CANCER DE MAMA HER 2+

Dr. Luis Miguel Zetina Toache Cancer Consultants GT

trastuzumab

Novel anti-HER2 therapies.

Baselga J Ann Oncol 2010;21:vii36-vii40

The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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 Cancer1

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 process13

Role of HER2 gene expression in breast carcinoma. Mnard 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.

Receptor activation is a complex, multistep process

1. Mnard 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.

Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness
Receptor specific ligands HER4 HER2 HER3 HER2 HER1, HER2, HER3*, or HER4

VEGF
HER1 (EGFR)

Plasma membrane

PI3K

SOS

Tyrosine kinase domains

Akt

P
MAP K

RAS

RAF MEK

Cytoplasm Cell proliferation Cell survival Cell mobility and invasiveness Nucleus

Transcription

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

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.

HER2 Overexpression in Breast Cancer

HER2 is overexpressed in ~ 25% of breast cancers

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

Overexpressed HER2 (10-100x) up to ~ 2,000,000 HER2 receptors

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.

Excessive cellular division

HER2 Overexpression Shortens Survival

HER2 oncogene amplification

HER2 oncoprotein overexpression

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 CNCER DE MAMA HER 2 POSITIVO

Estimacin 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 ao en USA
Extrapolado en un perodo de 25 aos podra prevenir ms de 50,000 recurrencias Estos resultados son consistentes con los europeos de Weisgerber-Kriegl presentados en ASCO 2008

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Trastuzumab: Mechanism of Action

Copyright 2005 Massachusetts Medical Society. All rights reserved.

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

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

HERA (ex-USA)
Observacin

BCIRG 006 (global)

FISH (n=3222)

IHC / FISH (n=5090)

1 ao 2 aos

1 ao

1 ao

NCCTG N9831 (USA)

IHC / FISH (n=3505) 1 ao Quimioterapia estndar Doxorubicina + ciclofosfamida 1 ao

NSABP B-31 (USA)

IHC / FISH (n=2030) 1 ao

Docetaxel

Docetaxel + carboplatino

Herceptin

Paclitaxel

FISH, hibridizacin fluorescente in situ

Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006

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

Pacientes (%) 100 80 60 40 20 Seguimiento medio: 2.9 aos Eventos n 222 ACPH 1989 397 1979 ACP HR=0.48; p0.00001
Aos desde la randomizacin

92.3%

87.9%

85.9%

86.4%

77.6%

52%
73.1%

0
0 No. at risk 1 1854 1800 2 1347 1235 3 868 753 4 522 460 5 202 168 6 4 8 7

*Eventos intencin de tratamiento: enfermedad recurrente,

cncer de mama contralateral, muerte por 2ndo primario. DFS: sobrevida libre de enfermedad

Perez et al 2007

Actualizacin de NCCTG N9831 / NSABP B-31 anlisis combinado: beneficio de OS*

Pacientes (%) 100 80 60 40 20 ACPH ACP
97.5% 95.9%

94.6% 92.7%

92.6% 89.4%

35%

n 1989 1979

HR=0.65; p=0.0007 0
0 No. at risk 1 1886 1863 2 1419 1376 3 938 898 4 570 562 5 217 211
Aos desde la randomizacin

*Eventos intencin de tratamiento: enfermedad recurrente, cncer de

mama contralateral, 2ndo primario, muerte

Perez et al 2007

Estudios de Herceptin adyuvante: beneficio en DFS probado

Seguimiento medio a 2 aos 2 4

HERA H 1 ao B-31 / N9831 ACPH

BCIRG 006 ACDH

BCIRG 006 DCarboH FinHer VH / DHa 0
Favorece a Herceptin

3
3

3
1 HR
No favorece a Herceptin

V, vinorelbina aSobrevida libre de recada

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

Estudios de Herceptin adyuvante: beneficio de OS probado

Seguimiento medio en aos 2 4

HERA H 1 ao B-31 / N9831 ACPH

BCIRG 006 ACDH

BCIRG 006 DCarboH FinHer VH / DHa 0
Favorece a Herceptin

3
3

3
1 HR
Joensuu et al 2006; Perez et al 2007; Slamon et al 2006; Smith et al 2007

No favorece a Herceptin

Estudio internacional, fase III, randomizado en CMLA: NOAH

CMLA HER2-positivo (IHC 3+ or FISH+) n=115
H + AP c3s x 3 ciclos H+P c3s x 4 ciclos H c3s x 4 ciclos + CMF c4s x 3 ciclos Ciruga seguida de radioterapiaa H continuada c3s hasta la semana 52
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: cncer de mama localmente avanzadolocally; P, paclitaxel (175 mg/m2); Gianni et al 2007 aPacientes positivos por receptor hormonal recibirn tamoxifeno adyuvante

CMLA HER2-negativo (IHC 0/1+) n=113

AP c3s x 3 ciclos P c3s x 4 ciclos CMF c4s x 3 ciclos

n=99
AP c3s x 3 ciclos P c3s x 4 ciclos CMF c4s x 3 ciclos Ciruga seguida de radioterapiaa

Ciruga seguida de radioterapiaa

Herceptin neoadyuvante duplica la tasa de respuesta patolgica

Pacientes (%) 50 40 30 20
23 17 43 p=0.29 38 p=0.43 20 16

p=0.002
p=0.003

10 0 Con H Sin H

HER2 negativo

Con H

Sin H

HER2 negativo

HER2 positivo pCR

HER2 positivo tpCR

tpCR: total pCR en mama y ganglios

Gianni et al 2007

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

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

HER2-positive (%)

HER2-negative (%)

P value

5-yr RFS

77

94

<0.001

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

Conclusions: The addition of 1 year of adjuvant trastuzumab significantly improved diseasefree and overall survival among women with HER2-positive breast cancer. The riskbenefit 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; BCIRG006 ClinicalTrials .gov number, NCT00021255.) Table 2. Therapeutic Index for Critical Clinical Events.* AC-T plus Clinical Event AC-T Trastuzumab number of events Total events 201 146 Distant breast-cancer recurrence 188 124 Grade 3 or 4 congestive heart failure 7 21 Acute leukemia 6 1

TCH 149 144 4 1

D. Slamon New England Journal of Medicine october 6, 2011 vol. 365 no. 14

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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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

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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

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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

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

Patients HER2+ by IHC (N = 111) HER2+ by FISH (n = 79) Response Rate, % 26 34 Median Time to Progression, Mos 3.5 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

Paclitaxel

Patients with HER2+ (IHC 2+/3+) MBC, no previous chemotherapy, measurable disease, KPS 60% (N = 469)

Previous adjuvant AC

(n = 96)
Herceptin + Paclitaxel

(n = 92)
AC No previous adjuvant AC

(n = 138)
Herceptin + AC

(n = 143)

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

Herceptin in MBC: The Pivotal Trial

Treatment Chemo Chemo + Herceptin

Objective Response Rate, % 32 50

Median TTP, Mos 4.6 7.4

Median OS, Mos 20.3 25.1

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

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

Herceptin in Triple-Combination Regimens: Response Rates

Yardley et al, 2004 (N = 24) Untch et al, 2004 (N = 25) Untch et al, 2004 (N = 26) Dirix et al, 2006 (N = 34) Chan et al, 2007 (N = 34) Fountzilas et al, 2004 (N = 40) Yardley et al, 2006 (N = 41) Miller et al, 2002 (N = 45) Venturini et al, 2006 (N = 45) Perez et al, 2005 (N = 43) Perez et al, 2005 (N = 48) Cortes et al, 2004 (N = 54) Yardley et al, 2002 (N = 61) Pegram et al, 2004 (N = 59) Pegram et al, 2004 (N = 62) Robert et al, 2006 (N = 92) Wardley et al, 2006 (N = 111) Forbes et al, 2006 (N = 130) 0 10 20 30 40 50 ORR (%)
H + Carbo + P
H+X+T H + Carbo + T H + Carbo + T H + Carbo + T H + Cisplatin + T H+G+P H + G + Carbo H+G+P H + E90 + C H + E60 + C H + Carbo + T H+V+X H+V+T

H+E+T
H + Carbo + P every 3 wks H + Carbo + P every wk H + TLC D-99 + P

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.

Cross-talk Between Signal Transduction and Endocrine Pathways

Growth Factor Estrogen
IGFR
EGFR/HER2

Plasma Membrane

P P P

P P

MoAb
SOS RAS RAF MEK
P

P13-K

AI
ER

Cell Survival

Akt

p90RSK

MAPK

Cytoplasm
P P P P

ER

ER

p160

CBP

Basal Transcription Machinery

Cell Growth

Nucleus

ERE

ER Target Gene Transcription

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

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

Estrogen receptor (ER) and growth factor (GF) pathway cross-talk in endocrine resistance: a working model.

Schiff R et al. Clin Cancer Res 2004;10:331s-336s

2004 by American Association for Cancer Research

Hormonal Therapy in HER2+ MBC

Regimen Trastuzumab (N = 79)[1] Anastrozole + trastuzumab (N = 103)[2] Anastrozole (N = 104)[2] Lapatinib + letrozole (N = 642)[3] Letrozole (N = 644)[3] Lapatinib (N = 138)[4] ORR, % 26 20 7 28 15 24 PFS, Mos 3.5-3.8 4.8 2.4 8.2 3.0 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.

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Blocks signaling through ErbB1 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
1+1 2+2 1+2

Downstream signaling cascade

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Lapatinib as First-line Treatment for HER2Amplified LABC or MBC

Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy
Endpoint Lapatinib 1500 mg/day (n = 69) 15 (22) 20 (29) 41 Lapatinib 500 mg BID (n = 69) 18 (26) 23 (33) 45 All Patients (N = 138) 33 (24) 43 (31) 43

Response rate, n (%) Clinical benefit rate, n (%) 6-mo PFS, %

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

Current therapeutic cascade in HER2+ MBC

HER2+ /ER + MBC

Good performance status Visceral disease Rapidly progressing

Poor performance status Non visceral disease Slow progression

Prior A.I.? YES NO

Herceptin + Chemotherapy

Herceptin monotherapy

Herceptin + Aromatase Inhibitor

Tratamiento mas all de progresin

Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab

Background: 39-yr-old woman diagnosed with stage IIA, breast cancer in 2004
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 Trastuzumab

Scans 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. What treatment option would you recommend at this time?

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 Trastuzumab

Scans 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. What treatment option would you recommend at this time?

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Mechanism of Action of Lapatinib Compared to Trastuzumab

T

Trastuzumab

Erb receptors
L L L L L L

Lapatinib

Downstream signaling pathways

Cell proliferation Cell survival

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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

Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m2/day on Days 1-14 every 21 days Capecitabine 2500 mg/m2/day on Days 1-14 every 21 days

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

*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.

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Lapatinib + Capecitabine in HER2+ MBC: TTP

Cumulative Progression Free (%)
Cumulative Progression Free (%) 100 80 60 40 20 0 0 20 40 Wks 60 80 TTP With 1 Previous Trastuzumab Regimen 100 80 60 40 TTP With > 1 Previous Trastuzumab Regimen Capecitabine Lapatinib + capecitabine Capecitabine Lapatinib + capecitabine

20 0
0 20 40 Wks 60 80

Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2positive 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.

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Lapatinib + Capecitabine in HER2+ MBC: Efficacy

Result Capecitabine (n = 201) 18.6 Capecitabine + Lapatinib (n = 207) 31.3 HR P Value

Median TTP, wks[1]

0.50

< .001

OS, wks[1]
ORR, %[2] Brain mets as site of first progression,* n (%)[2]
n=198

56.6
13.9 13 (6)

71.4
23.7 4 (2)

0.79
---

.077
.017 .045

in 2008 study. *Exploratory analysis.

1. Cameron D, et al. Oncologist. 2010;15:924-934 2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.

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Combining Lapatinib and Trastuzumab Increases Antitumor Activity

Tumor Volume (mm3)

1600 1400
1200 1000 800 600 400 200 0 13

Control Trastuzumab Lapatinib Trastuzumab + lapatinib

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

* *

16 19 21 23 Days After Injection *P < .05; P < .01 vs control; P < .05 vs trastuzumab; P < .01 vs both lapatinib and trastuzumab.

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
Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:16301639. Xia W, et al. Oncogene. 2004;23:646-653.

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

EGF104900 Estudio fase III: Bloqueo dual de Her2 en CMM

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 progresin Objetivos secundarios: Supervivencia global, respuesta, beneficio clnico

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

EGF104900 Estudiofase III: Bloqueo dual de Her2 en CMM

100 80%

Supervivencia Muertes, n (%) Mediana (m) 70% 6 meses SG HR (95% CI) Log-rank P value

L L+T (n = 145) (n = 146) 113 (78) 9.5 .026 105 (72) 14

80 Supervivencia global

60

56%

0.74 (0.57-0.97)

40 L L+T

41% 12 meses SG

20

10
88 65

Pacientes en riesgo, n L 148 121 L + T 148 102

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

15 20 25 Meses desde la aleatorizacin

64 47 43 28 25 13

30
1

35

Nuevas terapias anti Her2

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib

What 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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib

What 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

MBC = metastatic breast cancer

1. Slamon et al. New Eng J Med 2001; 344:783792

Pertuzumab

Mechanism of action

There are four receptors in the HER family

HER1/EGFR

HER2

HER3

HER4

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

EGFR = epidermal growth factor receptor

Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127137

HER2:HER3 dimers initiate the strongest mitogenic signalling

Homodimers
HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3

Heterodimers
HER1:HER4 HER2:HER3 HER2:HER4

HER1:HER1

HER3:HER4

+ + +

+ + +

Signalling activity

+ + + +

+ + +

Tzahar et al. Mol Cell Biol 1996;16:52765287; Citri et al. Exp Cell Res 2003;284:5465; Huang et al. Cancer Res 2010;70:12041214.

HER2 dimerises preferentially with HER3 to drive downstream signalling

HER2 Ligand-activated HER2:HER3 dimer HER3

P P P

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

Baselga, Swain. Nat Rev Cancer 2009;9:463475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127137; Graus-Porta et al. EMBO J 1997;16471655; Tzahar et al. Mol Cell Biol 1996;16:52765287; Lee-Hoeflich et al. Cancer Res 2008;68:58785887.

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

HER2

HER3

RAS

Sos

GRb2

Shc

P PP
RAF

PI3K P

P P P PDK1

Akt

Downstream PI3K/Akt signalling is mainly mediated by HER3 after transphosphorylation by HER2

MEK

mTOR Cyclin 01 p27 BAD

GSK36 NF B

MAPK

Apoptosis Cell cycle control Survival

Angiogenesis

Proliferation
Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127137; Olayioye et al. EMBO J 2000;19:31593167; Kim et al. J Biol Chem 1994;269:2474724755; Soltoff et al. Mol Cell Biol 1994;14:35503558; Baselga, Swain. Nat Rev Cancer 2009;9:463475; Rowinsky. Annu Rev Med 2004;55:433457;

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 survival14 Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5

HER2

HER3

Pertuzumab
Dimerisation domain

1. Agus et al. Cancer Cell 2002;2:127137; 2. Baselga. Cancer Cell 2002;2:9395; 3. Citri et al. Exp Cell Res 2003;284:5465. 4. Franklin et al. Cancer Cell 2004;5:317328; 5. Hughes et al. Mol Cancer Ther 2009;8:18851892

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

Pertuzumab Herceptin HER2 HER3

Subdomain IV
Herceptin does not inhibit ligandactivated HER2 dimerisation

Dimerisation domain
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

Herceptin prevents HER2 activation by extracellular domain shedding Herceptin inhibits ligand-independent HER2 signalling and flags cells for destruction by the immune system

Cho et al. Nature 2003;421:756760; Fendly et al. Cancer Res 1990;50:15501558; Franklin et al. Cancer Cell 2004;5:317328; Nahta et al. Cancer Res 2004;64:23432346; Scheuer et al. Cancer Res 2009;69:93309336

Pertuzumab

HER2-positive MBC combination studies

Summary of pertuzumab combination trials in HER2-positive breast cancer

EBC (Neo-adjuvant) NEOSPHERE (n=400) D+T vs D+T+P vs T+P vs D+P TRYPHAENA (n=225) D+FEC+T+P vs carboplatin+D+T+P

First-line MBC

Second-line MBC

Third-line MBC

CLEOPATRA (n=800) D+TP

PHEREXA (n=450) Capecitabine+TP

BO17929 cohorts 1+2 (n=66) P+T BO17929 cohort 3 (n=29) P mono then P+T

Enrolment complete Enrolling

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

NCI study (n=11) P+T

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

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

Aim for paradigm shift in treatment of breast cancer

Providing greater efficacy and better tolerability than Herceptin plus chemotherapy as single agent or in combination with a biologic replacing Herceptin plus chemotherapy

72

Anatomy of T-DM1

73

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

Trastuzumab-like activity by binding to HER2 to the HER2 protein T-DM1 binds on cancer cells Targeted intracellular delivery of a potent antimicrotubule agent, DM1

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

Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

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

HER2-positive MBC No prior chemotherapy for MBC (n=137)

DoR
CBR Pharmacokinetic properties Time to symptom progression

T-DM1

Trastuzumab + docetaxel

Fully recruited, results to be presented later this year

PI: Edith Perez

Clinicaltrials.gov

TDM4370g (EMILIA): ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the second-line setting
Primary endpoints PFS (independent assessment) Safety Secondary endpoints OS PFS (investigator assessment) ORR CBR DoR Quality of life TTF

HER2-positive incurable locally advanced breast cancer or MBC Prior trastuzumab and / or taxane (n=580)

T-DM1

Capecitabine + lapatinib

n=319 as of June 4, 2010 200 sites FPI: February 27 2009

TTF, time to treatment failure FPI, first patient in

Clinicaltrials.gov

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

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

HER2-positive MBC No prior chemotherapy (n=1092)

Trastuzumab + taxane

T-DM1 + pertuzumab

T-DM1 + placebo

Global study starts summer 2010 332 centers in 40 countries

Clinicaltrials.gov

T-DM1 and Pertuzumab: Binding to HER2

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

Pertuzumab
I II III IV III I II Dimerization domain Herceptin/T-DM1

IV

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

T-DM1 and Pertuzumab: Mechanism of Action

Pertuzumab
HER2

HER2 Dimer

T-DM1

Lysosome DM1

Nucleus

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

clinicaloptions.com/oncology

mTOR Inhibition May Overcome Trastuzumab Resistance

IGF-1R Nutrients EGFR/HER2 PI3K PTEN LKB1 AKT

Increased signaling through IGF-1R

Truncated HER2 Constitutive PI3K/AKT activation Absent or low PTEN

AMPK

TSC1 TSC2

Elevated AKT or pAKT

RHEB

Growth & proliferation

mTOR mTOR inhibitor

Angiogenesis

Cell metabolism

Downstream inhibition with mTOR inhibitor counters these resistance mechanisms Synergy of mTOR inhibition and trastuzumab in vitro and in vivo

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

clinicaloptions.com/oncology

Angiogenesis in MCF-7 Spheroids: Day 14

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

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

clinicaloptions.com/oncology

Targeted Agents for HER2+ Breast Cancer

Bevacizumab phase III Sunitinib phase II VEGFR
P P Akt/PKB P P PI3-K

Trastuzumab

VEGF
EGFR
P P

T-DM1 phase III

HER2
P

Pertuzumab phase III

PTEN

Everolimus phase III

Lapatinib phase III Neratinib phase III Gefitinib phase II

mTOR

4E-BP1 S6K1 elF-4E

Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis

Muchisimas Gracias
Dr. Luis Miguel Zetina Toache Cancer Consultants GT