Miquel Àngel Seguí Palmer

HER2+ Breast Cancer is characterized by overexpression of HER2 receptors

HER2+ Breast Cancer is characterized by overexpression of HER2 receptors

HER2+ status is associated with more aggressive brest cancer and poorer patients outcomes

HER2HER1/EGFR HER4HER3

Transmembranedomain

Intracellular tyrosine kinase domain

Extracellular ligand-binding domain

The human epidermal growth factor receptors (HER) are a family of structurally-related cell surface proteins

Rowinsky. Oncologist. 2003. Yarden et al. Nature Rev Mol Cell Biol. 2001

Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling

Tzahar et al. Mol Cell Biol. 1996. Lenferink et al. EMBO J. 1998

AKTPDK1

Cell cyclecontrol

Proliferation

ApoptosisSurvival

RAS Sos Grb2 Shc

MEK

Angiogenesis

Raf

PI3K

Cyclin D1

p27

BAD

GSK3ß

NFκBmTOR

MAPK

HER2 HER3

P P PPP

PP

HER2 signaling results in a multitude of cellular effects, including increased cellular proliferation and cell survival

Olayioye et al. EMBO J. 2000. Rowinsky. Oncologist. 2003

Treatment Algorithm (before Cleopatra)

In 1st line Combination of trastuzumab and a taxane

Slamon DJ et al. N Engl J Med. 2001;344:783-92

Efficacy of HER2-targeted therapy in metastatic breast cancer

Treatment Algorithm (before Cleopatra)

In 1st line Combination of trastuzumab and a taxane

Efficacy of HER2-targeted therapy in metastatic breast cancer

Lapatinib or Trastuzumab Plus Taxane (NCIC CTG MA.31)Gelmon KA et al. J Clin Oncol 2015, 32:1574-1583

1st line

2nd line

3rd line

Capecitabina + Lapatinib

QT + Trastuzumab

QT + Trastuzumab

Capecitabina + Lapatinib

Taxane + Trastuzumab

Geyer CE et al. N Engl J Med. 2006;355:2733-43. von Minckwitz G et al. J Clin Oncol. 2009;27:1999-2006

Treatment Algorithm (before Cleopatra and Emilia)

Efficacy of HER2-targeted therapy in metastatic breast cancer

GBG 26/BIG 3-05 phase III study

von Minckwitz et al. Eur J Cancer. 2011;47:2273-81

Post-progression survival according to anti-HER2 treatment or not as part of 3rd line treatment

Efficacy of HER2-targeted therapy in metastatic breast cancer

Efficacy of HER2-targeted therapy in metastatic breast cancer

Dawood et al. J Clin Oncol 2010

Efficacy of HER2-targeted therapy in metastatic breast cancer

Dawood et al. J Clin Oncol 2010

Efficacy of HER2-targeted therapy in metastatic breast cancer

Historical Evolution

Adjuvant Trastuzumab Trials: Disease-Free Survival

Romond et al. Cancer Res. 2012. Piccart-Gebhart et al. Cancer Res. 2012. Slamon et al. N Engl J Med. 2011. Spielmann et al. Breast Cancer Res Treat. 2007. Joensuu et al. J Clin Oncol. 2009

PLANNED JOINT ANALYSIS OF OVERALL SURVIVAL FROM NSABP B-31 AND NCCTG N9831

8-year incidence rate of deaths by cardiac causes: 0.2% (Trastuzumab regimen) and 0.1% (control arm)

Adjuvant Trastuzumab Data

Piccart-Gebhart M et al ASCO 2014

Piccart-Gebhart M et al ESMO 2014

Effect of Trastuzumab on Neo-Adjuvant Therapy for HER2-Positive Disease

Meta-analysis evaluating the pCR rate

Valachis et al., The Breast 2011

Effect of Trastuzumab on Neo-Adjuvant Therapy for HER2-Positive Disease

Buzdar A, et al. JCO 2005; 23:3676. Gianni et al., Lancet 2010

NOAH: tpCRMD Anderson: pCR

Lapatinib or trastuzumab added to preoperative chemotherapy for breast cancer

Forest plot of pCR: trastuzumab versus lapatinib

Valachis et al. Breast Cancer Res Treat. 2012

Potential Molecular Mechanisms of Trastuzumab Resistance

The landmark development of trastuzumab, a humanized monoclonal antibody targeting HER2, and other anti-HER2 agents such as lapatinib, a reversible HER2 tyrosine kinase inhibitor, have changed the course of HER2-positive disease; however, a subset of patients will still relapse.

Given this clinical reality, new anti-HER2 agents with different mechanisms of action have been developed

Novel anti-HER2 therapies or agents that interfere with the HER2 pathway and function

Dual HER2 Blockade

Lapatinib + trastuzumab

Lapatinib + trastuzumab vs. Lapatinib in HER2+ MBC progressing on or after trastuzumab

Dual HER2 Blockade

Overall Survival Progression-Free Survival

Dual HER2 Blockade

NeoALTTO: Study Design

NeoALTTO Study

Dual HER2 Blockade

Baselga et al. Lancet. 2012

EFS shown for the ITT population OS shown for the ITT population

Dual HER2 Blockade

Dual HER2 Blockade

Pertuzumab prevents HER2:HER3 dimer formation by inhibiting access to the HER2 dimerization domain

Dual HER2 Blockade

NEOSPHERE: Study Design

Dual HER2 Blockade

NeoSphere pCR rates: ITT Population Summary

Gianni L, et al. Lancet Oncol 2012; 13:25–32

Dual HER2 Blockade

NeoSphere pCR rates: ITT Population Summary

Gianni L, et al. Lancet Oncol 2012; 13:25–32

NeoSphere DFS (all arms of therapy, ITT population)

Dual HER2 Blockade

Gianni L et al. ASCO 2015

Neoadjuvant Treatment of Breast Cancer

Perjeta is indicated for use in combination with trastuzumab andchemotherapy for the neoadjuvant treatment of adult patients withHER2-positive, locally advanced, inflammatory, or early stage breastcancer at high risk of recurrence

CLEOPATRA: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer

Dual HER2 Blockade

Baselga et al. NEJM 2012

Swain SM et al. N Engl J Med 2015;372:724-34

Dual HER2 Blockade

Median progression-free survival: 18.7 months Median overall survival: 56.5 months

CLEOPATRA

Treatment Algorithm (after Cleopatra)

In 1st line Combination of trastuzumab, pertuzumab and a taxane

Swain SM et al. N Engl J Med 2015;372:724-34

Dual HER2 Blockade

Median progression-free survival: 18.7 months Median overall survival: 56.5 months

Adjuvant Trial: APHINITY

Dual HER2 Blockade

Trastuzumab emtansine (T-DM1)

The mAb, trastuzumab, is conjugated by a thioether linker to the highly potent antimicrotubule agent DM1

Trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1)

EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib

Verma S et al. N Engl J Med. 2012;367(19):1783-91

Progression-free Survivalas Assessed by an Independent Review Committee

EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib

Verma S et al. N Engl J Med. 2012;367(19):1783-91

EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib

Verma S et al. N Engl J Med. 2012;367(19):1783-91

Second Interim Analysis of Overall Survival

TH3RESA, a Phase III study of TDM1 versus TPC

Krop IE et al. Lancet Oncol. 2014;15(7):689-99

TH3RESA, a Phase III study of TDM1 versus TPC

Krop IE et al. Lancet Oncol. 2014;15(7):689-99

Progression-free survival by investigator assessment First interim overall survival analysis

MARIANNE: Trial Design

T-DM1

Progression-Free Survival by IRF

ORR: HT 67.9%, T-DM1 59.7%, T-DM1+P 64.2%DURATION OF RESPONSE: HT 12.5m, T-DM1 20.7m, T-DM1-P 21.2m

Ellis, ASCO 2015

MARIANNE: Progression Free Survival

T-DM1

1st line

2nd line

3rd line Capecitabina + Lapatinib

QT + Trastuzumab

QT + Trastuzumab

Capecitabina + Lapatinib

Docetaxel + Trastuzumab + Pertuzumab

TDM1

4th line

Lapatinib + Trastuzumab

TDM1 Early relapse

TDM1

TDM1Lapatinib + Trastuzumab

Treatment Algorithm(after CLEOPATRA, EMILIA & TH3RESA)

Efficacy of HER2-targeted therapy in metastatic breast cancer

Number of lines of chemotherapy by line and subtype

Median duration of chemotherapy according to line and subtype

Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to Tumor Subtype and Line of Therapy

Seah DSE et al. J Natl Compr Canc Netw 2014;12:71–80

• Overexpression of the HER2 predicts a poor prognosis in breast cancer.

• HER2 signaling is initiated by receptor homodimerization or heterodimerization with ligand-bound HER1, HER3, and HER4.

• The introduction of HER2-targeted therapies, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies

• Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance.

Conclusions (1)

• New anti-HER2 drugs have the potential to change clinical practice.

• The combination of pertuzumab plus trastuzumab plus a taxane, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival and overall survival.

• T-DM1 is clearly distinct from trastuzumab; it is a cytotoxic agent, albeit one with an exceptional tolerability profile and has demonstrated clinical superiority in trastuzumab-pretreated and trastuzumab-and lapatinib-pretreated patients.

• T-DM1 is now been recognized as the preferred treatment option in second and third line for patients with advanced HER2-positive breast cancer

Conclusions (2)

Research into HER2-positive metastaticbreast cancer has advanced, but that’sno reason to stop……