectively defined and powered at 5 years BCIRG 001 100 96% 89% 90 86% 84% 80 4+ TAC 70 60 4+ Nodes 1.08 0.75 50 0 6 12 18 24 30 36 42 48 TAC 282 279 273 265 251 132 59 10 0 4+ FAC 287 281 275 269 256 132 64 5 0 100 TAC 1-3 90 FAC 80 % Alive 70 60 50 0 6 12 18 24 30 36 42 48 Months Number at Risk TAC 463 462 459 453 449 261 112 14 1 1-3 FAC 459 457 453 444 422 243 107 28 1 Nabholtz et al, ASCO 2002 (Abs 141)

  38. DFS Relative Risk Reduction by Nodal Status BCIRG001 - DFS: Comparison by Nodal Status Original Analysis: 1-3 versus 4+ Nodes All (N=1491) Number of Positive Nodes 1-3 (N=922) 4-9 (N=420) 10+ (N=149) TAC Better FAC Better 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Hazard Ratio

  39. = survival = recurrence 5 Year Recurrence and Survival by number of Lymph Nodes 100% 80% 60% 40% 20% 0% 0 2 3 4 5 6-10 11-15 16-20 >20 1 Number of Pathologically Positive Axillary Lymph Nodes Results of a national survey by the ACS. Cancer 1980;45:2917 Nabholtz; May, 2002

  40. Disease Free Survival by Hormonal Status BCIRG 001 Negative Positive 100 100 90 90 TAC 80 80 FAC % Alive and Disease Free TAC 70 70 FAC 60 60 RR = 0.62 p = 0.005 RR = 0.68 p = 0.02 50 50 0 12 24 36 48 0 12 24 36 48 Months Months N at Risk N at Risk TAC 231 217 188 47 0 TAC 514 493 466 105 1 FAC 228 202 158 34 0 FAC 518 497 447 116 0 Nabholtz et al, ASCO 2002 (Abs 141)

  41. Disease Free Survival by HER2 status BCIRG 001 Negative (FISH) Positive (FISH) 100 100 90 90 TAC 80 80 % Alive and Disease Free TAC FAC 70 70 60 60 RR = 0.74 p = 0.06 RR = 0.59 p = 0.02 50 50 FAC 40 40 0 12 24 36 48 0 12 24 36 48 Months Months N at Risk N at Risk TAC 485 467 433 102 1 TAC 138 131 118 32 0 FAC 478 455 402 108 0 FAC 148 135 107 26 0 Nabholtz et al, ASCO 2002 (Abs 141)

  42. Taxanes Second Generation Pivotal Adjuvant Trials 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 ~9,000 pts N- Her 2 negative ~12,000 pts N+ Her 2 positive N+/High risk N- BCIRG 006 3,150 pts BCIRG 0XX BCIRG 005 3,130 pts Pilot Phase II (TCH) BCIRG 101 BCIRG 102 Nabholtz; May, 2002

  44. BCIRG 005 Adjuvant Breast Cancer Node Positive 4 x AC 60/600 mg/m2 4 x Docetaxel 100 mg/m2 Her2 – FISH 6 x TAC 75 75/50/500 mg/m2 N=3150 345 centres

  45. BCIRG 006 Adjuvant Breast Cancer Node Positive and High Risk Node Negative 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACT ACTH HER2 + FISH 1 Year Trastuzumab N=3150 480 centres 6 xDocetaxel and Platinum salts 75 mg/m2 75 mg/m2 or AUC 6 TCH 1 Year Trastuzumab

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

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