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PHARE* Trial results comparing6 to 12 months of trastuzumab in

adjuvant early breast cancer

Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, PierreKerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau,

Daniel Serin, Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios,Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany,

Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar.

Protocol ofHerceptin®

Adjuvant withReducedExposure

*lighthouse in French

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Disclosures

• Honoraria and Consultant for Roche,GlaxoSmithKline

• The PHARE trial is fully funded and conductedby the French National Cancer Institute

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Background

• 1 year of adjuvant trastuzumab has beenimproving DFS/OS(1, 2)

• 9 weeks of adjuvant trastuzumab providedsimilar magnitude of benefit(3)

• Concerns emerged with cardiac-toxicitiesfollowing trastuzumab exposure

1Piccart 2005 ; 2Romond 2005 ; 3Joensuu 2006

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Objectives• Primary objective

– Compare the effect of 6 months versus 12 months oftreatment with trastuzumab in terms of disease-free survival

– Disease-Free Survival (DFS) from randomization to first event• local, regional, or distant recurrence, contralateral breast, second

non-breast malignancies, or death from any cause

• Secondary objectives

– Cardiotoxicity

– Distant metastasis Free Survival

– Overall survival

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Eligibility• Non metastatic operable, histologically confirmed adenocarcinoma

of the breast

• Axillary nodes positive or negative and tumor size ≥ 10 mm

• At least four cycles of a chemotherapy for this breast cancer

• Patients for whom a 12-month adjuvant treatment withtrastuzumab has been initiated

• Baseline LVEF value 3 months after initiation of treatment withtrastuzumab allowing to pursue treatment

• Overexpression of HER2 in invasive component of primary tumor

• Signed informed consent

• Patients with history of other cancer eligible

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Study design

trastuzumab 6 months

trastuzumab up to 12 months

stop trastuzumab

Clinical examLVEF

3

Mammography

6 9 12 15 18 21 24 30 mos

…

0

RR

R: Randomization after informed consent

Up to 60 mos…

Stratification1. ER pos / neg2. Chemo: conco/ seq

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Statistical Methods

• Non inferiority randomized trial

– 2% variation in terms of absolute difference of recurrence

– The 95% CI HR margins should not cross the 1.15 boundary

– 1040 DFS events required for 80% power at 5% level

or

4 years of accrual and at least 2 years of follow-up

– HR were estimated from the stratified Cox model

• Accrual target: 3400 patients

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Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6

HR

Primary endpoint scenarii

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Study information

Trastuzumab 12 months1690 patients

Activated: 30/05/2006

Trastuzumab 6 months1690 patients

4 patients excluded from analysis1 Informed consent not signed1 Randomized twice2 HER2 negative after FISH testing

Randomization3384 patients

•May 28th 2010 – IDMC meeting

“After careful thought and lengthy debate we recommend that entry to the trial be suspended.We do not recommend, at this time, a crossover to a longer duration of intervention for the 6month group but would reserve the option of such a recommendation for the future, dependent onhow the data develop”

Closed: 09/07/2010Database locked: 31/07/2012

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Patient Characteristics12 months

n=16906 monthsn=1690

Age, median (range) 54 (21 – 86) 55 (23 – 85)

Tumor : 0 – 2 cm2 – 5 cm>5 cm

54.7%38.5%6.8%

52.4%39.8%7.8%

Nodes: negative1 – 3 nodes4 nodes

55.4%30.0%14.6%

54.7%30.2%15.1%

Positive Estrogen receptor 57.6% 58.8%

Inflammatory disease 3.5% 3.4%

SBR: IIIIII

3.1%41.0%55.6%

3.3%40.9%55.8%

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Treatment Characteristics

12 monthsn=1690

6 monthsn=1690

Type of Chemotherapy :No AnthracyclinesAnthracyclines no TaxanesAnthracyclines and Taxanes

10.2%15.9%73.9%

11.8%15.5%72.7%

Concomitant ChemotherapySequential Chemotherapy

57.8%42.2%

57.7%42.3%

Radiotherapy 87.7% 88.2%

Hormonotherapy 50.6% 50.2%

Trastuzumab duration, mean (sd) 11.8 (6.3) 6.3 (1.46)

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Cardiac toxicity

12 months(n=1690)

6 months(n=1690)

P

Cardiac events* 5.7% 1.9% <0.0001

LVEF** < 50% 6.3% 4.7% 0.04

LVEF** < 50% and > 10% 4.8% 3.6% 0.071

LVEF** > 50% and > 15% 7.4% 7.0% NS

* Investigator reported events (composite with clinical and LFEV finding)** Based on more than > 25,000 assessments

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DFS Events

12 mos(n=1690)

6 mos(n=1690)

DFS Events (n=395) 10.4% 13.0%

Local RecurrenceRegional RecurrenceDistant Recurrence

Controlateral Breast Cancer2nd Primary Malignancy

Death

1.1%0.6%6.4%

0.4%1.5%

0.4%

1.4%0.5%8.3%

0.7%1.5%

0.5%

42.5mos. median Follow-up

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0.00

0.25

0.50

0.75

1.00P

roba

bili

ty

1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

Disease Free Survival

* Cox model stratified by ER status and concomitant chemotherapy

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CI p-valueH 12m 176H 6m 219 1.28 (1.05 – 1.56) 0.29

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DFS Forest plot

All patients (3380) 1.28 (1.05 - 1.56)

Chemotherapy1.39 (1.05 - 1.85)1.17 (0.89 - 1.54)

Estrogene Receptor1.32 (1.01 - 1.74)1.23 (0.92 - 1.65)

Tumour size (cm)1.00 (0.71 - 1.42)1.46 (1.09 - 1.95)1.23 (0.75 - 2.00)

Nodal status1.31 (0.93 - 1.84)1.27 (0.90 - 1.78)1.22 (0.85 - 1.75)

Age yrs1.78 (0.70 - 4.53)1.32 (0.95 - 1.84)1.38 (0.95 - 2.01)1.08 (0.75 - 1.54)

Sequential (1428)Concomitant (1952)

Negative (1412)Positive (1968)

0-2 (1771)2-5 (1294)>5 (242)

Negative (1842)1-3 pos. nodes (1008)>3 pos. nodes (497)

<35 (129)35-49 (1065)50-59 (1059)>60 (1128)

0 .5 1 1.5 2 2.5HR

Favors 12moFavors 6mo

1.15

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0.00

0.25

0.50

0.75

1.00P

rob

abili

ty

1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

Overall Survival

* Cox model stratified by ER status and concomitant chemotherapy

42.5mos. median FU

99.3 97.2 95.2 93.1

99.9 98.7 96.9 95.0

Events HR 95%CI p-valueH 12m 66H 6m 93 1.47 (1.07 – 2.02)

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Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6HR

Primary endpoint scenarii

PHARE trial

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Conclusions• Results were inconclusive for the non-inferiority hypothesis

• A G-WAS ongoing to identify predictors for HER2+ BC risk andtrastuzumab response/toxicity (SIGNAL, 9000 pts recruited)

• Multivariate analysis will be presented at SABCS 2012

• PERSEPHONE, SHORTHER & SOLD trials results expected innext years

• Nevertheless, there was a trend favouring the standard 12months treatment

• There is a significant difference in cardiac events in favor of 6months treatment

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Acknowledgments

• All patients and their families

• The IDMC members

• French National Cancer Institute staff: Céline Faure-Mercier, Nicolas Thammavong, Nadia Bachouche,Claire Verbeke

• Marc Buyse and Xavier Paoletti for their input in theoriginal trial design

www.clinicaltrials.gov: NCT00381901www.e-cancer.fr: essai Phare

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All InvestigatorsACHILLE, ACHOUR, AGOSTINI, AL AUKLA, ALBIN, ALCARAZ, ALLEAUME, ALLIOT, ALTWEGG, AMSALHEM, ANDRE, ANTOINE, ARDISSON,

ARSENE, AUCLERC, AUDHUY, AULIARD, AVENIN, BARATS, BARBET, BATICLE, BAUMONT, BEERBLOCK, BEGUE, BEGUIER, BELLAICHE –

MICCIO, BERNARD, BERTON-RIGAUD, BESSON, BICHOFFE, BIELSA, BIRON, BONICHON-LAMICHHANE, BONNETERRE, BONS, BOUE,

BOUGNOUX, BOULANGER, BOURBOULOUX, BOURCIER, BOURGEOIS, BOUSQUET, BOUTAN –LAROZE, BRAIN, BRAIN, BREAU, BRUNA,

BURKI, CAILLEUX, CALS, CAMPONE, CAMPOS-GAZEAU, CAPITAIN, CAROLA, CARTRON, CAUVIN, CHAIGNEAU, CHANTELARD, CHEVRIER,

CHIEZE, CHIRAT, CHOLLET, CHOUAHNIA, CLAVREUL, CLIPPE, CLUET, COEFFIC, COJEAN-ZELEC, COLLARD, COMBE, COSTA, COTTU,

COUDERC, COUDERT, CRETIN, CURE, CUVIER, DALENC, DARLOY, DARUT-JOUVE, DAUBA, DE HARTINGH, DE SAINT HILAIRE, DEBLED,

DELALOGE, DELBALDO, DELECROIX, DELVA, DELZENNE, DEMARCHI, DENIS, DENIZON, DIAB, DIERAS, DIETMANN, DILLIES, DION,

DOHOLLOU, DOMAS, DOMONT, DRONY, DUFRESNE, DUJOLS, DUPUIS, DUPUY, DUPUY-BROUSSEAU, DURAND, DURANDO, DURIEUX,

DUTEL, DUVERT, EGRETEAU, EL AMARTI, EL KOURI, ELLIS, EXTRA, EYMARD, EZENFIS, FABBRO, FACCHINI, FALANDRY, FEDERICO, FERRANT,

FERRERO, FERRIERE, FICHET, FOLLANA, FREYER, FRIC, GABEZ, GALOTTE, GANEM, GARNIER, GAUTIER-FELIZOT, GEAY, GEDOUIN, GENET,

GHOUL, GIACCHETTI, GIRAUD, GIRRE, GLADIEFF, GLIGOROV, GOUBELY, GOUDIER, GOUTTEBEL, GREGET, GRENIER, GROSSAT, GUASTALLA,

GUARDIOLA, GUILLEMET, GUILLET, GUIMONT, GUINET, GUTIERREZ, HAJJAJI, HARDY-BESSARD, HENRY, HERVE, HOCINI, HOUYAU, IBANEZ

MARTIN, IURISCI, JACQUOT, JANSSEN, JAUBERT, JOUVE, JOVENIN, KANOUI, KARA –SLIMANE, KIRSCHER, KREITMANN, LAGUERRE,

LAHARIE- MINEUR, LAMY, LANCRY, LAPORTE, LARGILLIER, LAUCHE, LAURENCE, LAVAU-DENES, LE HEURTEUR, LE MAIGNAN, LE ROL,

LEBOUVIER SADOT, LEBRUN, LEDUC, LEFEUVRE, LEGOUFFE, LEGUEUL, LEHEURTEUR, LEVACHE, LEVY, LEYRONNAS, L'HELGOUALC'H,

LIGEZA-POISSON, LITOR, LLORY, LOISEAU, LUPORSI, MADRANGES, MAHOUR BACHA, MAILLART, MANDET, MANGOLD, MARI, MARTI,

MARTIN, MAURIAC, MAYER, MAYEUR, MEDIONI, MEFTI- LACHERAF, MERAD-BOUDIA, MEUNIER, MEUNIER, MIGNOT, MILLE, MISSET,

MONTCUQUET, MORAN RIBON, MORICEAU, MORVAN, MOULLET, MOURET-REYNIER, MOUTEL-CORVIOLE, NABHOLTZ, NETTER, N'GUYEN,

NOUYRIGAT, ODDOU-LAGRANIERE, ORFEUVRE, PARAISO, PAVLOVITCH, PETIT, PIPERNO-NEUMANN, PIPROT, PLANTADE, PLAT, PORTOIS,

POTTIER-KYNDT, POUESSEL, POURNY, PRIOU, PROVENCAL, RABAN, RAICHON PATRU, RAMEE, RATOANINA, RAY-COQUARD, RE, REBATTU,

RIGAL, RIVERA, ROCHE, ROCHE FORESTIER, ROHART DE CORDOUE, ROUSSEAU, RUCK, SAAD, SADKI-BENAOUDIA, SAINTIGNY, SALLES,

SALVAT, SARDA, SARRAZIN, SCHAEFFER, SERVENT, SEVIN –ROBICHE, SLAMA, SOULIE, SOYER, SPIELMANN, STEFANI, STEIN, TADRIST,

TARPIN, TARTAS, TEISSIER, TENNEVET, THEVENOT, TOCCANIER, TOURNIGAND, TRAGER-MAURY, TREDAN, TRESCA, TRILLET-LENOIR,

UWER, VALENZA, VAN PRAAGH, VAN-HULST, VANICA, VANNETZEL, VANNEUVILLE, VANOLI, VAULEON, VEDRINE, VENNIN, VEYRET,

VIGNOT, VIGNOUD, VILLANUEVA, VILLING, VINCENT, VOLOCH, WEBER, YAKENDJI, YAZBEK, YOUSSEF, ZYLBERAIT