Download Phase III Trial Comparing TAC with AC

Ten-year follow-up analysis of the BCIRG 001 trial
confirms superior DFS and OS benefit of adjuvant
TAC (docetaxel, doxorubicin, cyclophosphamide)
over FAC (fluorouracil, doxorubicin, cyclophosphamide)
in women with operable node-positive breast cancer
Martin M, Mackey J, Pienkowski T, Rolski J, Guastalla JP,
Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J,
Coleman R, Modiano M, Vinholes J, Pinter T, Childs B, Roessner
M, Wilson V, Rupin M, Vogel C
on behalf of the BCIRG 001 Investigators
NCT00688740
Sponsored by sanofi-aventis
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Disclosures
Dr Martin has received speaker's honoraria
from Sanofi-Aventis
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Adjuvant Chemotherapy
•
Adding a taxane to adjuvant anthracycline-based
regimens improves survival in patients with early breast
cancer1,2
•
The BCIRG 001 (TAX316) study showed that TAC
reduces the risk of relapse and death compared with
FAC in patients with node-positive early breast cancer3
–
Planned interim analysis; 399 DFS events
–
Median follow-up 55 months; data cut-off 15 July 2003
–
DFS HR=0.72 (95%CI 0.59–0.88, P=0.001)
–
OS HR=0.70 (95%CI 0.53–0.91, P=0.008)
1Nowak
AK, et al. Lancet Oncol 2004;5:372–380
Laurentiis M, et al. J Clin Oncol 2008;26:44–53
3Martin M, et al. N Engl J Med 2005;352:2302–2313
2De
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Final Analysis at 10-year Median Follow-up
•
DFS (primary endpoint) and OS
•
Rates of long-term toxicities, including
cardiac events and hematologic
malignancies
•
Data cut-off 11 March 2010
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Trial Design
n=1491
20 countries
112 centers
75 mg/m2
T Docetaxel
50 mg/m2
A Doxorubicin
C Cyclophosphamide 500 mg/m2
R
Stratification
• Nodal status
1-3
4+
• Center
Every 3 weeks for 6 cycles
F
A
C
Fluorouracil
500 mg/m2
Doxorubicin
50 mg/m2
Cyclophosphamide 500 mg/m2
Dexamethasone premedication, 8 mg bid, 3 days
Prophylactic ciprofloxacin 500 mg bid, days 5–14
No primary G-CSF prophylaxis was allowed
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Post Chemotherapy Treatment
T
A
C
F
A
C
Tamoxifen 20 mg/day for 5 years
• Patients with ER and/or PR positive tumors
Radiation Therapy
• All patients having breast-conserving surgery
• Each center’s guidelines after mastectomy
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Major Eligibility Criteria
•
Histologically proven node-positive breast cancer
•
Definitive surgery with axillary lymph node dissection
•
Stage T1–3, N1, M0
•
Normal hematologic, hepatic, renal, and cardiac
function
•
No more than 60 days between surgery
and randomization
•
Age ≤70 years and KPS ≥80%
•
Written informed consent
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
End Points and Follow-up
•
Objectives
– Primary: disease-free survival
– Secondary: overall survival, safety,
quality of life, tumor markers
•
Timing for follow-up visits
– Every 3 months for the first 2 years
– Every 6 months up to year 5
– Yearly from years 5 to 10
 Annual LVEF monitoring to evaluate long-term
cardiac risk
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Statistics
•
DFS (primary analysis)
–
–
–
•
Intention-to-treat (ITT)
Log-rank test, stratified for nodal status
(1 to 3 versus 4+ positive nodes)
HR and 95% CI by Cox proportional hazards regression
model
Adverse Events
–
–
NCI-CTC, version 1.0
Coding Symbols for Thesaurus of Adverse Reaction
Terms (COSTART)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Characteristics of the Patients (ITT)
TAC
(n=745)
FAC
(n=746)
49 (26–70)
49 (23–70)
Median KPS
100
100
Premenopausal, %
57
55
Mastectomy, %
60
59
Radiotherapy, %
69
72
Tamoxifen, %
68
68
Median age, range
Enrollment: 11 June 1997 to 03 June 1999
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Tumor Characteristics
TAC
(n=745)
FAC
(n=746)
≤2
40
43
>2 to 5
53
51
<5
8
6
1 to 3
63
62
4+
37
38
ER+ and/or PR+*
76
76
HER2/neu+ (FISH)*
21
22
% patients
Tumor size, cm
Nodal status
*Centrally reviewed
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
DFS Events (ITT) at 10 Years
TAC
(n=745)
FAC
(n=746)
All
(n=1491)
Local relapse
32 (4)
36 (5)
68 (5)
Regional relapse
9 (1)
14 (2)
23 (2)
174 (23)
214 (29)
388 (26)
2nd primary malignancy
56 (8)
53 (7)
109 (7)
Death NED
15 (2)
16 (2)
31 (2)
No. patients (%)
First DFS event
Distant relapse
Undefined DFS event
Lost to follow-up
NED=no evidence of disease
1 (0.1)
43 (6)
0
39 (5)
1 (<0.1)
82 (6)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
DFS at a Median 10-year Follow-up (ITT)
Disease-free survival probability
1.00
TAC: 76%
0.80
HR=0.72
95%CI: 0.59–0.88
Log-rank P=0.001
0.60
FAC: 69%
HR=0.80
95%CI: 0.68–0.93
Log-rank P=0.0043
0.40
0.20
0.00
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Disease-free survival time (months)
Number at Risk
TAC
745 737 710 678 659 639 617 596 583 562 551 541 530 519 508 491 478 463 444 418 387
FAC
746 730 699 659 618 584 558 541 523 510 499 484 471 453 437 429 414 392 378 351 333
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
DFS in Predefined Subgroups
In favor of TAC
Overall
ITT Adjusted*
0.80 (0.68 to 0.93)
1491
Number of positive nodes
[1-3]
0.72 (0.58 to 0.91)
926
Number of positive nodes
[4+]
0.87 (0.70 to 1.09)
565
Hormonal Receptor status
Negative
0.66 (0.49 to 0.89)
359
Hormonal Receptor status
Positive
0.84 (0.70 to 1.01)
1132
HER2/NEU status
Negative
0.88 (0.72 to 1.08)
943
HER2/NEU status
Positive
0.60 (0.43 to 0.83)
319
HER2/NEU status
Unknown
0.80 (0.54 to 1.18)
229
Menopausal status
Pre-menopausal
0.69 (0.55 to 0.86)
830
Menopausal status
Post-menopausal 0.93 (0.74 to 1.16)
661
*Adjusted for nodal status
0.2
In favor of FAC
0.6
1.0
1.4
1.8
Hazard Ratio (95%CI)
2.2
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
OS at a Median 10-year Follow-up (ITT)
1.00
Overall survival probability
TAC: 87%
HR=0.70
95%CI: 0.53–0.91
Log-rank P=0.008
0.80
0.60
FAC: 81%
HR=0.74
95%CI: 0.61–0.90
Log-rank P=0.002
0.40
0.20
0.00
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Survival time (months)
Number at Risk
TAC
745 742 732 718 704 693 677 661 650 645 635 622 612 603 594 584 571 563 547 524 495
FAC
746 740 731 724 704 684 657 642 625 608 591 581 573 557 546 532 517 501 482 460 443
429 deaths: 188 TAC; 241 FAC
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
OS in Predefined Subgroups
In favor of TAC
Overall
ITT Adjusted*
0.74 (0.61 to 0.90)
1491
Number of positive nodes
[1–3]
0.62 (0.46 to 0.82)
926
Number of positive nodes
[4+]
0.87 (0.67 to 1.12)
565
Hormonal Receptor status
Negative
0.69 (0.49 to 0.96)
359
Hormonal Receptor status
Positive
0.76 (0.60 to 0.96)
1132
HER2/NEU status
Negative
0.79 (0.61 to 1.01)
943
HER2/NEU status
Positive
0.66 (0.45 to 0.96)
319
HER2/NEU status
Unknown
0.71 (0.44 to 1.14)
229
Menopausal status
Pre-menopausal
0.65 (0.49 to 0.85)
830
Menopausal status
Post-menopausal 0.85 (0.65 to 1.11)
661
*Adjusted for nodal status
0.2
In favor of FAC
0.6
1.0
1.4
1.8
Hazard Ratio (95%CI)
2.2
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Cardiac Toxicities Reported as an AE
No. patients (%)
Congestive heart failure*
(cardiac function grade 3-4)
Grade 3 (mild, responsive to therapy)
Grade 4 (severe, refractory)
Serious adverse event
Death due to CHF
TAC
(n=744)
FAC
(n=736)
26 (4)
17 (2)
21 (3)
14 (2)
5 (1)
23 (3)
2 (0.3)
*Comparison of CHF rates not statistically significant:
TAC 3.5% (95%CI: 2.3–5.1) vs FAC 2.3% (95%CI: 1.4–3.7); Chi-square P=0.18
3 (0.4)
16 (2)
4 (1)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Cumulative Incidence of CHF
0.08
TAC
(n=744)
FAC
(n=736)
26
17
Reported in the first 55 months of follow-up
13
5
Reported in months 55 to 120 of follow-up
13
12
0.07
Number of CHF events
Probability of CHF
0.06
0.05
0.04
TAC
0.03
FAC
0.02
0.01
0.00
0
12
Number at Risk
744
713
TAC
736
716
FAC
24
36
48
60
72
84
96
108
120
484
429
437
392
Time from randomization to CHF event (months)
679
672
647
621
620
588
591
554
566
522
540
490
515
466
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Changes in LVEF
TAC
(n=744)
FAC
(n=736)
Nonevaluable patients, n
396
467
Evaluable patients, n
348
269
LVEF decrease >20%, n (% evaluable)
58 (17)
41 (15)
LVEF Decrease below normal limit,
41 (12)
27 (10)
n (% evaluable)
*Evaluable patients had an LVEF assessment at baseline and during the study period.
†Lower normal limit was 50% if normal limit was unknown.
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Hematologic Malignancies at 10 Years
No. patients (%)
Acute myeloid
leukemia
Chronic lymphocytic
leukemia
Myelodysplastic
Syndrome
TAC
n=744
FAC
n=736
4 (1)
1 (0.1)
0
1 (0.1)
2 (0.3)
1 (0.1)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Serious Adverse Events
•
•
•
•
SAEs occurred more frequently with TAC, but at lower rates
during follow-up
–
treatment (TAC 36%; FAC 9%)
–
follow-up (TAC 7%; FAC 5%)
During treatment, main AEs were hematologic
–
grade 3 or 4 neutropenia 66% TAC; 49% FAC
–
febrile neutropenia 25% TAC; 3% FAC
Most common AEs persisting into follow-up period
–
asthenia (TAC 32%; FAC 24%)
–
amenorrhea (TAC 47%; FAC 30%)
Rates of AEs starting or worsening during the follow-up period
were similar except for peripheral sensory neuropathy
(TAC 4%; FAC 1%)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Efficacy Summary
•
The survival benefit of TAC over FAC is maintained
at a median follow-up of 10 years
–
DFS
 20% reduction in risk of relapse (P=0.0043)
 10-year DFS rates: TAC 62%, FAC 55%
–
OS
 26% reduction in risk of death (P=0.002)
 10-year OS rates: TAC 76%, FAC 69%
•
TAC improves DFS irrespective of nodal, hormone
receptor, or HER2/neu status
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Safety Summary
•
CHF was reported in 3.5% and 2.3% of patients
treated with TAC and FAC, respectively (P=0.18)
•
Most CHF cases were grade 3
•
CHF was fatal in 2 TAC patients and 4 FAC patients
•
Significant LVEF decreases (>20%) were similar
between treatment groups (TAC 17%, FAC 15%)
•
Hematological malignancies were reported in 6
(0.8%) and 3 (0.4%) patients treated with TAC and
FAC (P=0.51; Fisher’s exact test)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Conclusions
•
The 10-year follow-up analysis confirms
that adjuvant docetaxel combined with
doxorubicin and cyclophosphamide (TAC)
provides a long-term disease-free
survival and overall survival benefit in the
treatment of women with node-positive
early breast cancer
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Acknowledgments
•
The women who participated in the study and
those who returned for follow-up
•
The investigators and their staff
•
The Independent Data Monitoring Committee
•
The Study Co-Chairs (John Mackey, Charles
Vogel)
•
The CIRG staff (Agathe Garcia, Matthieu Rupin)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
Investigators
Canada
Allan S, Chang J, Colwell B, Drolet Y, Dufresne J, Gelmon K, Holland D, Lesperance
B, Laing K, Mackey J, Potvin C, Provencher L, Rubin S, Sami A, Sehdev S, Trudeau
M, Verma S, Spadafora S, Whitlock P, Yelle L, Mackinnon J
USA
Avery B, Beck T, Begas A, George C, Glaspy J, Graham B, Hainsworth J, Iannotti N,
Limentani S, Marcom K, Modiano M, O’Rourke M, Robert N, Schnell F, Theall K,
Tongol J, Vogel C
Spain
Alba Conejo E, Alvarez Lopez I, Anton Torres A, Aranda Aguilar E, Cassinello J,
Garcia Puche JL, Lobo Samper F, Lopez Lopez R, Lopez Vega JM, Martin M, Munarriz
Gandia B, Murias Rosales A, Rodriguez Lescure A, Torres A
Poland
Karnicka-Mlodkowska H, Pienkowski T, Rolski J
UK
Coleman R, Price C, Sherwin E, Wardley A,
Greece
Georgoulias V
Hungary
Boer K, Juhos E, Pinter T
Germany
Oberhoff C
France
Guastalla JP
So. Africa
Moodley D
Brazil
Teixeira LC, Vinholes J
Egypt
Abd-El-Azim H, El-Zawahry H
Sweden
Fornander T, Nylen U
Austria
Schuller J
Israel
Lurie H, Merimsky O, Steiner M
Czech Rep
Abrahamova J, Finek J
Argentina
Martinez JL, Mickiewicz E, Orti R
Portugal
Chumbo M, Goncalves I
Uruguay
Viola A
Slovak Rep
Koza I