Past, Present and Future HER2 targeted therapy in breast cancer...vs Capecitabine and Lapatinib in...

Past, Present and Future HER2 targeted therapy

in breast cancer Joseph Gligorov MD, PhD

Tenon Hospital,

University Cancer Institute,

Paris VI, Sorbonne University

Paris, France

Disclosures

• Roche

• GSK

What we will talk about ?

The evolution of HER2+++ Breast Cancer treatments in different clinical situations

Past

Present

Future

Neoadjuvant Adjuvant Metastatic

METASTATIC

6

HR- HR+

HER2+ Breast Cancer

Bad prognosis

Tzb improve OS Independently

of HR status

Past

Present

Future


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

– Continue T-DM1

The first demonstration that continuing HER2 inhibition after 1st line MBC trastuzumab treatment is a valid option

Geyer et al. Von Minckwitz et al.

Xavier Pivot1, Bogdan Żurawski2, Rozenn Allerton3, Alessandra Fabi4, Eva Ciruelos5, Roma Parikh6, Michelle DeSilvio7, Sergio Santillana7,

Ramona Swaby7 and Vladimir Semiglazov8

EudraCT number: 2008-000673-38 ClinicalTrials.gov Identifier: NCT00820222

1CHU - Hôpital Jean Minjoz, Besançon, France; 2Centrum Onkologii im. prof. L. Lukaszczyka, Bydgoszcz, Poland; 3The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom; 4Instituto Nazionali Tumori Regina Elena, Roma, Italy;

5Hospital Universitario 12 de Octubre, Madrid, Spain; 6GlaxoSmithKline, Uxbridge, United Kingdom; 7GlaxoSmithKline, Collegeville, PA, USA; 8Petrov 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

trastuzumab plus capecitabine

• 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

Milestones

Trastuzumab 6 mg/kg q21 days +

Capecitabine 2500 mg/m2/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 +

Capecitabine 2000 mg/m2/day, days 1-14 q21 days

Primary endpoint: CNS endpoints (modified ITT)

17

18

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40

Lap + Cap

Tras + Cap

Aliv

e w

ith

ou

t p

rogr

ess

ion

(%

)

Time from randomisation (months)

271 147 49 20 20 7 Lap + Cap Subjects at risk

269 154 56 26 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 7

19

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40


Su

rviv

al

(%)

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

PFS and OS in patients with prior trastuzumab treatment (ITT)

20

Lap + Cap

Tras + Cap


Ali

ve

wit

ho

ut

pro

gre

ss

ion

(%

)

0 5 10 15 20 25 30 35 40

20

40

60

80

100

0


0 5 10 15 20 25 30 35 40

Su

rviv

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


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)


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)

PFS and OS in patients with no prior trastuzumab treatment (ITT)

21 NR, not reached

Lap + Cap

Tras + Cap


Aliv

e w

ith

ou

t p

rogr

ess

ion

(%

)

0 5 10 15 20 25 30 35 40

20

40

60

80

100

0


0 5 10 15 20 25 30 35 40

Su

rviv

al (

%)

20

40

60

80

100

0


104 51 18 8 3 2 65 31 14 8 5 110


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)


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 NR

Hazard ratio (95% CI) 1.67 (0.94, 2.96)

HER2+ Breast Cancer

Bad prognosis

Tzb improve OS Independently

of HR status

Continuous HER2 inhibition

Trastuzumab Lapatinib

Past

Present

Future


P P

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


Action

HER2


Nucleus

• Antibody-dependent cellular

cytotoxicity (ADCC)

• Inhibition of HER2 signaling

• Inhibition of HER2 shedding

P P

P


Action

Emtansine

release

Inhibition of

microtubule

polymerization

Internalization

HER2


T-DM1

Lysosome

Nucleus

P P

P

• Antibody-dependent cellular

cytotoxicity (ADCC)

• Inhibition of HER2 signaling

• Inhibition of HER2 shedding

median, seven prior agents for MBC; median follow-up, 17.4 months

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 Blackwell11

1Sunnybrook Odette Cancer Center, Toronto, Canada; 2Mount Vernon Cancer Center,

Northwood, UK; 3San Raffaele Hospital, Milan, Italy; 4Dana-Farber Cancer Institute,

Boston, MA, USA; 5Medical Office Hematology, Aschaffenburg, Germany; 6Massachusetts General Hospital, Boston, MA, USA; 7University of Miami Sylvester

Comprehensive Cancer Center, Miami, FL, USA; 8Seoul National University College of

Medicine, Seoul, Korea; 9Institut Curie, Paris, France; 10Genentech, Inc, South San

Francisco, CA, USA; 11Duke Cancer Institute, Durham, NC, USA

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/m2 PO bid, days 1–14, q3w

+

Lapatinib

1250 mg/day PO qd

PD

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 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

Pro

po

rtio

n p

rog

ress

ion

-fre

e

Time (months)

Unstratified HR=0.66 (P<0.0001).

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 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

Pro

po

rtio

n s

urv

ivin

g

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

Efficacy stopping boundary P=0.0037 or HR=0.727

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 therapya

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 aDefined as any systemic therapy including endocrine and chemotherapy

NR, not reached

From confirmatory OS analysis; data cut-off July 31, 2012.

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

• Activates ADCC

The mean duration of prior trastuzumab was 16.2 months

ORR: 24% CB: 50%

The mean duration of prior trastuzumab treatment was 87.2 weeks




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 Ross9 and S M Swain10

1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Department of Oncology, Asan Medical Center,

University of Ulsan, College of Medicine, Seoul, Korea; 3Division of Hematology and Medical Oncology, Department of

Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4Hospital Pérola Byington, São Paulo,

Brazil; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center,

Sungkyunkwan University School of Medicine, Seoul, Korea; 6Leningrad Regional Oncology Dispensary, St Petersburg,

Russian Federation; 7CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8Department of Oncology, Vall

d’Hebron University Hospital, Barcelona, Spain; 9Roche Products Limited, Welwyn, UK; 10Washington Cancer Institute,

Washington Hospital Center, Washington D.C., USA




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/m2, escalating to 100 mg/m2 if tolerated

1:1

n=402

Docetaxel* ≥6 cycles recommended

PD

Pertuzumab + trastuzumab

Docetaxel* ≥6 cycles recommended

PD

* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion




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)

* Numbers add up to more than 100% because patients could have received more than one therapy




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

Pro

gre

ss

ion

-fre

e s

urv

ival

(%)

Independent assessment HR = 0.62

95% CI, 0.51─0.75; p<0.0001

Investigator assessment HR = 0.65

95% CI, 0.54─0.78; p<0.0001




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

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

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 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)

Overa

ll s

urv

iva

l (%

)




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% 1.0%

Fall in LVEF to <50% and by

≥10 percentage points from

baseline

6.6% 3.8%

* LVSD was defined as NYHA class III/IV

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 Swain6

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

1



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)

4



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).

5



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



Biomarker analyses:

Exploration of prognostic effects

12



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


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

Covariate effect


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





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


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


Intracellular pathway markers, both arms pooled

* Slide 11

0.2 0.4 0.6 1 2





PIK3CA WT

PTEN Cyt H-score

PTEN Nuc H-score

pAKT Cyt H-score

pAKT Nuc H-score

Target:cen. ratio (c-myc)

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


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

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 32.9 3.3 6.6 10.9 13.2 16.4 19.7 23.0 26.3 29.6

Time (months)

101 events

63 events

Ind

ep

en

de

ntl

y-a

ssessed

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

Mut, mutated; WT, wild-type



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 1

21.8 12.5 13.8 8.6

Pla+T+D: WT Pla+T+D: Mut

Ind

ep

en

de

ntl

y-a

ssessed

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 32.9 3.3 6.6 10.9 13.2 16.4 19.7 23.0 26.3 29.6

PIK3CA mutation associated with poorer prognosis

Both arms

17




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


HER2+ Breast Cancer

Predictor of pCR

OS= f(pCR)

Continuous

HER2 inhibition Trastuzumab

Lapatinib

Defining treatments resistance

PI3Ki possibly the past

Past

Present

Future


NEOADJUVANT

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

What do we learn from the neaodjuvant trials ?

pCR impact on DFS according to the subtypes

Luminal A Luminal B/HER2- Luminal B/HER2+++

HER2+++ non luminal Triple negative ?

66

Overall population HER2 neg population HER2 pos w/o Tzb HER2 pos with Tzb

HER2+ Breast Cancer

Predictor of pCR OS & RFS= f(pCR)

Essentially in HER2+++,

HR- population

Past

Present

Future


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 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.

Subcut vs IV

250

200

150

100

50

0 0 2500 2000 1500 1000 500

Nominal time (h)

Mean t

rastu

zum

ab c

oncentr

ation

6 mg/kg IV 8 mg/kg SC

Ctrough*

*Ctrough 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

in patients with HER2-positive EBC

HER2+ Breast Cancer



RH- population

Trastuzumab IV & subcut

Past

Present

FuturE


The futur of drugs approval in HER2 positive breast cancers ?

HER2+ Breast Cancer



RH- population


Trastuzumab

based Double HER2

inhibition

Past

Present

Future


ADJUVANT

83

Joensuu H. et al. Clin. Cancer Res. 2003;9:923-930

HER2+ Breast Cancer

Bad prognosis HER2+++

assoc with Tam resistance

Past

Present

Future

Neoadjuvant Adjuvant

88

DFS ITT

OS ITT

DFS CA

OS CA

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

885 885 884 878 870 851 822 690 480

469 468 455 438 408 388 358 302 232

Gianni et al St Gallen 2011

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)

CT, chemotherapy; RT, radiotherapy

Dis

ease

-fre

e s

urv

ival

(%)

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

0 1 2 3 4 5 6 7 8 9

No. at risk

Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194

Trastuzumab 1 year 1552 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

Goldhirsch et al. ESMO 2012

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.

Protocol of Herceptin®

Adjuvant with Reduced Exposure

*lighthouse in French

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 2. Chemo: conco/ seq

0.00

0.25

0.50

0.75

1.00

Pro

babili

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-value H 12m 176 H 6m 219 1.28 (1.05 – 1.56) 0.29

Pivot et al. ESMO 2012

HER2+ Breast Cancer

Bad prognosis Tam resistance

Trastuzumab IV 1 year

Past

Present

Futur


Ld qd + Hc q3w for

52 weeks

Lb qd for 52 weeks

ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/– Herceptin

Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy

Concurrent taxanese for 12 weeks

aHerceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; bLapatinib 1500 mg; cHerceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; dLapatinib 1000 mg; ePaclitaxel 80 mg/m2 qw or docetaxel q3w

No taxane

Hc qw for 12 weeks

Ha q3w for 52 weeks

6-week washout

Lb qd for 34 weeks

HER2-positive early breast cancer (n=8000)

Ld qd + Hc q3w for

52 weeks

Lb qd for 52 weeks

Hc qw for 12 weeks

Ha q3w for 52 weeks

6-week washout

Lb qd for 34 weeks

Ld qd + Hc q3w for

52 weeks

Lb qd for 52 weeks

ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/– Herceptin

Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy

Concurrent taxanese for 12 weeks

aHerceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; bLapatinib 1500 mg; cHerceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; dLapatinib 1000 mg; ePaclitaxel 80 mg/m2 qw or docetaxel q3w

No taxane

Hc qw for 12 weeks

Ha q3w for 52 weeks

6-week washout

Lb qd for 34 weeks

HER2-positive early breast cancer (n=8000)

Ld qd + Hc q3w for

52 weeks

Lb qd for 52 weeks

Hc qw for 12 weeks

Ha q3w for 52 weeks

6-week washout

Lb qd for 34 weeks

Risk of inferiority Risk of inferiority

TEACH TYKERB Evaluation After Chemotherapy (TEACH) Trial

Results of the TEACH Trial

Lapatinib in Women with Early-Stage

HER2-Overexpressing Breast Cancer

A Double-blind, Placebo-controlled Phase III Trial

Paul Goss, Ian Smith, Joyce O’Shaughnessy, Bent Ejlertsen,

Manfred Kaufmann, Francis Boyle, Aman Buzdar, Pierre Fumoleau,

William Gradishar, Miguel Martin, Beverly Moy, Martine-Piccart-Gebhart,

Kathleen I. Pritchard, Deborah Linquist, Gursel Aktan, Erica Rappold,

Lisa Williams, Diane Finkelstein

TEACH Trial Study Design Eligibility

HER2+ local IHC3+ or FISH +ve

Resected Stage I-IIIc primary BRCA

No prior trastuzumab

Neo-/adjuvant chemotherapy (CMF,

anthracycline, or taxane

Appropriate endocrine therapy

RANDOMI ZAT ION

Placebo po qd x 1 yr

Lapatinib

1500 mg po qd x 1 yr

N ≈ 3,000

Stratification

− Time from initial diagnosis (≤ 4 vs > 4 yr)

− Lymph nodes (+ vs -)

− ER + and/or PgR+ vs ER-/PgR -

N = 3147 August 2006 – May 2008

33 countries

Diagnosis 4 yr

TEACH: Forest Plot of DFS for Subgroups

in ITT Population

Time since initial diagnosis

4 years (n=2248; L=175, P=219)

> 4 years (n=899; L =35, P=45)

< 1 year (n=647; L =55, P=79)

Hormone receptor status ER and/or PgR + (n=1859; L =125, P=136)

ER and PgR - (n=1288; L =85, P=128)

Lymph node involvement Positive (n=1753; L=146, P=174)

Negative (n=1394; L=64, P=90)

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50

Hazard Ratio (Lapatinib / Placebo)

L= lapatinib; P=placebo

Hazard Ratio (95% CI)

0.84 (0.69-1.03)

0.81 (0.52-1.26)

0.70 (0.50-0.99)

0.98 (0.77-1.25)

0.68 (0.52-0.89)

0.86 (0.69-1.07)

0.78 (0.57-1.07)

Favors Placebo Favors Lapatinib

clinicaloptions.com/oncology

HER2-Positive Breast Cancer: Applying the Latest Developments to Clinical Practice

N = 3806

S U R G E R Y

Central confirmation

of HER2 status

Randomization within 7 wks of surgery

Start treatment

within 1 wk

F O L L O W

U P

10

Y R S

R A N D O M I Z A T I O N

Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline–based chemotherapy allowed

Chemotherapy + trastuzumab and placebo Anthracycline or non-anthracycline–based chemotherapy allowed

Anti-HER2 therapy for a total of 1 yr (52 wks)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

N = 3806

ClinicalTrials.gov Identifier: NCT01358877

APHINITY: Study Schema

clinicaloptions.com/oncology

HER2-Positive Breast Cancer: Applying the Latest Developments to Clinical Practice

N = 3806

S U R G E R Y

Central confirmation

of HER2 status

Randomization within 7 wks of surgery

Start treatment

within 1 wk

F O L L O W

U P

10

Y R S

R A N D O M I Z A T I O N

Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline–based chemotherapy allowed

Chemotherapy + TDM1 and pertuzumab Anthracycline or non-anthracycline–based chemotherapy allowed

Anti-HER2 therapy for a total of 1 yr (52 wks)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

N = 1750

KAITLIN: Study Schema

HER2+ Breast Cancer



Trastuzumab subcut Double

inhibition

Past

Present

Future

Neoadjuvant Adjuvant

HER2+ Breast Cancer

Predictor of pCR OS= f(pCR)


Predictor of pCR

OS= f(pCR)



Continuous

HER2 inhibition Trastuzumab

Lapatinib

Trastuzumab

based Double HER2

inhibition

Trastuzumab subcut Double

inhibition

Defining treatments

resistance PI3Ki possibly the

past

Past

Present

Futur


THANKS

112

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