her2. dr

CANCER DE MAMAHER 2+

Dr. Luis Miguel Zetina Toache

Cancer Consultants GT

Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.

Trastuzumab:

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Novel anti-HER2 therapies:

Baselga J Ann Oncol 2010;21:vii36-vii40

HER pathways are of critical importance in cancer

“Beginning with benign hyperplasia and extending through invasive metastasis, a number of studies demonstrate that [HER family] receptor activation can play a major role in all aspects of cancer development.”

— Sliwkowski MX, “Alterations in the ErbB Signaling Network in Breast Cancer”1

1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.

Structure of a HER family receptor1

HER family receptors exist on the surface of cells and contain

extracellular, transmembrane,

and tyrosine kinase domains.

Each of these domains is responsible for a different

aspect of HER signaling pathways1

1. Burgess AW, Cho HS, Eigenbrot C, et al. Mol Cell. 2003;12:541-542.

Components of HER family receptors

Activation of HER receptors has numerous cellular effects and is a complex process

Receptor activation is a complex, multistep process

1. Ménard S, Tagliabue E, Campiglio M, Pupa SM. J Cell Phys. 2000;182:150-162. 2. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426. 3. Olayioye MA, Neve RM, Lane HA, Hynes NE. EMBO J. 2000;19:3159-3167.

Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys; Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness

Adapted from Hudis. N Engl J Med. 2007;357:39

Akt

SOS

RAS

RAF

MEK

VEGF

MAPK

P

P

PP

Receptor specificligands HER1, HER2,

HER3*, or HER4HER2

HER1(EGFR)

HER2HER4

HER3

Tyrosine kinasedomains

Plasmamembrane

PI3K

Cell proliferationCell survivalCell mobility and invasiveness

Cytoplasm

NucleusTranscription

Receptor regulation through internalization

Receptor internalization is an important regulator of HER family signaling in normal

cells, and is retained in cancerous cells1

: 1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.

Adapted with permission from Lippincott Williams & Wilkins. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.

Normal (1x)~ 25,000-50,000 HER2

receptors

Overexpressed HER2 (10-100x)

up to ~ 2,000,000 HER2 receptors

Excessive cellular division

HER2 Overexpression in Breast Cancer

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182.

HER2 is overexpressed in ~ 25% of breast cancers

HER2 Overexpression Shortens Survival

HER2 oncogeneamplification

HER2 oncoproteinoverexpression

Shortened survival

Median Survival From First Diagnosis

HER2 overexpressing 3 years HER2 normal 6-7 years

Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.

TRATAMIENTO DE CÁNCER DE MAMA

HER 2 POSITIVO

http://labmed.ascpjournals.org/content/41/6/364/F2.large.jpg

Estimación de las recurrencias prevenidas por el uso de trastuzumab en EBC en USA

(M Danese; SABCS 08 poster 2107)

• Los datos del SEER estiman que Trastuzumab adyuvante previene 2,800 recurrencias en 1 año en USA

• Extrapolado en un período de 25 años podría prevenir más de 50,000 recurrencias

• Estos resultados son consistentes con los europeos de Weisgerber-Kriegl presentados en ASCO 2008

PILAR DE TRATAMIENTO PARA PTES HER 2 POSITIVAS

clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer

Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.

Trastuzumab: Mecanismo de accion

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Estudios de Herceptin en Adyuvancia:>13,000 pacientes tratados

NCCTG N9831 (USA)

HERA (ex-USA) BCIRG 006 (global)

NSABP B-31 (USA)

Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006FISH, hibridización fluorescente in situ

IHC / FISH (n=5090)

Observación

1 año

2 años

IHC / FISH (n=3505)

1 año

1 año

FISH(n=3222)

1 año

1 año

IHC / FISH (n=2030)

1 año

DocetaxelDocetaxel + carboplatino

Doxorubicina + ciclofosfamida Herceptin

Quimioterapia

estándar Paclitaxel

Análisis combinado de NCCTG N9831 actualizado / NSABP B-31: Beneficio de DFS*

Perez et al 2007

Pacientes (%)

73.1%

86.4%

0 1 2 3 4 5 6 7

Años desde larandomización

77.6%

85.9%92.3%

87.9%

Seguimiento medio: 2.9 años

HR=0.48; p0.00001

ACPHACP

Eventos222397

n19891979

18541800

13471235

868753

522460

202168

48

No.at risk

*Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, muerte por 2ndo primario. DFS: sobrevida libre de enfermedad

0

20

40

60

80

100

52%

Actualización de NCCTG N9831 / NSABP B-31 – análisis combinado: beneficio de OS*

89.4%95.9%

92.7%

92.6%97.5% 94.6%

0

20

40

60

80

100

0 1 2 3 4 5

Años desde larandomización

HR=0.65; p=0.0007

ACPHACP

n19891979

18861863

14191376

938898

570562

217211

No.at risk

*Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, 2ndo primario, muerte Perez et al 2007

Pacientes (%)

35%

Estudios de Herceptin adyuvante:beneficio en DFS probado

Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2007

B-31 / N9831 ACPH 4

3BCIRG 006 ACDH

HERA H 1 año 2

V, vinorelbinaaSobrevida libre de recaída

0 1 2Favorece aHerceptin

No favorecea Herceptin

HR

Seguimiento medio a 2 años

BCIRG 006 DCarboH 3

FinHer VH / DHa 3

0 1 2Favorece aHerceptin

No favorece aHerceptin

HR

Estudios de Herceptin adyuvante:beneficio de OS probado

B-31 / N9831 ACPH

BCIRG 006 ACDH

HERA H 1 año

BCIRG 006 DCarboH

FinHer VH / DHa

4

3

2

Seguimiento medio en años

3

Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2007

3

Conclusions:The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials .gov number, NCT00021255.)

Table 2. Therapeutic Index for Critical Clinical Events.* AC-T plus Clinical Event AC-T Trastuzumab TCH number of eventsTotal events 201 146 149Distant breast-cancer recurrence 188 124 144Grade 3 or 4 congestive heart failure 7 21 4Acute leukemia 6 1 1†

D. Slamon New England Journal of Medicine october 6, 2011 vol. 365

no. 14

APc3s x 3 ciclos

Pc3s x 4 ciclos

CMFc4s x 3 ciclos

APc3s x 3 ciclos

Pc3s x 4 ciclos

CMFc4s x 3 ciclos

Cirugía seguida deradioterapiaa

Cirugía seguida de radioterapiaa

Cirugía seguida de radioterapiaa

H + APc3s x 3 ciclos

H + P c3s x 4 ciclos

H c3s x 4 ciclos+ CMF c4s x 3 ciclos

H continuada c3shasta la semana 52

Estudio internacional, fase III, randomizado en CMLA: NOAH

AP, doxorubicina (60 mg/m2), paclitaxel (150 mg/m2); CMF, ciclofosfamida, metotrexate, fluorouracilo; H, Herceptin (8 mg/kg dosis de carga, luego 6 mg/kg);CMLA: cáncer de mama localmente avanzadolocally; P, paclitaxel (175 mg/m2); aPacientes positivos por receptor hormonal recibirán tamoxifeno adyuvante

CMLA HER2-positivo(IHC 3+ or FISH+)

CMLA HER2-negativo(IHC 0/1+)

n=115 n=113 n=99

Gianni et al 2007

Herceptin neoadyuvante duplica la tasa de respuesta patológica

0

10

20

30

40

50

Con H Sin H HER2 negativo

Con H Sin H HER2 negativo

Pacientes (%)

HER2 positivo HER2 positivo

pCR tpCR

43

23

17

38

2016

p=0.29

p=0.002p=0.003

p=0.43

tpCR: total pCR en mama y ganglios Gianni et al 2007

HER2-positive (%) HER2-negative (%) P value

5-yr RFS 77 94 <0.001

High Risk of Recurrence for Breast Cancer Patients with HER2-Positive Node Negative Tumors 1 cm or Smaller

Gonzalez-Angulo AM, et al. J Clin Oncol 2009;27(34):5700-6

Y los tumores menores de 2 cms, ganglios (-) ?


Case 1: Woman With MBC and No Previous Trastuzumab Presentation: 58-yr-old woman was found to have

architectural distortion in the right breast, upper outer quadrant, on routine screening mammography

– Core needle biopsy confirmed invasive ductal carcinoma, estimated by imaging to be a T1 lesion

Treatment: She underwent lumpectomy/SLNB that revealed a 0.9-cm intermediate-grade invasive ductal carcinoma that was ER+/PgR+/HER2+ by FISH, with a Ki-67 value of 30%

– 2 sentinel nodes were removed and found to be uninvolved by cancer

T1 NO MO G2 ER/PR+ HER2+


Case 1: Woman With MBC and No Previous Trastuzumab Follow-up: She received adjuvant radiation therapy followed by

letrozole for 1 yr, at which time she was seen by her oncologist for new cough and mild shortness of breath

– CT scan of the chest revealed a mild right pleural effusion and several nodules up to 1 cm in size in the right, middle, and lower lobes

– Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC, consistent with breast primary

– No other metastases were detected by CT or bone scan

There are no clinical trials available at your center for which she is eligible. You review multiple treatment options with her and she tells you she would like to take the treatment that has the highest chance of leading to a response and to a prolonged survival, as she recently found out her daughter is pregnant with her first grandchild


Case 1: Woman With MBC and No Previous Trastuzumab

What treatment option would you recommend at this time?

A. Trastuzumab plus chemotherapy

B. Trastuzumab plus aromatase inhibitor

C. Lapatinib plus capecitabine

D. Single-agent aromatase inhibitor

E. Trastuzumab single agent


Case 1: Woman With MBC and No Previous TrastuzumabWhat treatment option would you recommend at this time?

A. Trastuzumab plus chemotherapy (preferred choice)

B. Trastuzumab plus aromatase inhibitor

C. Lapatinib plus capecitabine

D. Single-agent aromatase inhibitor

E. Trastuzumab single agent

Single-Agent Trastuzumab in First-line Treatment of HER2+ MBC

Patients Response Rate, %

Median Time to Progression, Mos

HER2+ by IHC(N = 111)

26 3.5

HER2+ by FISH (n = 79)

34 4.9

Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.

Herceptin Combinations as First-line Therapy for MBC: Pivotal Phase III Trial

Patients with HER2+ (IHC 2+/3+) MBC, no previous

chemotherapy, measurable

disease, KPS ≥ 60%

(N = 469)No previous

adjuvantAC

Paclitaxel(n = 96)

Herceptin+ Paclitaxel

(n = 92)

AC(n = 138)

Herceptin+ AC

(n = 143)

Previousadjuvant

AC

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

Herceptin in MBC: The Pivotal Trial

Treatment ObjectiveResponse Rate, %

Median TTP, Mos Median OS, Mos

Chemo 32 4.6 20.3

Chemo +Herceptin

50 7.4 25.1

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

P < .001 for all 3 comparisons.Despite crossover at TTP

Herceptin in Triple-Combination Regimens: Response Rates

ORR (%)

H + Carbo + T

H + V + T

H + E90 + C

H + E60 + C

H + Carbo + T

H + V + X

H + G + P

H + G + Carbo

H + G + P

H + E + T

H + Carbo + P every 3 wks

H + Carbo + P every wk

H + TLC D-99 + P

H + Carbo + T

H + Carbo + T

H + Cisplatin + T

H + Carbo + P

H + X + T

Forbes et al, 2006 (N = 130)

Wardley et al, 2006 (N = 111)

Robert et al, 2006 (N = 92)

Pegram et al, 2004 (N = 62)

Pegram et al, 2004 (N = 59)

Yardley et al, 2002 (N = 61)

Cortes et al, 2004 (N = 54)

Perez et al, 2005 (N = 48)

Perez et al, 2005 (N = 43)

Venturini et al, 2006 (N = 45)

Miller et al, 2002 (N = 45)


Fountzilas et al, 2004 (N = 40)

Chan et al, 2007 (N = 34)

Dirix et al, 2006 (N = 34)

Untch et al, 2004 (N = 26)

Untch et al, 2004 (N = 25)


0 10 20 30 40 50 60 70 80 90 100

Herceptin in Recommended First-line Combinations for HER2+ MBC

HER2+ disease without previous Herceptin: Herceptin plus

• Paclitaxel ± carboplatin

• Docetaxel

• Vinorelbine

• Capecitabine

HER2+ disease with previous Herceptin: Herceptin plus

• Other first-line agents

• Capecitabine

• Lapatinib (without cytotoxic therapy)

NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.

SOSRAS

RAF

BasalTranscription

Machineryp160

Cross-talk Between Signal Transduction and Endocrine Pathways

Adapted from Johnston SRD. Clin Cancer Res. 2005;11:889s-899s.

ERE ER Target Gene Transcription

ER CBPPP P P

ER

Pp90RSK

AktP

MAPKP

CellSurvival

Cytoplasm

Nucleus

ER

P13-KP

P

PPP

P

CellGrowth

MEKP

PlasmaMembrane

AI

MoAb

EGFR/HER2

IGFRGrowth FactorEstrogen

Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant breast cancer, with opportunities for targeted intervention.

Johnston S R Clin Cancer Res 2010;16:1979-1987

©2010 by American Association for Cancer Research

Hormonal Therapy in HER2+ MBC

Regimen ORR, % PFS, Mos

Trastuzumab (N = 79)[1] 26 3.5-3.8

Anastrozole + trastuzumab (N = 103)[2] 20 4.8

Anastrozole (N = 104)[2] 7 2.4

Lapatinib + letrozole (N = 642)[3] 28 8.2

Letrozole (N = 644)[3] 15 3.0

Lapatinib (N = 138)[4] 24 NA

1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.2. Mackey JR, et al. SABCS 2006. Abstract 3.3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.


Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Downstream signaling cascade

Downstream signaling cascade

1 + 11 + 1 2 + 22 + 2 1 + 21 + 2 Blocks signaling throughErbB1 and ErbB2 homodimers and heterodimers

Might also prevent signaling through heterodimers between these receptors and other ErbB family members

Potentially blocks multiple ErbB signaling pathways

Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment

Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment


Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy

Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks

Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients)

Lapatinib as First-line Treatment for HER2-Amplified LABC or MBC

Endpoint Lapatinib1500 mg/day

(n = 69)

Lapatinib500 mg BID

(n = 69)

All Patients(N = 138)

Response rate, n (%) 15 (22) 18 (26) 33 (24)

Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31)

6-mo PFS, % 41 45 43

Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.

Herceptin +Chemotherapy

Current therapeutic cascade in HER2+ MBC

HER2+ /ER + MBC

Good performance statusVisceral disease

Rapidly progressing

Poor performance statusNon visceral disease

Slow progression

Herceptinmonotherapy

Herceptin +Aromatase

Inhibitor

Prior A.I.?

YES NO

Tratamiento mas allá de progresión


Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Background: 39-yr-old woman diagnosed with stage IIA, breast cancer

in 2004. T2 N0 MO

– 2.6-cm tumor

– ER+/PgR-/HER2+

Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen

Follow-up: 1 yr after end of chemotherapy, she is found to have bone and lymph node metastases

– Lymph node biopsy reveals the tumor is negative for hormone receptors (ER/PgR) and continues to overexpress HER2

Treatment: she receives 6 cycles of TCH and achieves CR

– She continues on maintenance single-agent trastuzumab without progression for almost 2 yrs


Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.


A. Switch to lapatinib/capecitabine

B. Switch to lapatinib/trastuzumab

C. Switch to trastuzumab and new chemotherapy

D. Start chemotherapy without HER2-targeted therapy

E. Switch to lapatinib alone


Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.


A. Switch to lapatinib/capecitabine (preferred choice)

B. Switch to lapatinib/trastuzumab (reasonable)

C. Switch to trastuzumab and new chemotherapy

D. Start chemotherapy without HER2-targeted therapy

E. Switch to lapatinib alone


1 2

Downstream signaling pathways

Cell proliferation Cell survival

21 1 2

TrastuzumabT

LapatinibL L L L L L

Erb receptors

Mechanism of Action of LapatinibCompared to Trastuzumab


Patients with HER2+ progressive MBC or

stage IIIB/IIIC LABC with T4 lesion and unlimited

previous therapies*

Primary endpoint: TTP

Secondary endpoints: OS, PFS, ORR

Primary endpoint: TTP

Secondary endpoints: OS, PFS, ORR

Lapatinib1250 mg/day PO +

Capecitabine 2000 mg/m2/day on

Days 1-14 every 21 days

Lapatinib1250 mg/day PO +

Capecitabine 2000 mg/m2/day on


Capecitabine2500 mg/m2/day on


Capecitabine2500 mg/m2/day on


*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant).

Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer


Lapatinib + Capecitabine in HER2+ MBC:TTP

Cameron D, et al. Oncologist. 2010;15:924-934.

TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab Regimen

CapecitabineLapatinib + capecitabine

Cu

mu

lati

ve P

rog

ress

ion

Fre

e (%

)

100

80

60

40

20

00 20 40 60 80

Wks

100

80

60

40

20

00 20 40 60 80

WksC

um

ula

tive

Pro

gre

ssio

n F

ree

(%)

CapecitabineLapatinib + capecitabine

Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc.


Result Capecitabine(n = 201)

Capecitabine + Lapatinib(n = 207†)

HR P Value

Median TTP, wks[1] 18.6 31.3 0.50 < .001

OS, wks[1] 56.6 71.4 0.79 .077

ORR, %[2] 13.9 23.7 -- .017

Brain mets as site of first progression,* n (%)[2]

13 (6) 4 (2) -- .045

† n=198 in 2008 study.*Exploratory analysis.

1. Cameron D, et al. Oncologist. 2010;15:924-9342. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.

Lapatinib + Capecitabine in HER2+ MBC: Efficacy


Combining Lapatinib and Trastuzumab Increases Antitumor Activity

Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:1630-1639. Xia W, et al. Oncogene. 2004;23:646-653.

Tum

or

Vo

lum

e (

mm

3 )

1600

1400

1200

1000

800

600

400

200

013 16 19 21 23

Days After Injection*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab.

ControlTrastuzumabLapatinibTrastuzumab + lapatinib*

*†‡ †

†

§

Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28:803-814, copyright 2009.

Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse model

– Effect was durable: no tumor relapse observed at 8 mos after treatment

Lapatinib induced accumulation of inactive HER2 at plasma membrane

– Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells

In vivo activity was consistent with in vitro data demonstrating the combination as synergistic

http://www.nature.com/onc/index.html

http://www.nature.com/onc/index.html

Blackwell KL, et al. J ClinOncol. 2010;28:1124-1130.

Patients with HER2+ (FISH/IHC3+) MBC and

progression on anthracycline, taxane, and

Herceptin

Lapatinib 1500 mg/day PO(n = 148)

Lapatinib 1000 mg/day PO + Herceptin 4 mg/kg → 2 mg/kg IV weekly

(n = 148)

Objetivo primario: supervivencia libre de progresión

Objetivos secundarios: Supervivencia global, respuesta, beneficio clínico

EGF104900 Estudio fase III: Bloqueo dual de Her2 en CMM

Supervivencia L (n = 145)

L + T (n = 146)

Muertes, n (%) 113 (78) 105 (72)

Mediana (m) 9.5 14

HR (95% CI) 0.74 (0.57-0.97)

Log-rank P value .026

6 meses SG

80%

70%

12 meses SG

56%

41%

Blackwell KL, et al. SABCS 2009. Abstract 61.

Su

pe

rviv

enci

a g

lob

al

Pacientes en riesgo, n148148

LL + T

121102

8865

6447

4328

2513

0

20

40

60

80

100

0 5 10 15 20 25 35Meses desde la aleatorización

1

30

LL + T

EGF104900 Estudiofase III: Bloqueo dual de Her2 en CMM

Nuevas terapias anti Her2


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib Presentation: 56-yr-old woman was diagnosed with stage III ER+/

PgR-/HER2+ breast cancer

– Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab

Follow-up: 3 yrs after completing maintenance trastuzumab, she was diagnosed with bone and lung metastases

– Treatment: docetaxel/trastuzumab

Follow-up: after achieving PR that lasted for 9 mos, she developed liver metastases

– Treatment: lapatinib/capecitabine

Follow-up: she achieved SD for 6 mos, after which she developed lung and lymph node metastases


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?

A. Lapatinib/trastuzumab

B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer

C. Trastuzumab plus bevacizumab

D. Lapatinib/trastuzumab/chemotherapy

E. Trastuzumab plus chemotherapy


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?

A. Lapatinib/trastuzumab (reasonable)

B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice)

C. Trastuzumab plus bevacizumab

D. Lapatinib/trastuzumab/chemotherapy

E. Trastuzumab plus chemotherapy (reasonable)

Can we further optimise the treatment of HER2-positive MBC in the future?

Despite the proven efficacy of the standard of care, Herceptin plus chemotherapy, a proportion of patients with HER2-

positive breast cancer will not respond, while the majority of patients with MBC will progress within 1 year1

1. Slamon et al. New Eng J Med 2001; 344:783–792

MBC = metastatic breast cancer

Pertuzumab

Mechanism of action

There are four receptors in the HER family

• Receptors are able to homo- and heterodimerise• HER2 does not appear to have a direct ligand and HER3 lacks

kinase activity• However, HER2 and HER3 are highly complementary to each other

HER2HER1/EGFR HER4HER3

Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137EGFR = epidermal growth factor receptor

Homodimers Heterodimers

HER2:HER3 dimers initiate the strongest mitogenic signalling

HER1:HER1HER2:HER2

HER3:HER3HER4:HER4

HER1:HER2 HER1:HER3HER1:HER4

HER2:HER4HER3:HER4

Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.

Signalling activity

+ + ++ + + + ++ + + ++ + + +

+

HER2:HER3

HER2 dimerises preferentially with HER3 to drive downstream signalling

Phosphorylation of the HER3 intracellular domain by HER2 initiates a signalling cascade

Ligand-activatedHER2:HER3 dimer

Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137; Graus-Porta et al. EMBO J 1997;1647–1655; Tzahar et al. Mol Cell Biol 1996;16:5276–5287;

Lee-Hoeflich et al. Cancer Res 2008;68:5878–5887.

HER2 HER3

PP

P P

Akt

Shc

HER2:HER3 dimerisation initiates multiple signalling pathways, including increased tumour cell proliferation

Downstream PI3K/Akt signalling is

mainly mediated by HER3 after

transphosphorylation by HER2

Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127–137; Olayioye et al. EMBO J 2000;19:3159–3167; Kim et al. J Biol Chem 1994;269:24747–24755; Soltoff et al. Mol Cell Biol 1994;14:3550–3558;Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Rowinsky. Annu Rev Med 2004;55:433–457;

HER2 HER3

GRb2

SosRAS

PI3KPP

PP PDK

1

PP P

RAF

MEK

MAPKP

P

mTOR

Cyclin 01

GSK36NF

BBADp2

7

Angiogenesis Proliferation

Cell cyclecontrol

Apoptosis

Survival

Pertuzumab is the first in a new class of targeted anticancer therapeutic agents called HER2 Dimerisation Inhibitors

• By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival1–4

• Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5

HER2

Dimerisationdomain

1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328;

5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892

Pertuzumab

HER3

Herceptin and pertuzumab bind to different epitopes on HER2 and show complementary mechanism of actions

HER2

Dimerisationdomain

Cho et al. Nature 2003;421:756–760; Fendly et al. Cancer Res 1990;50:1550–1558; Franklin et al. Cancer Cell 2004;5:317–328;Nahta et al. Cancer Res 2004;64:2343–2346; Scheuer et al. Cancer Res 2009;69:9330–9336

Pertuzumab

HER3

Herceptin

Subdomain IV• Herceptin does not inhibit ligand-

activated HER2 dimerisation• Herceptin prevents HER2 activation

by extracellular domain shedding• Herceptin inhibits ligand-

independent HER2 signalling and flags cells for destruction by the immune system

• Pertuzumab inhibits ligand-activated HER2 dimerisation

• Pertuzumab flags cells for destruction by the immune system

• Pertuzumab suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER2-driven signalling

Pertuzumab

HER2-positive MBC combination studies

Summary of pertuzumab combination trials in HER2-positive breast cancer

EBC(Neo-

adjuvant)

First-line MBC Third-line MBCSecond-line MBC

BO17929 cohorts 1+2 (n=66)

P+TBO17929 cohort 3 (n=29)

P mono then P+T

NCI study (n=11)

P+T

CLEOPATRA (n=800)D+T±P

PHEREXA (n=450)

Capecitabine+T±P

NEOSPHERE (n=400)

D+T vs D+T+P vsT+P vs D+P

TRYPHAENA (n=225)

D+FEC+T+P vscarboplatin+D+T+P

Enrolling

Enrolment complete

Data on file. Genentech USA, Inc., CA, USA andF Hoffmann-La Roche Ltd., Basel, Switzerland

D = docetaxel; EBC = early-stage breast cancer;FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer;P = pertuzumab; T = Herceptin

74

Providing greater efficacy and better tolerability than Herceptin plus chemotherapy

as single agent or in combination with a biologic

“… replacing Herceptin plus chemotherapy”

Aim for paradigm shift in treatment of breast cancer

Trastuzumab-DM1 (T-DM1) is a first-in-class antibody drug-conjugate (ADC)

75

Anatomy of T-DM1

T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

• Trastuzumab-like activity by binding to HER2• Targeted intracellular delivery of a potent antimicrotubule

agent, DM1

TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC

Primary endpoints• PFS (independent

assessment)• Safety

Secondary endpoints• OS• ORR• DoR • CBR• Pharmacokinetic

properties• Time to symptom

progression

HER2-positive MBCNo prior chemotherapy for MBC

(n=137)

T-DM1 Trastuzumab + docetaxel

Fully recruited, results to be presented later this year

Clinicaltrials.govPI: Edith Perez

• Se observó una mejora significativa de la SSP en las pacientes del grupo de trastuzumab emtansina (n= 67) en comparación con el grupo de Herceptin + quimioterapia (n = 70), (mediana de SSP: 14,2meses frente a 9,2; HR: 0,59; p: 0,035).• La TRO fue mayor en el grupo de trastuzumab emtansina que en el de Herceptin + quimioterapia(64,2% frente al 58,0%).• Los eventos adversos (EA) frecuentes y graves (grado 3 o superior) disminuyeron significativamenteen el grupo de trastuzumab emtansina en comparación con el grupo de Herceptin + quimioterapia:Los EA más frecuentes en el grupo de trastuzumab emtansina fueron fatiga (49,3%), náuseas (47,8%),un aumento de las cifras de una enzima específica secretada por el hígado y otros órganos (aspartatoaminotransferasa o AST, 39,1%) y fiebre (39,1%). Los EA más frecuentes en el grupo de Herceptin +quimioterapia fueron pérdida de cabello (66,7%), una cifra reducida de un tipo específico deleucocitos (neutropenia, 63,6%), diarrea (45,5%) y fatiga (45,5%). Coincidiendo con resultados yapublicados, EA graves (grado 3 o superior) se notificaron con menor frecuencia en el grupo detrastuzumab emtansina que en el de Herceptin + quimioterapia (46,4% frente a 89,4%), al igual quesuspensiones del tratamiento por EA (7,2% frente a 28,8%). Los EA graves más frecuentes en el grupode trastuzumab emtansina consistieron en una cifra aumentada de dos enzimas hepáticas diferentes(ALT y AST) y una cifra baja de plaquetas (8,7%). Los EA graves más frecuentes en el grupo de3/5Herceptin + quimioterapia consistieron en una cifra reducida de un tipo específico de leucocitos(neutropenia, 60,6%), una cifra total reducida de leucocitos (leucocitopenia, 25,8%) y fiebre asociadacon una cifra reducida de un tipo específico de leucocitos (neutropenia febril, 13,6%).• Los datos de la supervivencia global no están maduros en este momento. El número de fallecimientosen cada grupo del estudio fue idéntico. Según los investigadores, ninguna muerte estaba relacionadacon el tratamiento (trastuzumab emtansina o Herceptin + quimioterapia).

TDM4370g (EMILIA): ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the second-line setting

Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● OS● PFS (investigator assessment)● ORR● CBR ● DoR● Quality of life● TTF

n=319 as of June 4, 2010200 sites

FPI: February 27 2009

HER2-positive incurable locally advanced breast cancer or MBC

Prior trastuzumab and / or taxane(n=580)

T-DM1 Capecitabine + lapatinib

Clinicaltrials.govTTF, time to treatment failureFPI, first patient in

TDM4788g/BO22589 (MARIANNE): first-line T-DM1 + pertuzumab vs trastuzumab + docetaxel

Clinicaltrials.gov

Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● ORR (independent assessment)● OS● 1-year survival● PFS● ORR (investigator assessment)● CBR● TTF● DoR● Safety and tolerability

HER2-positive MBCNo prior chemotherapy

(n=1092)

Trastuzumab + taxane

T-DM1 + placebo

T-DM1 +pertuzumab

Global study starts summer 2010332 centers in 40 countries

T-DM1 and Pertuzumab: Binding to HER2

Diéras V, et al. SABCS 2010. Abstract P3-14-01.

Pertuzumab-HER2 Complex Herceptin/T-DM1-HER2 Complex

Pertuzumab

Dimerization domain

Herceptin/T-DM1

IV IV

III

II

I

III

II

I

T-DM1 and Pertuzumab: Mechanism of Action

Diéras V, et al. SABCS 2010. Abstract P3-14-01.

Pertuzumab

HER2

HER2 DimerT-DM1

DM1

Lysosome

Nucleus


Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.

mTOR

AKT

AMPKTSC1 TSC2

PTENLKB1

PI3K

RHEB

IGF-1R EGFR/HER2Increased signaling through IGF-1R

Constitutive PI3K/AKT activation

Elevated AKT or pAKT

Absent or low PTEN

Truncated HER2

Nutrients

mTOR inhibitorGrowth &

proliferation

Angiogenesis Cellmetabolism

Downstream inhibition with mTOR inhibitor counters these resistance mechanisms

Synergy of mTOR inhibition and trastuzumab in vitro and in vivo

mTOR Inhibition May Overcome Trastuzumab Resistance


Angiogenesis in MCF-7 Spheroids: Day 14

MCF-7 Neo:3.5 x mag.

Mature vasculature No vessel buds

Development stopped

MCF-7 Neo:3.5 x mag.

Mature vasculature No vessel buds

Development stopped

MCF-7 HER-2/neu:10 x mag.

High number mature vessels Vessel buds in center of tumor

Vasculature still growing

MCF-7 HER-2/neu:10 x mag.

High number mature vessels Vessel buds in center of tumor

Vasculature still growing


P

P

P

P

Cell growth, proliferation, survival, metastasis, angiogenesis

Akt/PKB

mTOR

S6K1

PI3-K

Lapatinibphase III

Gefitinibphase II

Everolimusphase III

EGFR HER2

4E-BP1

elF-4E

Protein synthesis

Neratinibphase III

Pertuzumabphase III

Trastuzumab

T-DM1 phase III

P

P

P

P

PTEN

VEGFRSunitinibphase II

Bevacizumabphase III VEGF

Targeted Agents for HER2+ Breast Cancer

Muchisimas Gracias

Dr. Luis Miguel Zetina Toache

Cancer Consultants GT

her2. dr

Health & Medicine

breast cancer her2

her2 overexpression

n engl j

recurrencias en

breast carcinoma

breast cancer1

sliwkowski mx

j cell phys