Past, Present and Future HER2 targeted therapy in breast cancer

(1)

Past, Present and Future

HER2 targeted therapy

in breast cancer

Joseph Gligorov MD, PhD

Tenon Hospital,

University Cancer Institute,

Paris VI, Sorbonne University

(2)

Disclosures

• Roche

(3)

(4)

The evolution of HER2+++ Breast Cancer treatments

in different clinical situations

Past

Present

Future

(5)

(6)

6

(7)

HER2+ Breast Cancer

Bad prognosis

Tzb improve OS

Independently

of HR status

Past

Present

Future

(8)

Do we have arguments to continue antiHER2

treatments beyond trastuzumab & lapatinib in HER2

positive MBC ?

• 2 hypothesis:

• No

• Yes: with which molecule

–

Continue trastuzumab and change associated systemic

treatment

–

Continue lapatinib and change associated systemic treatment

–

Continue trastuzumab and lapatinib

–

Continue pertuzumab

(9)

The first demonstration that continuing HER2 inhibition after 1st

line MBC trastuzumab treatment is a valid option

(10)

(11)

(12)

(13)

(14)

Xavier Pivot

1 _{, Bogdan Żurawski}

2 _{, Rozenn Allerton}

3 _{, Alessandra Fabi}

4 _,

Eva Ciruelos

5 _{, Roma Parikh}

6 _{, Michelle DeSilvio}

7 _{, Sergio Santillana}

7 _,

Ramona Swaby

7 _{and Vladimir Semiglazov}

8 EudraCT number: 2008-000673-38

ClinicalTrials.gov Identifier: NCT00820222

1

_{CHU - Hôpital Jean Minjoz}

_,

_Besançon,

_France;

2

_{Centrum Onkologii im. prof. L. Lukaszczyka, Bydgoszcz, Poland;}

3

_{The Royal}

Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom;

4

_{Instituto Nazionali Tumori Regina Elena, Roma, Italy;}

5

_{Hospital Universitario 12 de Octubre, Madrid, Spain;}

6

_{GlaxoSmithKline, Uxbridge, United Kingdom;}

7

_{GlaxoSmithKline,}

Collegeville, PA, USA;

8

_{Petrov Research Institute of Oncology, St. Petersburg, Russian Federation}

CEREBEL (EGF111438): An open-label randomised

Phase III study comparing the incidence of CNS

metastases in patients with HER2+ metastatic breast

cancer, treated with lapatinib plus capecitabine versus

(15)

• Conditional approval granted for lapatinib plus capecitabine in

EU: June 2008

• CEREBEL was a Specific Obligation measure required by CHMP

• First patient randomised:

April 2009

• IDMC meeting for preplanned IA: June 6, 2012;

• Study terminated based on IDMC recommendation:

June 11, 2012

• Final analysis database lock: June 11, 2012; n=540

15

(16)

Trastuzumab 6 mg/kg q21 days

+

Capecitabine 2500 mg/m

2 _{/day, days 1-14 q21 days}

R

A

N

D

O

M

I

S

E

D

Key eligibility

• HER2+ MBC*

• Prior anthracyclines

or taxanes

• Any line therapy

• No CNS metastases**

• Evaluable systemic dx

Study design

16 Phase III Planned N=650

*FISH+/IHC 3+

**No CNS metastases at baseline confirmed by independently reviewed MRI scan

Pivot et al, SABCS 2011 : 20% failure at screening with MRI

Stratification

• Prior trastuzumab

–

yes vs no

• Prior MBC tx

–

0 vs >1

Lapatinib 1250 mg/day

+

(17)

Primary endpoint: CNS endpoints (modified ITT)

(18)

18

0

20

40

60

80

100

0

5

10

15

20

25

30

35

40 Lap + Cap

Tras + Cap

A

liv

e

without

p

ro

gr

essio

n

(

%)

Time from randomisation (months)

271

147

49

20

7 Lap + Cap

Subjects at risk

269

154

56

26

15 Tras + Cap

Investigator-assessed PFS (ITT population)

Lap + Cap

(N=271)

Tras + Cap

(N=269)

Events, n (%)

160 (59)

134 (50)

Median PFS, months

6.6

8.0 Hazard ratio (95% CI)

1.30 (1.04 -1.64)

Stratified log-rank p-value

0.021

4

(19)

19

0

20

40

60

80

100

0

5

10

15

20

25

30

35

40 Time from randomisation (months)

Surv

iv

a

l

(%

)

Lap + Cap

Tras + Cap

OS (ITT population)

Lap + Cap

(N=271)

Tras + Cap

(N=269)

Events, n (%)

70 (26)

58 (22)

Median OS, months

22.7

27.3 Hazard ratio (95% CI)

1.34 (0.95 -1.90)

Stratified log-rank p-value

0.095

271

194

129

79

48

27 Lap + Cap

Subjects at risk

269

207

140

97

61

29 Tras + Cap

7

6

1

(20)

PFS and OS in patients with prior trastuzumab

treatment (ITT)

20 Lap + Cap

Tras + Cap

Time from randomisation (months)

A

li

v

e

w

ithou

t prog

re

s

ion

(%

)

0

5

10

15

20

25

30

35

40

20

40

60

80

100

0 Time from randomisation (months)

0

5

10

15

20

25

30

35

40 Sur

viv

al

(

%)

20

40

60

80

100

0

Subjects at risk Lap + Cap Tras + Cap 167 96 31 12 4 2 89 25 12 7 2 159 Subjects at risk Lap + Cap Tras + Cap 167 127 87 53 34 17 159 126 86 57 38 17 5 5 1

Lap + Cap

Tras + Cap

Investigator-assessed PFS

OS

Lap + Cap

(N=167)

Tras + Cap

(N=159)

Events, n (%)

103 (62)

86 (54)

Median PFS, months

6.6

6.1 Hazard ratio (95% CI)

1.13 (0.85, 1.50)

Lap + Cap

(N=167)

Tras + Cap

(N=159)

Events, n (%)

43 (26)

38 (24)

Median OS, months

22.7

27.3 Hazard ratio (95% CI)

1.18 (0.76, 1.83)

(21)

PFS and OS in patients with no prior

trastuzumab treatment (ITT)

21 NR, not reached

Lap + Cap

Tras + Cap

Time from randomisation (months)

Ali

ve w

it

hou

t

pr

og

res

si

on

(

%)

0

5

10

15

20

25

30

35

40

20

40

60

80

100

0 Time from randomisation (months)

0

5

10

15

20

25

30

35

40 Sur

viv

al

(

%)

20

40

60

80

100

0

Subjects at risk Lap + Cap Tras + Cap 104 51 18 8 3 2 65 31 14 8 5 110 Subjects at risk Lap + Cap Tras + Cap 104 67 42 26 14 10 110 81 54 40 23 12 2 1

Lap + Cap

Tras + Cap

Investigator-assessed PFS

OS

Lap + Cap

(N=104)

Tras + Cap

(N=110)

Events, n (%)

57 (55)

48 (44)

Median PFS, months

6.3

10.9 Hazard ratio (95% CI)

1.70 (1.15, 2.50)

Lap + Cap

(N=104)

Tras + Cap

(N=110)

Events, n (%)

27 (26)

20 (18)

Median OS, months

NR

Hazard ratio (95% CI)

1.67 (0.94, 2.96)

(22)

(23)

(24)

(25)

(26)

HER2+ Breast Cancer

Bad prognosis

Tzb improve OS

Independently

of HR status

Continuous

HER2 inhibition

Trastuzumab

Lapatinib

Past

Present

Future

(27)

P

Trastuzumab Emtansine (T-DM1): Mechanism of

Action

HER2

Adapted from LoRusso PM, et al.

Clin Cancer Res

2011.

Nucleus

Antibody:

Trastuzumab

Emtansine

Cytotoxic:

DM1

Stable linker:

MCC

(28)

Trastuzumab Emtansine (T-DM1): Mechanism of

Action

HER2

Adapted from LoRusso PM, et al.

Clin Cancer Res

2011.

Nucleus

• Antibody-dependent cellular

cytotoxicity (ADCC)

• Inhibition of HER2 signaling

• Inhibition of HER2 shedding

P

(29)

Trastuzumab Emtansine (T-DM1): Mechanism of

Action

Emtansine

release

Inhibition of

microtubule

polymerization

Internalization

HER2

Adapted from LoRusso PM, et al.

Clin Cancer Res

2011.

T-DM1

Lysosome

Nucleus

P

• Antibody-dependent cellular

cytotoxicity (ADCC)

• Inhibition of HER2 signaling

• Inhibition of HER2 shedding

(30)

(31)

median, seven prior

agents for MBC;

median follow-up, 17.4

months

(32)

32 www.esmo2012.org

Updated Overall Survival Results From EMILIA,

a Phase 3 Study of Trastuzumab Emtansine (T-DM1)

vs Capecitabine and Lapatinib in HER2-Positive

Locally Advanced or Metastatic Breast Cancer

S Verma,

1 _{D Miles,}

2 _{L Gianni,}

3 _{IE Krop,}

4 _{M Welslau,}

5 J Baselga,

6 _{M Pegram,}

7 _{D-Y Oh,}

8 V Diéras,

9 E Guardino,

10 _{L Fang,}

10 _{MW Lu,}

10 _{S Olsen,}

10 _{K Blackwell}

11

1 _{Sunnybrook Odette Cancer Center, Toronto, Canada;}

2 _{Mount Vernon Cancer Center,}

Northwood, UK;

3 _{San Raffaele Hospital, Milan, Italy;}

4 _{Dana-Farber Cancer Institute,}

Boston, MA, USA;

5 _{Medical Office Hematology, Aschaffenburg, Germany;}

6 _{Massachusetts General Hospital, Boston, MA, USA;}

7 _{University of Miami Sylvester}

Comprehensive Cancer Center, Miami, FL, USA;

8 _{Seoul National University College of}

Medicine, Seoul, Korea;

9 _{Institut Curie, Paris, France;}

10 _{Genentech, Inc, South San}

(33)

33 www.esmo2012.org

EMILIA Study Design

• Stratification factors:

World region, number of prior chemo regimens for MBC or

unresectable LABC, presence of visceral disease

• Primary endpoints:

PFS by independent review, OS, and safety

• Key secondary endpoints:

PFS by investigator, ORR, DOR

• Statistical considerations:

Hierarchical statistical analysis was performed in pre-specified

sequential order: PFS by independent review → OS → secondary endpoints

PFS analysis: 90% power to detect HR=0.75; 2-sided alpha 5%

OS analyses: 80% power to detect HR=0.80; 2-sided alpha 5%

1:1

HER2-positive LABC

or MBC (N=980)

• Prior taxane and

trastuzumab

• Progression on

metastatic treatment

or within 6 months of

adjuvant treatment

PD

T-DM1

3.6 mg/kg q3w IV

Capecitabine

1000 mg/m

2 PO bid, days 1–14, q3w

+

Lapatinib

1250 mg/day PO qd

PD

(34)

34 www.esmo2012.org

Progression-Free Survival

by Independent Review

496

404

310

176

129

73

53

35

25

14

9

8

5

1

0

495

419

341

236

183

130

101

72

54

44

30

18

9

3

1

0 Cap + Lap

T-DM1

No. at risk by independent review:

Median

(months)

No. of

events

Cap + Lap

6.4

304 T-DM1

9.6

265 Stratified HR=0.650 (95% CI, 0.55, 0.77)

P

<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30 Pr

op

ortio

n

prog

ress

ion

-free

Time (months)

Unstratified HR=0.66 (

P

<0.0001).

(35)

35 www.esmo2012.org

Progression-Free Survival Subgroup Analyses

Pre-specified Stratification Factors

Median,

mos

T-DM1

HR

(95% CI)

Median,

mos

Cap + Lap

Total

n

Baseline

characteristic

T-DM1

better

Cap + Lap

better

Hazard ratio

0.2

0.5

1

2

5

9.6 0.66 (0.56, 0.78)

6.4

991 All patients

8.5

10.9

9.6 0.70 (0.51, 0.98)

0.56 (0.41, 0.74)

0.73 (0.56, 0.94)

5.7

6.4

6.9

270

317

404 World region

US

Western Europe

Other

10.3

8.5 0.68 (0.55, 0.85)

0.63 (0.49, 0.82)

6.7

5.7

609

382 Number prior chemo regimens

for MBC or unresectable LABC

0–1

>1

9.6

8.5 0.55 (0.45, 0.67)

0.96 (0.71, 1.30)

5.7

10.2

669

322 Disease involvement

Visceral

Nonvisceral

(36)

36 www.esmo2012.org

Overall Survival: Confirmatory Analysis

496 471 453 435 403 368 297 240 204 159 133 110

86

63

45

27

17

7

4 495 485 474 457 439 418 349 293 242 197 164 136 111

86

62

38

28

13

5 Cap + Lap

T-DM1

No. at risk:

Time (months)

78.4%

64.7%

51.8%

85.2%

0

2

4

6

8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.0

0.2

0.4

0.6

0.8

1.0 Pr

op

ortio

n

surv

iv

ing

Data cut-off July 31, 2012

; Unstratified HR=0.70 (

P

=0.0012).

Median (months) No. of events

Cap + Lap

25.1

182 T-DM1

30.9

149 Stratified HR=0.682 (95% CI, 0.55, 0.85);

P

=0.0006

(37)

37 www.esmo2012.org

Cap + Lap

T-DM1

Baseline

characteristic

Total

n

Median

(mos)

Median

(mos)

HR

(95% CI)

T-DM1

Better

Cap + Lap

Better

All patients

991

25.1

30.9

0.70 (0.56, 0.87)

Age group

<65 years

853

24.6

30.9

0.66 (0.52, 0.83)

65–74 years

113

27.1 NR

0.74 (0.37, 1.47)

≥75 years

25 NR

11.1

3.45 (0.94, 12.65)

ER and PR status

ER+ and/or PR+

545

25.3

31.9

0.62 (0.46, 0.85)

ER

–

and PR

–

426

23.7

27.1

0.75 (0.54, 1.03)

Line of therapy

a

First-line

118

27.9 NR

0.61 (0.32, 1.16)

Second-line

361 NR

27.1

0.88 (0.61, 1.27)

Third- and later-line

512

23.3

33.9

0.62 (0.46, 0.84)

Overall Survival Subgroup Analyses

Hazard ratio

0.2

0.5

1

2

5 a

_{Defined as any systemic therapy including endocrine and chemotherapy}

NR, not reached

(38)

Copyrights for this presentation are held by the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011

38 Pertuzumab and trastuzumab have complementary

mechanisms of action

ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain

HER2

Dimerization

domain

Pertuzumab

HER1/3/4

Trastuzumab

Subdomain IV

Trastuzumab:

• Inhibits ligand-independent HER2

signaling

• Activates ADCC

• Prevents HER2 ECD shedding

Pertuzumab:

• Inhibits ligand-dependent HER2

dimerization and signaling

(39)

The mean duration of prior trastuzumab was 16.2 months

ORR: 24%

CB: 50%

(40)

The mean duration

of prior trastuzumab

treatment was 87.2

weeks

(41)

A Phase III, Randomized, Double-Blind, Placebo-Controlled

Registration Trial to Evaluate the Efficacy and Safety of

Placebo + Trastuzumab + Docetaxel vs.

Pertuzumab + Trastuzumab + Docetaxel

in Patients with Previously Untreated HER2-Positive

Metastatic Breast Cancer (CLEOPATRA)

J Baselga

,

1 _{S-B Kim,}

2 _{S-A Im,}

3 _{R Hegg,}

4 _{Y-H Im,}

5 _{L Roman,}

6 J L Pedrini,

7 J Cortés,

8 _{A Knott,}

9 _{E Clark,}

9 _{G Ross}

9 _{and S M Swain}

10

1

_{Massachusetts General Hospital Cancer Center, Boston, MA, USA;}

2

_{Department of Oncology, Asan Medical Center,}

University of Ulsan, College of Medicine, Seoul, Korea;

3

_{Division of Hematology and Medical Oncology, Department of}

Internal Medicine, Seoul National University College of Medicine, Seoul, Korea;

4

Hospital Pérola Byington, São Paulo,

Brazil;

5

_{Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center,}

Sungkyunkwan University School of Medicine, Seoul, Korea;

6

_{Leningrad Regional Oncology Dispensary, St Petersburg,}

Russian Federation;

7

_{CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil;}

8

_{Department of Oncology, Vall}

d’Hebron University Hospital, Barcelona, Spain;

9

_{Roche Products Limited, Welwyn, UK;}

10

_{Washington Cancer Institute,}

(42)

42 Study design

MBC, metastatic breast cancer; PD, progressive disease

Patients with

HER2-positive MBC

centrally confirmed

(N = 808)

Placebo + trastuzumab

n=406

• Randomization was stratified by geographic region and prior treatment

status (neo/adjuvant chemotherapy received or not)

• Study dosing q3w:

− Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance

−

Trastuzumab:

8 mg/kg loading dose, 6 mg/kg maintenance

−

Docetaxel:

75 mg/m

2 _{, escalating to 100 mg/m}

2 _{if tolerated}

1:1

n=402

Docetaxel*

≥6 cycles recommended

PD

Pertuzumab + trastuzumab

Docetaxel*

≥6 cycles recommended

PD

(43)

43 Prior therapy for breast cancer

Placebo

+ trastuzumab

+ docetaxel

(n = 406)

Pertuzumab

+ trastuzumab

+ docetaxel

(n = 402)

Prior (neo)adjuvant chemotherapy, n (%)

Yes

No

192 (47.3)

214 (52.7)

184 (45.8)

218 (54.2)

**Components of (neo)adjuvant therapy*, n (%)**

Anthracycline

Hormones

Taxane

Trastuzumab

164 (40.4)

97 (23.9)

94 (23.2)

41 (10.1)

150 (37.3)

106 (26.4)

91 (22.6)

47 (11.7)

(44)

44 Independently and investigator-assessed PFS

D, docetaxel; PFS, progression-free survival; T, trastuzumab

0

5

10

15

20

25

30

35

40

0

10

20

30

40

50

60

70

80

90

100 Time

(months)

Pertuzumab + T + D

Placebo + T + D

Independently assessed

Pertuzumab + T + D

Placebo + T + D

Investigator-assessed

Pr

og

ress

ion

-free

surv

iv

al

(%

)

Independent assessment

_{95% CI, 0.51─0.75; p<0.0001}

HR = 0.62

Investigator assessment

HR = 0.65

(45)

45

808

0.63

0.52 ‒

0.76

432

0.63

0.49 ‒

0.82

376

0.61

0.46 ‒

0.81

306

0.72

0.53 ‒

0.97

135

0.51

0.31 ‒

0.84

114

0.46

0.27 ‒

0.78

253

0.68

0.48 ‒

0.95

681

0.65

0.53 ‒

0.80

127

0.52

0.31 ‒

0.86

789

0.64

0.53 ‒

0.78

19

0.55

0.12 ‒

2.54

480

0.62

0.49 ‒

0.80

30

0.64

0.23 ‒

1.79

261

0.68

0.49 ‒

0.95

37

0.39

0.13 ‒

1.18

630

0.55

0.45 ‒

0.68

178

0.96

0.61 ‒

1.52

388

0.72

0.55 ‒

0.95

408

0.55

0.42 ‒

0.72

12 ─

721

0.60

0.49 ‒

0.74

767

0.64

0.53 ‒

0.78 n

HR

95% CI

All

No

Yes

Europe

North America

South America

Asia

<65 years

≥65 years

<75 years

≥75 years

White

Black

Asian

Other

Visceral disease

Non-visceral disease

Positive

Negative

Unknown

IHC 3+

FISH-positive

0

0.2 ER/PgR status

Disease type

Race

Age group

Region

HER2 status

Prior (neo)adjuvant chemotherapy

0.4

0.6

1

2 Independently assessed PFS in predefined subgroups

ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence

in situ

hybridization; PgR, progesterone receptor;

PFS, progression-free survival

Favors

placebo

Favors

pertuzumab

Unstratified analyses

(46)

46 Independently assessed PFS by prior trastuzumab

therapy in patients with (neo)adjuvant therapy

PFS, progression-free survival

Placebo

+ trastuzumab

+ docetaxel

Median PFS, months

Pertuzumab

+ trastuzumab

+ docetaxel

Median PFS, months

Hazard ratio

(CI)

Prior (neo)adjuvant

trastuzumab treatment

(n = 88)

10.4

16.9

0.62 (0.35

‒

1.07)

No prior (neo)adjuvant

trastuzumab treatment

(n = 288)

12.6

21.6

0.60 (0.43

‒

0.83)

(47)

47 Overall survival: Predefined interim analysis

Median follow-up: 19.3 months, n = 165 OS events

D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0

5

10

15

20

25

30

35

40

45

0

10

20

30

40

50

60

70

80

90

100 n at risk

Pertuzumab + T + D 402

387

367

251

161

87

31

4

0

406

383

347

228

143

67

24

2

0

0 Placebo + T + D

Time (months)

Ptz + T + D: 69 events

Pla + T + D: 96 events

HR = 0.64*

95% CI 0.47

‒

0.88 p = 0.0053*

* The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)

O

v

erall

surv

iv

a

l

(%

)

(48)

48 Cardiac tolerability

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

Placebo

+ trastuzumab + docetaxel

(n = 397)

Pertuzumab

+ trastuzumab + docetaxel

(n = 407)

Investigator-assessed

symptomatic LVSD*

1.8%

1.0%

Independently adjudicated

symptomatic LVSD*

1.0%

Fall in LVEF to <50% and by

≥10 percentage points from

baseline

6.6%

3.8%

(49)

Copyrights for this presentation are held by the author/presenter. Contact [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – Henry B. Gonzalez Convention Center – December 4–8, 2012

Biomarker analyses in CLEOPATRA: A Phase III,

placebo-controlled study of pertuzumab in HER2-positive,

first-line metastatic breast cancer (MBC)

J Baselga

,

1 J Cortés,

2 _{S-A Im,}

3 _{E Clark,}

4 A Kiermaier,

5 _{G Ross,}

4 _{and S M Swain}

6

1

_{Memorial Sloan-Kettering Cancer Center, New York, NY;}

2

_{Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain;}

3

_{Department of Internal Medicine, Seoul National University College of Medicine, Korea;}

4

_{Roche Products Limited, Welwyn, United Kingdom;}

5

_{F. Hoffmann-La Roche Limited, Basel, Switzerland;}

6

_{Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC}

(50)

50 The HER2 signalling pathway

ER

Nucleus

c-myc

Raf

MEK 1/2

MAPK

Akt

GSK3

BAD

Cell-cycle

progression

PTEN

mTOR

p27

Cyclin D1, E

FKHR

Grb2

_Sos

Cell survival

Ras

Shc

Sos

Grb2

PI3K

Cell proliferation

ER

HER2

sHER2

Adapted from:

Gianni L,

et al

. SABCS 2011 (Abstract S5-1).

EGFR

HER2

HER3

IGF1R

HER ligands

(AREG, EGF, TGFα)

(51)

51 The HER2 signalling pathway

Selection of biomarkers

ER

Nucleus

c-myc

Raf

MEK 1/2

MAPK

Akt

GSK3

BAD

Cell-cycle

progression

PTEN

mTOR

p27

Cyclin D1, E

FKHR

Grb2

_Sos

Cell survival

Ras

Shc

Sos

Grb2

PI3K

Cell proliferation

ER

HER2

EGFR

HER2

HER3

IGF1R

sHER2

HER ligands

(AREG, EGF, TGFα)

Adapted from:

Gianni L,

et al

. SABCS 2011 (Abstract S5-1).

(52)

52 Assay method

Marker

Successful analyses,

n

IHC

(by modified H-score)

HER2

HER3

IGF1R

PTEN

pAKT

806

497

486

497

465 qRT-PCR

(by CR)

EGFR

HER2

HER3

AREG

Betacellulin

720

748

740

673

583 FISH

c-myc

591 Mutational analyses

PIK3CA

(8 mutations, 4 hotspots)

684 ELISA

(serum analyses)

sHER2

AREG

EGF

TGFα

723

714

727

721 Assay methods

CR, concentration ratio

6

(53)

Biomarker analyses:

Exploration of prognostic effects

(54)

54 Prognostic effects independent of treatment arm

Serum markers, both arms pooled

* Slide 9

Covariate effect

The treatment benefit with the addition of pertuzumab was maintained in all cases

HR < 1.00 in all cases (p < 0.0001)*

0.2

0.4

0.6

1

2 High biomarker levels

with better prognosis

Low biomarker levels

with better prognosis

Serum AREG [pg/mL]

714

1.13 0.93, 1.38 0.2229

Serum EGF [pg/mL]

727

0.96 0.79, 1.17 0.6965

Serum TGFα [pg/mL]

721

1.15 0.94, 1.40 0.1660

Serum sHER2 [ng/mL]

729

1.23 1.01, 1.49 0.0433

PFS

n*

HR

95% CI

p-value

13

(55)

55 Covariate effect

Prognostic effects independent of treatment arm

HER ligands and RTKs, both arms pooled

* Slide 10

The treatment benefit with the addition of pertuzumab was maintained in all cases

HR < 1.00 in all cases (p = 0.0004 – < 0.0001)*

0.2

0.4

0.6

1

2 High biomarker levels

with better prognosis

Low biomarker levels

with better prognosis

AREG

mRNA (qRT

‒

PCR)

Betacellulin

mRNA (qRT

‒

PCR)

EGFR

mRNA (qRT

‒

PCR)

HER2 Mem H-score

HER2

mRNA (qRT

‒

PCR)

HER3

mRNA (qRT

‒

PCR)

HER3 Mem H-score

HER2/HER3

mRNA (qRT

‒

PCR)

IGF1R Mem H-score

PFS

n*

HR

95% CI

p-value

673

0.94 0.77, 1.16 0.5783

583

1.08 0.86, 1.35 0.5055

720

1.09 0.89, 1.34 0.3845

748

0.77 0.63, 0.93 0.0080

806

0.83 0.69, 1.00 0.0502

740

0.81 0.66, 0.98 0.0348

497

0.86 0.67, 1.09 0.2042

740

0.85 0.70, 1.04 0.1142

486

1.18 0.93, 1.51 0.1721

14

(56)

56 Prognostic effects independent of treatment arm

Intracellular pathway markers, both arms pooled

* Slide 11

0.2

0.4

0.6

1

2 High biomarker levels

with better prognosis

Low biomarker levels

with better prognosis

PIK3CA

WT

PTEN Cyt H-score

PTEN Nuc H-score

pAKT Cyt H-score

pAKT Nuc H-score

Target:cen. ratio (

c-my

c)

The treatment benefit with the addition of pertuzumab was maintained in all cases

HR < 1.00 in all cases (p = 0.0003 – < 0.0001)*

Covariate effect

PFS

n*

HR

95% CI

p-value

557

0.63 0.49, 0.80 0.0001

497

1.17 0.92, 1.48 0.2091

497

1.12 0.88, 1.42 0.3622

465

1.09 0.85, 1.41 0.4854

465

0.80 0.62, 1.02 0.0741

591

1.07 0.84, 1.36 0.5762

15

(57)

57

13.8

8.6 Pla+T+D: WT

Pla+T+D: Mut

PIK3CA

mutation associated with poorer prognosis

Trastuzumab plus placebo arm

0

10

20

30

40

50

60

70

80

90

100

0

3.3

6.6

10.9

13.2

16.4

19.7

23.0

26.3

29.6

32.9 Time (months)

101 events

63 events

In

d

ep

en

d

en

tl

y

-assessed

PF

S

(%

)

Number at risk

Pla+T+D WT

191

164

136

114

66

46

23

17

9

3

1 Pla+T+D Mut

90

76

56

37

21

17

8

4

3

2

1

16

(58)

58 Number at risk

Pla+T+D WT

191

164

136

114

66

46

23

17

9

3

1 Pla+T+D Mut

90

76

56

37

21

17

8

4

3

2

1 Ptz+T+D WT

190

179

159

137

90

71

46

26

16

5

3 Ptz+T+D Mut

86

71

61

44

29

25

12

6

2

1

21.8

12.5

13.8

8.6 Pla+T+D: WT

Pla+T+D: Mut

In

d

ep

en

d

en

tl

y

-assessed

PF

S

(%

)

0

10

20

30

40

50

60

70

80

90

100 Time (months)

101 events

63 events

45 events

83 events

Ptz+T+D: WT

Ptz+T+D: Mut

0

3.3

6.6

10.9

13.2

16.4

19.7

23.0

26.3

29.6

32.9 PIK3CA

mutation associated with poorer prognosis

Both arms

17

(59)

59

• The prognostic impact of

PIK3CA

mutations cannot be attributed to a

specific mutation, nor to mutation(s) in a specific exon, based on the

available dataset

–

182 mutations detected overall (32%)

• Exon 7: 12; exon 9: 39; exon 20: 131

Pla+T+D

Ptz+T+D

PIK3CA

status

Patients,

n

Events

Median,

months

Patients,

n

Events

Median,

months

HR

(95% CI)

Mut

90

63

8.6

86

45

12.5

0.64 (0.43, 0.93)

WT

191

101

13.8

190

83

21.8

0.67 (0.50, 0.89)

Overall

406

242

12.4

402

191

18.5

0.62 (0.51, 0.75)

Shorter median PFS observed with mutated

PIK3CA

while treatment effect is maintained

18

(60)

HER2+ Breast Cancer

Predictor of pCR

OS= f(pCR)

Continuous

HER2 inhibition

Trastuzumab

Lapatinib

Defining

treatments

resistance

PI3Ki possibly

the past

Past

Present

Future

(61)

(62)

0

20

40

60

80

100

0

2

4

6

8 Year

p=0.00005

pINV

cPR

cNR

pCR

2

4

6

8 pINV

cPR

cNR

pCR

p=0.0008

Wolmark N: JNCI Monogr, 2001

RFS

OS

(63)

(64)

(65)

pCR impact on DFS

according to the subtypes

Luminal A

Luminal B/HER2-

Luminal B/HER2+++

HER2+++ non luminal

Triple negative

(66)

66

(67)

HER2+ Breast Cancer

Predictor of pCR

OS & RFS= f(pCR)

Essentially in

HER2+++,

HR- population

Past

Present

Future

(68)

(69)

(70)

pCR of primary tumour: intent-to-treat population

0

10

20

30

40

50 With H

Without H

HER2

negative

With H

Without H

HER2

negative

Patients,

%

HER2 positive

pCR

tpCR

43%

23%

17%

38%

20%

16%

p=0.29

p=0.002

p=0.003

p=0.43

tpCR: total pathologic complete response in breast and nodes

Gianni et al. 2008;

Eiermann et al 2008;

Semiglazov et al 2008.

(71)

Subcut vs IV

250

200

150

100

50

0

500 1000

1500

2000

2500

Nominal time (h)

Mea

n

trastuzu

mab

con

cen

tratio

n

6 mg/kg IV

8 mg/kg SC

C

trough

*

*C

trough

of 20 µg/mL depicts PK target established from

preclinical xenograft models

Wynne C et al., Clin. Pharmacol. 2012 Feb 22 [Epub ahead of print]

Exposure to trastuzumab comparable for

8 mg/kg subcutaneous vs 6 mg/kg intravenous

(72)

(73)

(74)

HER2+ Breast Cancer

Predictor of pCR

OS & RFS= f(pCR)

Essentially in

HER2+++,

RH- population

Trastuzumab

IV & subcut

Past

Present

FuturE

(75)

(76)

(77)

(78)

(79)

The futur of drugs approval

(80)

HER2+ Breast Cancer

Predictor of pCR

OS & RFS= f(pCR)

Essentially in

HER2+++,

RH- population

Trastuzumab

IV & subcut

Trastuzumab

based

Double HER2

inhibition

Past

Present

Future

(81)

(82)

(83)

83

(84)

(85)

(86)

HER2+ Breast Cancer

Bad prognosis

HER2+++

assoc with

Tam resistance

Past

Present

Future

Neoadjuvant

Adjuvant

(87)

(88)

88 DFS ITT

OS ITT

DFS CA

(89)

DFS (landmark analysis): selective

crossover and no crossover

100

80

60

40

20

0

0 Months from randomisation

No.

at risk

Patients alive

and disease

free (%)

Selective crossover

No crossover

6

12

18

24

30

36

42

48

885

884

878

870

851

822

690

480

469

468

455

438

408

388

358

302

232 Gianni et al St Gallen 2011

(90)

(91)

(92)

(93)

(94)

(95)

(96)

OBSERVATION

n=1698

Women with locally determined

HER2-positive invasive early breast cancer

Surgery + (neo)adjuvant CT

RT

Centrally confirmed IHC 3+ or FISH+

and LVEF ≥ 55%

Randomization

1 year Trastuzumab

8 mg/kg – 6 mg/kg

3 weekly schedule

n=1703

2 years Trastuzumab

8 mg/kg – 6 mg/kg

3 weekly schedule

n=1701

After ASCO 2005,

option of switch

to Trastuzumab

HERA TRIAL DESIGN

Accrual 2001 – 2005 (n=5102)

(97)

Disease

-free

surv

iv

al

(%

)

Years from randomization

89.1%

86.7%

81.0%

81.6%

75.8%

76.0%

HERA trial: DFS FOR 2 YEARS VS. 1 YEAR

OF TRASTUZUMAB AT 8 YRS MFU

100

80

60

40

20

0

1

2

3

4

5

6

7

8

9 No. at risk

Trastuzumab 2 years

1553

1442

1361

1292

1223

1153

1051

633

194 Trastuzumab 1 year

1552

1413

1319

1265

1214

1180

1071

649

205 Trastuzumab 1 year

Trastuzumab 2 years

Pts

Events HR (2 vs 1)

95% CI

p-value

2 years

1553

367

0.99 (0.85-1.14)

0.86 1 year

1552

367

(98)

PHARE*

Trial results comparing

6 to 12 months of trastuzumab in

adjuvant early breast cancer

Xavier Pivot

, Gilles Romieu, Hervé Bonnefoi, 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.

P

rotocol of

H

erceptin

®

A

djuvant with

R

educed

E

xposure

*lighthouse in French

(99)

Study design

trastuzumab 6 months

trastuzumab up to 12 months

stop trastuzumab

Clinical exam

LVEF

3 Mammography

6

9

12

15

18

21

24 30 mos

…

0 R

R: Randomization after informed consent

Up to 60 mos…

Stratification

1. ER pos / neg

(100)

0.00

0.25

0.50

0.75

1.00 P

rob

ab

ili

ty

1690

1586

1353

939

526

23 H 6m

1690

1613

1390

980

544

18 H-12m

At risk

0

12

24

36

48

60 Months

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-value

H 12m 176

H 6m

219 1.28 (1.05 – 1.56) 0.29

(101)

HER2+ Breast Cancer

Bad prognosis

Tam resistance

Trastuzumab IV

1 year

Past

Present

Futur