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FACULTY DISCLOSURES - DJS
Advisory Boards: BioMarin, Genentech/Roche, Pfizer, Novartis,
Stock: Amgen, Pfizer, BioMarin
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Phase III Trial Comparing
AC→T with AC→TH and with TCHin the Adjuvant Treatment of
HER2-Amplified Early Breast Cancer Patients:
10-year Follow-up analysis
Study sponsored by sanofiSupport from Genentech
Slamon D, Eiermann W, Robert N, Giermerk J, Martin M, Jasiowka M, Mackey J, Chan A, Liu M, , Pinter T, Valero V, Falkson C, Fornander T, Shiftan T,
Bensfia S, Hitier S, Xu N, Bee-Munteanu V, Drevot P, Press M, Crown J, on behalf of the BCIRG 006 Investigators.
San Antonio Breast Cancer Symposium, December 8-12, 2015
After the presentation, these slides will be available at:
www.sabcs.orgwww.trio.org
San Antonio Breast Cancer Symposium, December 8-12, 2015
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6
1 Year Trastuzumab
N=3,222
1 Year Trastuzumab
ACT
ACTH
TCH
Her 2+(Central FISH)
N+or high risk N-
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
BCIRG 006 Trial Design
Stratified by Nodes and Hormonal Receptor Status
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Endpoints
Primary Endpoint:• Disease-free Survival: defined as all BC
relapses; 2nd primary malignancies; death from any cause
Secondary Endpoints:• Overall Survival• Toxicity• Pathologic & Molecular Markers
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Patient Characteristics
Randomized (n=3,222)
AC→Tn=1,073
AC→THn=1,074
TCHn=1,075
% % %
Age < 50 years 52 52 54
KPS = 100 80 79 80
Mastectomy 60 63 60
Radiotherapy 68 67 69
Hormonotherapy 51 51 51
Enrollment: April 2001 to March 2004 San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Tumor CharacteristicsAC→T
n=1,073AC→THn=1,074
TCHn=1,075
% % %Number of nodes +
0 29 29 29
1 – 3 38 38 39
4 – 10 22 24 23
> 10 11 9 10
Tumor Size (cm)
2 41 38 40
> 2 and 5 53 55 54
> 5 6 7 6
ER and/or PR + 54 54 54 San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Crossover
33 patients (3.1%) of the 1,073 randomized to the control arm (AC→T) crossed-over to receive trastuzumab
96.9 % of the control arm enrollment remained intact for long-term DFS, OS and safety comparisons
San Antonio Breast Cancer Symposium, December 8-12, 2015
EFFICACY(Current Analysis & Evolution Over Time)
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Final Analysis
Median follow-up time = 10.3 years
876 Disease Free Survival Events (33% more than at the prior 5 yr analysis point)
511 Deaths (46% more than at the prior 5 yr analysis point)
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG-006 DFS Events 1st/2nd/3rd/4th Planned Efficacy Analyses
(cutoff dates 30Jun2005/01Nov2006/16Oct2009/17Feb2015)
• Median follow-up time = 23/36/65/124
montths
• 322/462/656/876 DFS Events
• 84/185/348/511 Deaths
Initial Disease Free Survival from1st Analysis – June 2005
% D
ise
ase
Fre
e
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5Year from randomization
77%
86%
80%
84%
80%86%
93%
91%
Patients Events1073 147 AC->T1074 77 AC->TH1075 98 TCH
HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002
73%
BCIRG 006 - Oct 2009 Disease Free Survival – 3rd Analysis (5yrs)
75%
81%
84%
BCIRG-006 Disease Free Survival Final Analysis(10.3yrs)
74.6%
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Overall Survival (10.3 yrs)
78.7%
83.3%
85.9%
San Antonio Breast Cancer Symposium, December 8-12, 2015
Do Higher Risk HER2-positive Breast Cancers Require Anthracycline-based
Rx ????
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 DFS Lymph Node Positive
62.2%
68.4%
69.6%
BCIRG 006 DFS Lymph Node ≥4
53.6%
62.9%
62.8%
General Safety
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006Grade 3/4 Non-Hematological Toxicity
AC→Tn=1,050
AC→THn=1,068
TCHn=1,056
% % %Arthralgia 3.2 3.3 1.4*Myalgia 5.2 5.1 1.8*
Fatigue 7.0 7.2 7.2
Hand-foot syndrome 1.9 1.4 0.0*
Stomatitis 3.5 2.9 1.4*Diarrhea 3.0 5.6 5.4Nausea 5.9 5.7 4.8
Vomiting 6.2 6.7 3.5*Irregular menses 27.3 24.5 26.7
Yellow=*Statistically significant less events
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006Specific non-hematological toxicity (all grades)
AC→Tn=1,050
AC→THn=1,068
TCHn=1,056
% % %Neuropathy-sensory 48.8 50.1 36.1*
Neuropathy-motor 5.2 6.4 4.3*
Nail changes 49.4 43.7 28.7*
Myalgia 53.0 55.4 38.9*
Renal failure 0.0 0.0 0.1
Creatinine Grade 3/4 0.6 0.3 0.1
Yellow=*Statistically significant less events
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Grade 3/4 Hematological Toxicity
AC→Tn=1,050
AC→THn=1,068
TCHn=1,056
% % %Neutropenia 63.5 71.6 66.2*
Leucopenia 51.9 60.4 48.4*
Febrile neutropeniaNeutropenic infection
9.311.9
11.012.6
9.611.2
Anemia 2.3 3.0* 5.4
Thrombocytopenia 1.6 2.1* 6.1 Acute Leukemias: #(%)
6 (0.6) 2 (0.1) 1 (0.1**)
Yellow=*Statistically significant less events
**B-cell lymphoma developed 24 months after TCH in this pt and represented her ITT DFS event. The acute leukemia occurred 20 months after rx with CHOP for the B cell lymphoma.San Antonio Breast Cancer Symposium, December 8-12, 2015
Cardiac Safety
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Cardiovascular risk factors
Randomized (n=3,222)AC→T
n=1,073AC→THn=1,074
TCHn=1,075
Age Median Range
49 yrs(23 - 74 yrs)
49 yrs(22 - 74 yrs)
49 yrs(23 - 73 yrs)
Risk factors (# of patients) Diabetes Hypercholesterolemia Hyperlipidemia Obesity (BMI > 30) Hypertension
385420
214178
364710
242178
284312
234190
Radiotherapy (# of patients) After chemotherapy To left chest
718378
723349
729364
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Cardiac Deaths and CHF
AC→Tn=1,050
AC→THn=1,068
TCHn=1,056
Cardiac related death 0 0 0
Cardiac left ventricular function (CHF) Grade 3 / 4
8 21 4
p=0.0005
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006 Patients with >10% relative LVEF decline
AC→T n = 1,018
AC→TH n = 1,042
TCH n = 1,031
Number of Patients
120 200 97
p<0.0001
San Antonio Breast Cancer Symposium, December 8-12, 2015
BCIRG 006
Mean LVEF - All Observations (3rd Analysis)
AC->T
TCH
AC->TH
AC->T (N=1014)AC->TH (N=1042)TCH (N=1030)
BCIRG-006 Mean LVEF - All Observations (Final Analysis)
LVEF
poi
nts
%
Time since randomization (months) San Antonio Breast Cancer Symposium, December 8-12, 2015
Therapeutic Index – Most Recent 006 Data
ACTH TCH
DFS Events 269 279
Grade 3 / 4 CHF 21 4
Totals 290 283
Rx-Related Leukemias
7(8)*
*Only in AC-Rx patients
0(1)****Leukemia developed after
CHOP Rx
Sustained LVEF Loss >10%
200 97
San Antonio Breast Cancer Symposium, December 8-12, 2015
Conclusions
10-year follow-up: DFS and OS data show a sustained and significant efficacy advantage of AC-TH and TCH over a non-trastuzumab regimen (AC-T)
With regards to DFS & OS, there is no statistical advantage of AC-TH over TCH with only 10 DFS events now separating the two experimental arms
This numerical advantage however comes at a cost of 5-fold more clinical congestive heart failures in AC-TH than in TCH (21 cases versus 4 cases), a higher rate of leukemia and a higher rate of sustained LVEF loss >10% from baseline.
San Antonio Breast Cancer Symposium, December 8-12, 2015
Acknowledgements All participating Patients and Investigators
IDMC (Chair, S Swain) and Independent Cardiac Panel
Central laboratories: M Press (USC), G Sauter (Basel)
NBCC: F Visco and C Hinestrosa
IDDI: H Fourmanoir, F Piette
TRIO Central Team: S Ayuk, V Bee, M Burton, P Drevot, C Elmahdi, H Fung, R Mustapha, NJ Valli
Sanofi & Genentech/Roche
**The Group of 20**San Antonio Breast Cancer Symposium, December 8-12, 2015
San Antonio Breast Cancer Symposium, December 8-12, 2015
ARGENTINACassanelloFeinGiacomiKorbenfeldAlvarezAUSTRALIA/NZAbdbiRedfernBegbieBeithChanChirgwinClaringboldClinganCraftEpsteinDewarGanjuGaudenGreenGrimesHarveyIsaacsJamesonKannourakisKoczwaraKotasekLewisLinksBeadle
RansomRichardsonSchwarzSelva-NayagamStewartBealeWhiteWalpoleYoungAUSTRIADittrichSeveldaBELGIUMCocquytDemolDirixMebisVerhoevenHuizingBOSNIABeslijaBRAZILFerrariLagoSanchesSchwartsmannBULGARIATimchevaTzekovaCANADADorreen
DufresneSmiljanicLatreilleLopezMackeyZibdawiRobidouxProvencherRoySehdevWilsonCOLOMBIAGomezSanchezVargasCROATIAGrgicMarkulin-GrgicSeparovicVrdoljakCYPRUSKakouriCZECH REPUBLICPetruzelkaFeltlVyzulaEGYPTAzimEl-KhodaryESTONIAPadrikValvere
FRANCEBonneterrePaoliTchiknavorianCamponeCarolaColinDalivoustAmmarguellatFerreroGligorovBachelotJaubertKhayatMedioniPriouRochéTaziTournigandValenzaVannetzelGERMANYBaumannBehringerBreitbachBrunnertRunnebaumChristensenClemensConradDuboisHanusch
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GREECEGeorgouliasHONG KONGKwongHUNGARYBoérDankPinterKocsisINDIAAdvaniGuptaJulkaRanadeIRELANDBirdCrownGroganKeaneKennedyMcCaffreyO’ReillyISRAELAsnaEfratFriedGeffenIsacsonKaufmanRizelIsacsonSteiner
Principal Investigators involved in the study (I)
Moss
Laufman
LimentaniLink
MalamudMac AndrewMcCroskeyMcKeenMenaMillsModianoMoore
Gluck
Moroose
GonzalesGoodmanGreenwald
HoffmanHolmesJhangianiJonesJusticeJuturiKalmanKennedyKincaidKoneru
Hajdenberg
Lad
Lemon
Lower
Rinaldi
Robert (USO)RodriguezRubinRussell
Schwatzberg
ShafferShiftan
SparanoSylvester
Nael
Tansino
Orlowski
PagePatelPattonPerzePerkins
Petruska
PhilipPolikoffPosada
RahmanRangineni
Reich
Nair
Olopade
Reiling
Silvermann
Principal Investigators involved in the study (II)ITALYBaroneBonettiGamucciGaspariniIaffaioliMarangoloMassacesiMosciettiNardiPanettaRavaioliLEBANONAbi GergesChahineGhosnSaghirMEXICOChanSilvaVallePOLANDCzerepinskaKarnicka-MlodowskaPienkowskiRolskiWojtukiewiczZaluski
ROMANIABadulescuGhilezanRomanStanculeanuRUSSIAGarinGorbunovaSemiglazovSLOVAKIAKozaSpanikSLOVENIAMatosTakac
SOUTH-AFRICABeltchevDe BruyneMaartMoodleyPiennaarRapoportSlabber
SOUTH KOREAAhnBangChoiImRo
SPAINAdroverAlba ConejoAlbiol RodriguezAles MartinezAlonso RomeroAlvarezAngel Garcia-SaenzArandaArcusa LanzaBaena CanadaCalvo MartinezCrespo MassieuDominguezFlorian GericoGonzales FarreJara SanchesLoboMargeli
Mel LorenzoOltra FerrandoSWEDENFornanderSWITZERLANDAaproTAIWANChaoLiuTUNISIAFrikhaMezlini
TURKEYAydinerOzisikUKArmstrongChanSherwinURUGUAYKrygierRodriguezUSAAbukabrAdlerAnsariArenaBeallBeattieBerdeauxBrufskiBurrisBuryCarrollChakrabartiChitneniChowhanCobbDiaz-DreisbachFain
Robertson
SalehSavin
Schleider
Slamon
SolkySmith
TezcanUlrichValeroVargas-CubaVaughnVogelWaintraub
WiermannWitekYunusVENEZUELADe JoghnVera
Wallmark
FalkonFesen
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