PHARE* Trial results of subset analysis comparing 6 to 12 … · PHARE* Trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer Protocol

PHARE* Trial results of subset

analysis comparing 6 to 12

months of trastuzumab in

adjuvant early breast cancer

Protocol of

Herceptin®

Adjuvant with

Reduced

Exposure

adjuvant early breast cancer

*lighthouse in French

Xavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat,

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.

Disclosures

• Honoraria and Consultant for Roche, GlaxoSmithKline

• The PHARE trial is fully funded and conducted by the • The PHARE trial is fully funded and conducted by the

French National Cancer Institute (INCa)

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 with trastuzumab has been initiated

X Pivot et al, ESMO 2012, LBA5_PR

trastuzumab has been initiated

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

• Overexpression of HER2 in invasive component of primary tumor

• Signed informed consent

• Patients with history of other cancer eligible

Study design

trastuzumab 6 months

trastuzumab up to 12 months

stop trastuzumab

RRStratification

1. ER pos / neg

2. Chemo: conco/ seq stop trastuzumab

Clinical examLVEF

3

Mammography

6 9 12 15 18 21 24 30 mos

…

0

R: Randomization after informed consent

Up to 60 mos…

2. Chemo: conco/ seq

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

oror

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

– HR were estimated from the stratified Cox model

• Accrual target: 3400 patients

Study informationActivated: 30/05/2006

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

Randomization3384 patients

Trastuzumab 12 months1690 patients

Trastuzumab 6 months1690 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 6 month group but would reserve the option of such a recommendation for the future, dependent on how the data develop”

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

Patient Characteristics12 monthsn=1690

6 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 nodes

55.4%30.0%

54.7%30.2%1 – 3 nodes

≥4 nodes30.0%14.6%

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%

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%Sequential Chemotherapy 42.2% 42.3%

Radiotherapy 87.7% 88.2%

Hormonotherapy 50.6% 50.2%

Trastuzumab duration, mean (sd) 11.8 (2.03) 6.3 (1.46)

DFS Events

12 mos(n=1690)

6 mos(n=1690)

DFS Events (n=394) 10.4% 13.0%

Local RecurrenceRegional Recurrence

1.1%0.6%

1.4%0.5%

42.5mos. median Follow-up

Regional RecurrenceDistant Recurrence

Controlateral Breast Cancer2nd Primary Malignancy

Death

0.6%6.4%

0.4%1.5%

0.4%

0.5%8.3%

0.7%1.5%

0.5%

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HR (95% CI): 1.28 (1.05 - 1.56)

Disease Free Survival

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CI p-value

T 12m 176

0.00

0.25

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1690 1586 1353 939 526 23T-6m

1690 1613 1390 980 544 18T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6m

* Cox model stratified by ER status and concomitant chemotherapy

T 12m 176

T 6m 219 1.28 (1.05 – 1.56) 0.29

Equivalent

Superior

A

B

Primary endpoint scenarios

Non Inferior

Inferior

C

D

E

.85 1 1.15 1.3 1.45 1.6

HR

PHARE trial

X Pivot et al, ESMO 2012, LBA5_PR

Subgroup effects

Objective and strategyof subgroup analysis

• The aim of this analysis was to assess the trastuzumab

duration effects for specific subgroups

– Identified by pre-defined stratification factors

• Estrogen receptor status• Estrogen receptor status

• Sequential or concomitant administration of trastuzumab with

chemotherapy

• Assess heterogeneity by interaction tests

– 0.10 significance level

Trastuzumab duration effect:according to ER

0.50

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HR = 1.34 : 95%CI: (1.02 - 1.76), p=0.037

0.50

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DFS

Pro

ba

bil

ity

HR = 1.23 : 95%CI: (0.92 - 1.65), p=0.15

ER negative ER positive

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

ER negative 92 716 0.888 117 696 0.829

ER positive 83 974 0.920 102 994 0.912

0.00

0.25

DF

S P

rob

ab

ilit

y

696 639 544 373 207 8T-6m

716 668 568 410 221 6T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER negative 0.00

0.25

DFS

Pro

ba

bil

ity

994 947 809 566 319 15T-6m

974 945 822 570 323 12T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER positive

Trastuzumab duration effect:Treatment modalities

0.50

0.75

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HR = 1.15 : 95%CI: (0.88 - 1.53), p=0.32

0.50

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HR = 1.41 : 95%CI: (1.06 - 1.86), p=0.016

Sequential Concomitant

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

Sequential 84 729 0.904 117 747 0.857

Concomitant 91 961 0.907 102 943 0.896

0.00

0.25

DF

S P

rob

ab

ilit

y

943 894 748 454 217 4T-6m

961 922 774 478 220 1T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mConcomitant0.00

0.25

DF

S P

rob

ab

ilit

y

747 692 605 485 309 19T-6m

729 691 616 502 324 17T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mSequential

Estrogen Receptorand Chemo-trastuzumab modalities

DFS Main effects model Nested Interaction model

N=3380 HR 95% CI P HR 95% CI P

ER + 0.61 (0.50 – 0.75) <0.0001 0.52 (0.39–0 .68) <0.0001

Conc 0.83 (0.68 – 1.01) 0.065 0.71 (0.54–0.93) 0.013

ER* Conc --- 1.41 (0.95–2.09) 0.093

• Significant interaction– * Reference category

LR test –3077.38 –3075.96 0.092

Sequential Concomitant

ER – HR* = 1.00 HR = 0.71(0.59 – 0.85)

ER + HR = 0.52(0.39 – 0.68)

HR = 0.51(0.39 – 0.67)

Sequential Concomitant

ER – HR* = 1.00 HR = 0.83(0.68 – 1.01)

ER + HR = 0.61(0.50 – 0.75)

HR = 0.51(0.38 – 0.67)

Trastuzumab duration effect:ER negative – Sequential modality

.006

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HR = 1.57 : 95%CI: (1.08 - 2.28)

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

46 312 0.875 69 314 0.786

HR = 1.57 (1.08 – 2.28)

0

.002

.004

Ha

zard

ra

te

0 12 24 36 48 60Months

T-12m T-6mER neg - Sequential

0.00

0.25

314 282 244 188 113 8T-6m

312 288 254 210 130 5T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER neg - Sequential

Trastuzumab duration effect: ER negative – concomitant modality

.004

.006

0.50

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y

HR = 1.10 : 95%CI: (0.73 -1.65)

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

46 404 0.898 48 382 0.866

HR = 1.10 (0.73 – 1.65)

0

.002

.004

Ha

zard

ra

te

0 12 24 36 48 60Months

T-12m T-6mER neg - Concomitant

0.00

0.25

382 357 300 185 94 0T-6m

404 380 314 200 91 1T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER neg - Concomitant

Trastuzumab duration effect: ER positive- Sequential modality

.004

.006

Ha

zard

ra

te

0.25

0.50

0.75

1.00

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y

HR = 1.25 : 95%CI: (0.81 -1.91)

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

38 417 0.925 48 433 0.908

HR = 1.25 (0.81 – 1.91)

0

.002

Ha

zard

ra

te

0 12 24 36 48 60Months

T-12m T-6mER pos - Sequential

0.00

0.25

433 410 361 297 196 11T-6m

417 403 362 292 194 12T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER pos - Sequential

Trastuzumab duration effect: ER positive- concomitant modality

.004

.006

Ha

zard

ra

te

0.50

0.75

1.00

DF

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ab

ilit

y

HR = 1.23 : 95%CI: (0.83 -1.82)

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

45 557 0.913 54 561 0.916

HR = 1.23 (0.83 –1.82)

0

.002

Ha

zard

ra

te

0 12 24 36 48 60Months

T-12m T-6mER pos - Concomitant

0.00

0.25

561 537 448 269 123 4T-6m

557 542 460 278 129 0T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER pos - Concomitant

Conclusion

ER and Chemotherapy modalities

1.57 (1.08 - 2.28)

1.25 (0.81 - 1.91)

ER - Sequential (676)

ER + Sequential (850)

1.10 (0.73 - 1.65)

1.23 (0.83 - 1.82)

1.28 (1.05 - 1.56)

ER - Concomitant (786)

ER + Concomitant (1118)

All patients (3380)

0 1.15 2

Conclusion

• PHARE failed to show that 6 months of trastuzumab is non

inferior to 12 months

• Subgroups analysis suggested

– Sequential modality for ER negative tumors impacted the overall

results

– Results in other groups seemed compatible with non-inferiority

hypothesis

• PHARE longer FU & PERSEPHONE, SHORTHER & SOLD

trial results are expected

Acknowledgments

• All patients and their families

• The IDMC members

• French National Cancer Institute staff:

Céline Faure-Mercier, Nicolas Thammavong, Céline Faure-Mercier, Nicolas Thammavong,

Nadia Bachouche, Claire Verbeke

• Marc Buyse and Xavier Paoletti for their input in the

original trial design

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

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, 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, VANLEMMENS, VANNETZEL, VANNEUVILLE,

VANOLI, VAULEON, VEDRINE, VENNIN, VEYRET, VIGNOT, VIGNOUD, VILLANUEVA, VILLING, VINCENT, VOLOCH, WEBER, YAKENDJI,

YAZBEK, YOUSSEF, ZYLBERAIT

BACK UP

Conclusion

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0.75

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Trastuzumab duration effect: subgroup other patients

Trastuzumab duration effect: subgroup ER negative – Sequential

modality

0.00

0.25

0.50

DF

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ab

ilit

y

314 282 244 188 113 8T-6m

312 288 254 210 130 5T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER neg - Sequential

HR = 1.57 : 95%CI: (1.08 - 2.28)

0.00

0.25

0.50

DF

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rob

ab

ilit

y1376 1304 1109 751 413 15T-6m

1378 1325 1136 770 414 13T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mOther groups

HR = 1.18 : 95%CI: (0.93 -1.49)