nct00688740 sponsored by sanofi-aventis

Ten-year follow-up analysis of the BCIRG 001 trialconfirms superior DFS and OS benefit of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide)

over FAC (fluorouracil, doxorubicin, cyclophosphamide)

in women with operable node-positive breast cancer

NCT00688740Sponsored by sanofi-aventis

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 Con behalf of the BCIRG 001 Investigators

San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010

BCIRG 001

DisclosuresDr Martin has received speaker's

honoraria from Sanofi-Aventis


BCIRG 001Adjuvant 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;5:372–3802De Laurentiis M, et al. J Clin Oncol 2008;26:44–533Martin M, et al. N Engl J Med 2005;352:2302–2313


BCIRG 001Final 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


BCIRG 001Trial Design

Fluorouracil 500 mg/m2 Doxorubicin 50 mg/m2

Cyclophosphamide500 mg/m2

Docetaxel 75 mg/m2

Doxorubicin 50 mg/m2

Cyclophosphamide500 mg/m2

TAC

FAC

R

Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5–14No primary G-CSF prophylaxis was allowed

Every 3 weeks for 6 cycles

Stratification• Nodal status

1-3 4+

• Center

n=149120 countries112 centers


BCIRG 001Post Chemotherapy Treatment

TAC

FAC

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


BCIRG 001Major 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


BCIRG 001End 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


BCIRG 001Statistics

• 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)


BCIRG 001Characteristics of the Patients (ITT)

TAC(n=745)

FAC(n=746)

Median age, range 49 (26–70) 49 (23–70)Median KPS 100 100Premenopausal, % 57 55Mastectomy, % 60 59Radiotherapy, % 69 72Tamoxifen, % 68 68

Enrollment: 11 June 1997 to 03 June 1999


BCIRG 001

% patientsTAC

(n=745)FAC

(n=746)Tumor size, cm

≤2 40 43>2 to 5 53 51<5 8 6

Nodal status1 to 3 63 624+ 37 38

ER+ and/or PR+* 76 76HER2/neu+ (FISH)* 21 22

Tumor Characteristics

*Centrally reviewed


BCIRG 001

No. patients (%)TAC

(n=745)FAC

(n=746)All

(n=1491)First DFS event

Local relapse 32 (4) 36 (5) 68 (5)Regional relapse 9 (1) 14 (2) 23 (2)Distant relapse 174 (23) 214 (29) 388 (26)2nd primary malignancy 56 (8) 53 (7) 109 (7)Death NED 15 (2) 16 (2) 31 (2)Undefined DFS event 1 (0.1) 0 1 (<0.1)

Lost to follow-up 43 (6) 39 (5) 82 (6)

DFS Events (ITT) at 10 Years

NED=no evidence of disease


BCIRG 001

TAC: 76%

FAC: 69%

DFS at a Median 10-year Follow-up (ITT)

Number at RiskTAC 745 737 710 678 659639 617 596 583 562 551 541 530 519 508491 478463 444 418387FAC 746 730 699 659 618584 558 541 523 510 499 484 471 453 437429 414392 378 351333

Dis

ease

-fre

e su

rviv

al p

roba

bilit

y

0.00

0.20

0.40

0.60

0.80

1.00

Disease-free survival time (months)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120

HR=0.7295%CI: 0.59–0.88Log-rank P=0.001

HR=0.8095%CI: 0.68–0.93Log-rank P=0.0043


BCIRG 001DFS in Predefined Subgroups

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 statusNegative 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-menopausal0.93 (0.74 to 1.16) 661

In favor of TAC In favor of FAC

Hazard Ratio (95%CI)0.2 0.6 1.0 1.4 1.8 2.2*Adjusted for nodal status


BCIRG 001OS at a Median 10-year Follow-up (ITT)

429 deaths: 188 TAC; 241 FAC

Number at RiskTAC 745 742 732 718 704693 677 661 650 645 635 622 612 603 594584 571563 547 524495FAC 746 740 731 724 704684 657 642 625 608 591 581 573 557 546532 517501 482 460443

Ove

rall

surv

ival

pro

babi

lity

0.00

0.20

0.40

0.60

0.80

1.00

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120

TAC: 87%

FAC: 81%

HR=0.7095%CI: 0.53–0.91Log-rank P=0.008

HR=0.7495%CI: 0.61–0.90Log-rank P=0.002

Survival time (months)


BCIRG 001OS in Predefined Subgroups

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 statusNegative 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-menopausal0.85 (0.65 to 1.11) 661

In favor of TAC In favor of FAC

Hazard Ratio (95%CI)0.2 0.6 1.0 1.4 1.8 2.2

*Adjusted for nodal status


BCIRG 001Cardiac Toxicities Reported as an AE

No. patients (%)TAC

(n=744)FAC

(n=736)Congestive heart failure*(cardiac function grade 3-4)

Grade 3 (mild, responsive to therapy)

Grade 4 (severe, refractory)

26 (4)

21 (3) 5 (1)

17 (2)

14 (2) 3 (0.4)

Serious adverse event 23 (3) 16 (2)

Death due to CHF 2 (0.3) 4 (1)*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


BCIRG 001Cumulative Incidence of CHF

Number at RiskTAC 744 713 679 647 620 591 566 540 515 484 437FAC 736 716 672 621 588 554 522 490 466 429 392

Prob

abili

ty o

f CH

F

0.00

0.01

0.03

0.04

0.06

0.08

Time from randomization to CHF event (months)0 12 24 36 48 60 72 84 96 108 120

0.02

0.05

0.07

TAC(n=744)

FAC(n=736

)Number of CHF events 26 17

Reported in the first 55 months of follow-up

13 5

Reported in months 55 to 120 of follow-up

13 12

TAC

FAC


BCIRG 001Changes in LVEF

TAC(n=744)

FAC(n=736)

Nonevaluable patients, n

Evaluable patients, n

396

348

467

269 LVEF decrease >20%, n (% evaluable)LVEF Decrease below normal limit, n (% evaluable)

58 (17)41 (12)

41 (15)27 (10)

*Evaluable patients had an LVEF assessment at baseline and during the study period.†Lower normal limit was 50% if normal limit was unknown.


BCIRG 001Hematologic Malignancies at 10 Years

No. patients (%)TAC

n=744FAC

n=736Acute myeloid leukemia 4 (1) 1 (0.1)

Chronic lymphocytic leukemia

0 1 (0.1)

Myelodysplastic Syndrome 2 (0.3) 1 (0.1)


BCIRG 001Serious 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%)


BCIRG 001Efficacy Summary

• The survival benefit of TAC over FAC is maintainedat 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


BCIRG 001Safety 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)


BCIRG 001Conclusions

• 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


BCIRG 001Acknowledgments

• 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)


BCIRG 001

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 VHungary Boer K, Juhos E, Pinter T Germany Oberhoff CFrance Guastalla JP So. Africa Moodley DBrazil Teixeira LC, Vinholes J Egypt Abd-El-Azim H, El-Zawahry HSweden Fornander T, Nylen U Austria Schuller JIsrael Lurie H, Merimsky O, Steiner M Czech Rep Abrahamova J, Finek JArgentina Martinez JL, Mickiewicz E, Orti R Portugal Chumbo M, Goncalves I

Uruguay Viola A Slovak Rep Koza I

Investigators

nct00688740 sponsored by sanofi-aventis

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