Transcript Docetaxel in combination with adriamycin / epirubicin in

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
1970s
1980s
1990s
2000s
• 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
Chemotherapy Drug Development
NEW SINGLE AGENT
2nd LINE
1st LINE
ADJUVANT
NEW
COMBINATIONS
Single agents
First-line breast cancer
Drug
Year of
CR + PR
publication
(%)
Taxotere (75-100mg/m²)
1993 - 95
48 - 68
Taxol (175 - 250 mg/m² : 3-24hr) 1991 - 95
29 - 63
Doxorubicin (60-75mg/m²)
1974 - 94
43 - 54
Capecitabine
1995 - 99
35 - 50
Navelbine
1992 - 94
30 - 41
Gemcitabine
1995 - 97
25 - 37
Carboplatin
1985 - 93
7 - 35
Cisplatin
1978 -88
9 - 50
Cyclophosphamide
1959 - 68
36
Fluorouracil
1961 - 81
28
Methotrexate
1952 - 81
26
Mitomycin C
1976 - 85
32
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
• First-Line:
• 3 Hour-infusion
Studies
Pts
RR
6
273
46%
(175-250 mg/m2)
• 24 Hour-infusion
(32-60)
3
59
(135-250 mg/m2)
• Second-line:
• 3 Hour-infusion
(32-62)
6
202
(135-250 mg/m2)
• 24 Hour-infusion
(125-140 mg/m2)
25%
(6-42)
6
273
(175-250 mg/m2)
• 96 Hour-infusion
50%
46%
(24-33)
2
53
39%
(30-48)
RANDOMIZED PHASE II TRIALS PACLITAXEL (P)
METASTATIC BREAST CANCER
TTF or TTP
Patients
(nb)
ORR (%)
P value
Nabholtz et al
P 135 mg/m2
1993/JCO 1996
vs
P 175 mg/m2
Schedule: 3 hr infusion
471
22
3
10.5
29
NS
4.2
.02
11.7
NS
Peretz et al
ECCO 95
P as 3-hr infusion
vs
P as 24-hr infusion
Dose: 175 mg/m2
521
P 175 mg/m2
vs
P 210 mg/m2
vs
P 250 mg/m2
Schedule: 3-hr infusion
475
Study Design
Winer et al
ASCO 98
Median Months
P value
Overall Survival
Median Months
P value
29
No difference
NA
31
NA
NS
21
3.8
9.8
28
4.1
11.8
22
NS
4.8
.03
11.9
NS
RANDOMIZED PHASE II TRIALS PACLITAXEL (P)
METASTATIC BREAST CANCER
Study
Smith et al
NSABP B26
JCO 1999
Holmes et al
ASCO 98
Design
Patients
(nb)
P as 3-hr infusion
vs
P as 24-hr infusion
Dose: 250 mg/m2
563
P as 3-hr infuson
179
vs
P as 96-hr infusion
Dose: 3-hr Arm: 250mg/m2
96-hr Arm: 140 mg/m2
ORR (%)
P value
40
TTF or TTP
Overall Survival
Median Mos Median Mos
P value
P value
NA
No Difference
NA
11
50
0.02
23
29
NS
10
NS
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
MD Anderson Study Design
Green et al, Proc. ASCO 2002 ((Abst
Abst 135)
N=236
Pre and Postmenopausal
R
A
N
D
O
M
I
Z
A
T
I
O
N
Pac = Paclitaxel
Pac weekly
N-: 80 mg / m2 x12
N-: 150 mg/m2 x3
q.4w: 4 cycles
Pac q.3w
250 mg/m2/24 h
q.3w x 4
236 pts evaluable
pCR: W
N+: 28.0%
3W N+: 13.7%
S
U
R
G
E
R
Y
FAC x 4
N-: 29.4%
N-: 13.4%
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
Final Results – ITT
Type
Authors
First Line
Fumoleau
Trudeau
Seidman
Ten Bokkel
Valero
Ravdin
Valero
Ravdin
Bonneterre
Second Line
Anthracycline
resistant
Patients
117
Response
Rate
56.4%
(47.4-65.4%)
111
48.6%
(39.4-57.9%)
105
41.7%
(32.0-59.4%)
Pivotal Phase III Trials Monochemotherapy
Taxotere vs:
RR
TTP
OS
Second Line after anthracycline
MV
(Nabholtz JCO 99)
MF
(Sjostrom EJC 99)
30 vs 12%
19 vs 11 wks
11.4 vs 8.7 mos
p<.001
p<.001
p<.0097
42 vs 21%
27 vs 13 wks
p<.0001
p<.0001

NS
(crossover)
First and Second line after alkylating agent
Doxorubicin
(Chan JCO ‘99)
48 vs 33%
26 vs 21 wks
p=.008
NS

NS
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
Paclitaxel
Docetaxel
Study
Status
AT vs AC
AT>AC
Nabholtz et al, 1999
TAC vs FAC
TACFAC
Nabholtz et al, 2001
Mackey et al, 2002***
ET vs FEC
ET>FEC
Bonneterre et al,
2001
Study
AT vs FAC
Jassem et al, 2001
AT vs AC
Biganzoli et al, 2000
ET vs EC
Carmichael, 2001
ET vs EC
Luck et al, 2000
Konecny et al, 2001
* ASCO 2000 in all pts.
** ASCO 2001 in HER2 positive pts. *** ASCO 2002
Status
AT>FAC
AT=AC
ET=EC
ET=EC*
ET>EC**
Development of Adjuvant Chemotherapy
Breast Cancer
1970s
• Before anthracyclines
• CMF, CMFVP
• With anthracyclines
1980s
1990s
2000s
• 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
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
Taxane Adjuvant Trials
Number of patients
First Generation
31,000
Paclitaxel
10,000
Docetaxel
21,000
Second Generation
Total
25,000
Paclitaxel
12,000
Docetaxel
13,000
56,000
Paclitaxel Adjuvant Studies
CALGB 9344 Study Design
N=3170
Node+
Pre and
PostPostmenopausal
ER+ or PR+
R
A
N
D
O
M
I
Z
A
T
I
O
N
A60C x 4
P175/3h x 4
A90+G90+G-CSFC x 4
N=3060
Node+
Pre and
PostPostmenopausal
A75C x 4
ER+ or PR+ patients received Tamoxifen x 5 yrs
A = Doxorubicin
C = Cylophosphamide
P = Paclitaxel
NSABP B
-28 Study Design
B-28
None
ER+ or PR+
R
A
N
D
O
M
I
Z
A
T
I
O
N
AC x 4
P225/3h x 4
AC x 4
All patients 50 years and those <50 with ER+ or PR+ tumors
received Tamoxifen x 5 yrs
A = Doxorubicin
C = Cylophosphamide
P = Paclitaxel
Nabholtz; May, 2002
CALGB 9344 Update
ASCO
5/98
sNDA
4/99
NIH CDC
11/00
Median F/U (mos)
18
30
52
Number of Events
Recurrences
Deaths
453
200
624
342
901
589
22%*
26%*
22%*
26%*
13%*
14%
Reduction in
Hazard of recurrence
Hazard of death
*p<0.05
CALGB 9344:
Disease Free Survival by Subgroup
Proportion Disease-Free
1.00
AC  T
AC
Receptor Status
Positive
0.75
0.50
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.
NSABP B-28 Disease-free Survival and
Survival All Patients
AC
n=1525
ACT
RR*
n=1528 (95%CI)
P
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
NSABP-B28
CALGB 9344
Tx4
A (↑ doses) C x 4
Tx4
A (fixed dose) C x 4
Nil
± Tamoxifen X 5 Y (given to 70%)
Delayed Administration
Nil
± Tamoxifen X 5 Y (given to 85%)
Concomitant Administration
N=3060
N=3170
30 %
54 %
 4 N+ 1-3 N+
Premenopausal:
ER+:
62 %
58%
 4 N+ 1-3 N+
< 50 y of age: 51 %
ER+:
66 %
B-28
Survival
Patients Not Receiving Tamoxifen
n=237
n=237
(95%CI)
pvalue
52
39
0.75
0.20
AC
Deaths
AC
T
RR
(0.49-1.16)
* RR Adjusted for # (+) nodes and operation
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
II
III
I
Mamounas, Dec 2001
B-27
Pathologic Response (pCR) in Breast
No Tumor
30%
Non-Invasive
P < 0.001
20%
18.7%
9.8%
10%
25.6%
13.7%
0
3.9%
6.9%
AC
(1,492 pts)
AC Taxotere
(718 pts)
Mamounas, Dec 2001
Tax301 Study
Conducted by the Aberdeen Breast Group
First Phase
Second Phase
All Patients
4 cycles of
CVAP
4 cycles of docetaxel
4 cycles of CVAP
Final Assessment / Surgery
4 cycles of docetaxel
Hutcheon et al. SABCS 2001, abs 506
Tax301
Pathological Response Rates
pNR
pCR
Miller & Payne
Grade of
Pathological
Response
No Initial Response
Docetaxel
n = 45
1
25%
22%
4%
2
31%
18%
20%
3
29%
26%
23%
4
13%
16%
19%
5
2%
18%
34%
Initial Response
CVAP
Docetaxel
n = 50
n = 47
Hutcheon et al. SABCS 2001, abs 506
Taxotere First Generation Trials: Polychemotherapy
BCIRG 001
N+
North American
Intergroup
N+ 1-3/N0
6 x TAC
(75,50,500)
6 x FAC
(500,50,500)
4 x AT
(60,60)
4 x AC
(60,600)
1500 patients
3200 patients
BCIRG 001
Design
F
A
C
R
Stratification:
• Nodes:
1-3
4+
• Center
5-FU
500 mg/m2
Doxorubicin
50 mg/m2
Cyclophosphamide 500 mg/m2
Every 3 weeks x 6 cycles
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)
BCIRG 001
Disease Free Survival (ITT)
Median follow-up: 33 months / n=1,491
% Alive and Disease Free
100
90
82%
80
TAC
74%
70
# Events
60
TAC
119
FAC
170
Total
289
RR
p-value
0.68
0.001
FAC
50
0
Number at Risk
TAC 745
FAC 746
6
12
18
24
Months
30
36
42
48
736
729
710
699
678
656
654
605
373
334
152
150
23
31
1
0
Nabholtz et al, ASCO 2002 (Abs 141)
BCIRG 001
Confirmatory Analyses: DFS
Analysis
Main Analysis
(Stratified by nodes)
Cohort
ITT
Unadjusted
ITT
Cox Model*
ITT
RR
p
0.68
(0.54 – 0.86)
0.67
(0.53 – 0.85)
0.64
(0.50 – 0.81)
0.001
0.0008
0.0002
*Controls for nodes, age, tumor size, histology, ER/PR, HER2
Nabholtz et al, ASCO 2002 (Abs 141)
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
6
10
Death NED
7
4
119
170
Nabholtz et al, ASCO 2002 (Abs 141)
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
% Alive and Disease Free
100
90%
90
TAC
79%
80
FAC
70
60
RR
p-value
1-3 Nodes
0.50
0.0002
4+ Nodes
0.86
0.33
TAC
1-3
69%
FAC
67%
4+
50
0
6
12
18
24
30
36
42
48
427
393
227
212
250
224
123
110
103
98
49
52
14
26
9
5
1
0
0
0
Months
Number at Risk
TAC 463
1-3
FAC 459
4+ TAC 282
FAC 287
462
454
274
275
452
438
258
261
437
417
241
239
Nabholtz et al, ASCO 2002 (Abs 141)
BCIRG 001
Overall Survival by Nodal Status
Prospectively defined and powered at 5 years
100
96%
1-3
89%
90
% Alive
TAC
86%
84%
80
FAC
4+
TAC
70
60
RR
p-value
1-3 Nodes
0.46
0.006
4+ Nodes
1.08
0.75
50
0
6
12
18
24
30
36
42
48
Months
Number at Risk
1-3 TAC 463
FAC 459
462
457
459
453
453
444
449
422
261
243
112
107
14
28
1
1
TAC
FAC
279
281
273
275
265
269
251
256
132
132
59
64
10
5
0
0
4+
282
287
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)
0.2
TAC Better
0.4
0.6
0.8
FAC Better
1.0
Hazard Ratio
1.2
1.4
1.6
1.8
2.0
5 Year Recurrence and Survival by
number of Lymph Nodes
100%
80%
= survival
60%
= recurrence
40%
20%
0%
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
BCIRG 001
Disease Free Survival by Hormonal Status
% Alive and Disease Free
Negative
Positive
100
100
90
90
TAC
80
80
TAC
70
60
RR = 0.62
p = 0.005
FAC
70
60
50
FAC
RR = 0.68
p = 0.02
50
0
N at Risk
TAC 231
FAC 228
12
217
202
24
Months
188
158
36
48
47
34
0
0
0
N at Risk
TAC 514
FAC 518
12
493
497
24
Months
466
447
36
105
116
48
1
0
Nabholtz et al, ASCO 2002 (Abs 141)
BCIRG 001
Disease Free Survival by HER2 status
% Alive and Disease Free
Negative (FISH)
Positive (FISH)
100
100
90
90
TAC
80
80
FAC
70
60
50
TAC
70
60
RR = 0.74
p = 0.06
50
40
RR = 0.59
p = 0.02
FAC
40
0
N at Risk
TAC 485
FAC 478
12
467
455
24
Months
433
402
36
102
108
48
1
0
0
N at Risk
TAC 138
FAC 148
12
131
135
24
Months
118
107
36
48
32
26
0
0
Nabholtz et al, ASCO 2002 (Abs 141)
Taxanes Second Generation Pivotal Adjuvant
Trials
Study
Intergroup
(led by ECOG)
NSABP-B30
BCIRG 005
Design
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)
AC (x4)  T 100 (x4) vs
AT 50/75* (x4) vs
TAC 75/50/500* (x4)
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-
BCIRG 0XX
Her 2 negative
~12,000 pts
N+
BCIRG 005
3,130 pts
Her 2 positive
N+/High risk NBCIRG 006
3,150 pts
Pilot Phase II
(TCH)
BCIRG 101
BCIRG 102
Nabholtz; May, 2002
BCIRG 005
Adjuvant Breast Cancer
Node Positive
4 x AC 60/600 mg/m 4 x Docetaxel 100 mg/m
2
Her2 –
FISH
N=3150
345 centres
6 x TAC 75 75/50/500 mg/m
2
2
BCIRG 006
Adjuvant Breast Cancer
Node Positive and High Risk Node Negative
4 x Docetaxel
4 x AC
60/600 mg/m2
100 mg/m2
ACT
HER2 +
ACTH
FISH
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
Conclusion
Taxanes: chemotherapies of the 1990’s
for breast cancer
• Established role in advanced breast
cancer
• Entering adjuvant setting…