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
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:
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
Studies Pts 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
1993/JCO vs
P 175 mg/m
Schedule: 3 hr infusion NS NS
Peretz et al P as 3-hr infusion No difference NA
ECCO vs
P as 24-hr infusion NA NS
Dose: 175 mg/m2
Winer et al P 175 mg/m
ASCO vs
P 210 mg/m vs
P 250 mg/m
Schedule: 3-hr infusion NS 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 B vs
JCO P as 24-hr infusion
Dose: 250 mg/m
Holmes et al P as 3-hr infuson NA
ASCO vs
P as 96-hr infusion
Dose: 3-hr Arm: 250mg/m 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,

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
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
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

19. 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

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)
Number of Events Recurrences Deaths
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 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 ( )
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
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 %

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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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:
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)

32. 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)

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

34. 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)

35. 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)

36. 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)

37. 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)

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. 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

40. 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)

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 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)

42. 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

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. 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

45. 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/m mg/m2 or AUC 6
TCH
1 Year Trastuzumab

46. 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…