FACULTY DISCLOSURES - DJS Advisory Boards: BioMarin, Genentech/Roche, Pfizer, Novartis, Stock: Amgen, Pfizer, BioMarin San Antonio Breast Cancer Symposium,

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.


After the presentation, these slides will be available at:

www.sabcs.orgwww.trio.org


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


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


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


EFFICACY(Current Analysis & Evolution Over Time)


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)


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%


BCIRG 006 Overall Survival (10.3 yrs)

78.7%

83.3%

85.9%


Do Higher Risk HER2-positive Breast Cancers Require Anthracycline-based

Rx ????


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


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


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



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**)


**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


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


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


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


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


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.


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


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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

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Robertson

SalehSavin

Schleider

Slamon

SolkySmith

TezcanUlrichValeroVargas-CubaVaughnVogelWaintraub

WiermannWitekYunusVENEZUELADe JoghnVera

Wallmark

FalkonFesen

Documents

FACULTY DISCLOSURES - DJS Advisory Boards: BioMarin, Genentech/Roche, Pfizer, Novartis, Stock: Amgen, Pfizer, BioMarin San Antonio Breast Cancer Symposium,