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

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 1980s 1990s 2000s

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

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

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

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)

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/m2 471 22 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

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 98 vs P as 96-hr infusion 29 10 Dose: 3-hr Arm: 250mg/m2 NS NS 96-hr Arm: 140 mg/m2

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

Paclitaxel Neoadjuvant Studies Nabholtz; May, 2002

Docetaxel Worldwide: 8 Phase I Dose and schedule for Phase II,III Dose: 100mg/m2 One hour infusion Every three weeks

Phase II Studies: Breast

Pivotal Phase III Trials Monochemotherapy Nabholtz, May, 2001.

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

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

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

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 1980s 1990s 2000s

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

Taxane Adjuvant Trials Number of patients First Generation 31,000 Paclitaxel 10,000 Docetaxel 21,000 Second Generation 25,000 12,000 13,000 Total 56,000

Paclitaxel Adjuvant Studies Nabholtz; May, 2002

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

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 1 2 3 4 5 6 Years Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.

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

Large Taxane Trials Reported as of 11/2000 CALGB 9344 NSABP-B28 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=3170 N=3060 54 % 30 %  4 N+ 1-3 N+  4 N+ 1-3 N+ Premenopausal: 62 % ER+: 58% < 50 y of age: 51 % ER+: 66 %

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

Operable Breast Cancer 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

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

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

Miller & Payne Grade of Pathological Response Tax301 Pathological Response Rates Miller & Payne Grade of Pathological Response No Initial Response Docetaxel n = 45 Initial Response 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

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

R Design F 5-FU 500 mg/m2 Doxorubicin 50 mg/m2 A BCIRG 001 Design F A C 5-FU 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 R Every 3 weeks x 6 cycles Stratification: Nodes: 1-3 4+ Center T A C Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14 Nabholtz et al, ASCO 2002 (Abs 141)

Disease Free Survival (ITT) BCIRG 001 Median follow-up: 33 months / n=1,491 100 90 82% 74% TAC 80 % Alive and Disease Free 70 FAC # Events RR p-value TAC 119 0.68 0.001 FAC 170 Total 289 60 50 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 Nabholtz et al, ASCO 2002 (Abs 141)

Confirmatory Analyses: DFS BCIRG 001 Confirmatory Analyses: DFS Analysis Cohort RR p Main Analysis (Stratified by nodes) ITT 0.68 (0.54 – 0.86) 0.001 Unadjusted 0.67 (0.53 – 0.85) 0.0008 Cox Model* 0.64 (0.50 – 0.81) 0.0002 *Controls for nodes, age, tumor size, histology, ER/PR, HER2 Nabholtz et al, ASCO 2002 (Abs 141)

Sites of First Events TAC n= 745 FAC n= 746 Metastatic 80 119 BCIRG 001 Sites of First Events TAC n= 745 FAC n= 746 number of events Metastatic 80 119 Local/Regional 23 31 Contralateral 3 6 Other 2nd Primary 10 Death NED 7 4 170 Nabholtz et al, ASCO 2002 (Abs 141)

Planned Additional Analyses Disease Free Survival and Overall Survival 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)

BCIRG 001 Disease Free Survival by Nodal Status Prospectively defined and powered at 5 years TAC FAC 6 12 18 24 30 36 42 48 Months Number at Risk 463 462 452 437 427 250 103 14 1 459 454 438 417 393 224 98 26 50 60 70 80 90 100 % Alive and Disease Free 1-3 TAC FAC 6 12 18 24 30 36 42 48 4+ 282 274 258 241 227 123 49 9 287 275 261 239 212 110 52 5 50 60 70 80 90 100 0.33 0.86 4+ Nodes 69% 67% 90% 79% RR p-value 1-3 Nodes 0.50 0.0002 Nabholtz et al, ASCO 2002 (Abs 141)

BCIRG 001 Overall Survival by Nodal Status Prospectively defined and powered at 5 years TAC 6 12 18 24 30 36 42 48 4+ FAC 282 279 273 265 251 132 59 10 287 281 275 269 256 64 5 50 60 70 80 90 100 0.75 1.08 4+ Nodes 86% 84% 100 96% 89% TAC 1-3 90 FAC 80 % Alive 70 RR p-value 1-3 Nodes 0.46 0.006 60 50 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)

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

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

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

Disease Free Survival by HER2 status BCIRG 001 Negative (FISH) Positive (FISH) 100 100 90 90 TAC 80 80 % Alive and Disease Free TAC 70 FAC 70 60 60 50 242 with missing FISH RR = 0.74 p = 0.06 50 RR = 0.59 p = 0.02 FAC 40 40 12 24 36 48 12 24 36 48 Months Months N at Risk N at Risk TAC 485 467 433 102 1 TAC 138 131 118 32 FAC 478 455 402 108 FAC 148 135 107 26 Nabholtz et al, ASCO 2002 (Abs 141)

Taxanes Second Generation Pivotal Adjuvant Trials Study Design 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) A = Adriamycin; C = Cyclophosphamide; T = Taxotere; P = paclitaxel; *recent change

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

Adjuvant Breast Cancer 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

Adjuvant Breast Cancer Node Positive and High Risk Node Negative BCIRG 006 Adjuvant Breast Cancer Node Positive and High Risk Node Negative 4 x AC 60/600 mg/m2 4 x Docetaxel 100 mg/m2 ACT HER2 + FISH ACTH 1 Year Trastuzumab N=3150 480 centres 6 x Docetaxel and Platinum salts 75 mg/m2 75 mg/m2 or AUC 6 TCH 1 Year Trastuzumab

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