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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
The human epidermal growth factor receptors (HER)
are a family of structurally-related cell surface proteins
Extracellular ligand-binding domain
HER1/EGFR
HER2
HER3
HER4
Transmembrane
domain
Intracellular tyrosine kinase domain
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
HER2 signaling results in a multitude of cellular effects,
including increased cellular proliferation and cell survival
HER2
RAS
Sos Grb2 Shc
HER3
P P
PDK1
P
AKT
P P PI3K
P
P
Raf
GSK3ß
MEK
NFκB
mTOR
BAD
Cyclin D1
p27
MAPK
Angiogenesis
Apoptosis
Survival
Cell cycle
control
Proliferation
Olayioye et al. EMBO J. 2000. Rowinsky. Oncologist. 2003
Efficacy of HER2-targeted therapy
in metastatic breast cancer
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
Lapatinib or Trastuzumab Plus Taxane (NCIC CTG MA.31)
Gelmon KA et al. J Clin Oncol 2015, 32:1574-1583
Efficacy of HER2-targeted therapy
in metastatic breast cancer
Treatment Algorithm
(before Cleopatra and Emilia)
1st line
Taxane + Trastuzumab
2nd line
Capecitabina +
Lapatinib
QT +
Trastuzumab
3rd line
QT +
Trastuzumab
Capecitabina +
Lapatinib
Geyer CE et al. N Engl J Med. 2006;355:2733-43. von Minckwitz G et al. J Clin Oncol. 2009;27:1999-2006
Efficacy of HER2-targeted therapy
in metastatic breast cancer
Post-progression survival according to anti-HER2
treatment or not as part of 3rd line treatment
GBG 26/BIG 3-05 phase III study
von Minckwitz et al. Eur J Cancer. 2011;47:2273-81
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
Adjuvant Trastuzumab Data
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)
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
MD Anderson: pCR
NOAH: tpCR
Buzdar A, et al. JCO 2005; 23:3676. Gianni et al., Lancet 2010
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
Dual HER2 Blockade
Lapatinib + trastuzumab vs. Lapatinib in HER2+
MBC progressing on or after trastuzumab
Progression-Free Survival
Overall Survival
Dual HER2 Blockade
NeoALTTO: Study Design
Dual HER2 Blockade
NeoALTTO Study
Baselga et al. Lancet. 2012
Dual HER2 Blockade
EFS shown for the ITT population
OS shown for the ITT population
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
Dual HER2 Blockade
NeoSphere DFS (all arms of therapy, ITT population)
Gianni L et al. ASCO 2015
Neoadjuvant Treatment of Breast Cancer
Perjeta is indicated for use in combination with trastuzumab and
chemotherapy for the neoadjuvant treatment of adult patients with
HER2-positive, locally advanced, inflammatory, or early stage breast
cancer at high risk of recurrence
Dual HER2 Blockade
CLEOPATRA: Pertuzumab in Combination with Trastuzumab
and Docetaxel for HER2-Positive Metastatic Breast Cancer
Baselga et al. NEJM 2012
Dual HER2 Blockade
CLEOPATRA
Median progression-free survival: 18.7 months
Median overall survival: 56.5 months
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
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
Adjuvant Trial: APHINITY
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
EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib
Progression-free Survival
as Assessed by an Independent Review Committee
Verma S et al. N Engl J Med. 2012;367(19):1783-91
EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib
Second Interim Analysis of Overall Survival
Verma S et al. N Engl J Med. 2012;367(19):1783-91
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
Progression-free survival by
investigator assessment
First interim overall survival analysis
Krop IE et al. Lancet Oncol. 2014;15(7):689-99
T-DM1
MARIANNE: Trial Design
T-DM1
MARIANNE: Progression Free Survival
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
Efficacy of HER2-targeted therapy
in metastatic breast cancer
Treatment Algorithm
(after CLEOPATRA, EMILIA & TH3RESA)
1st line
Docetaxel + Trastuzumab +
Pertuzumab
2nd line
TDM1
TDM1
Early relapse
3rd line
Capecitabina +
Lapatinib
QT +
Trastuzumab
Lapatinib +
Trastuzumab
TDM1
4th line
QT +
Trastuzumab
Capecitabina +
Lapatinib
Lapatinib +
Trastuzumab
TDM1
Use and Duration of Chemotherapy in Patients With Metastatic
Breast Cancer According to Tumor Subtype and Line of Therapy
Number of lines of chemotherapy
by line and subtype
Median duration of chemotherapy
according to line and subtype
Seah DSE et al. J Natl Compr Canc Netw 2014;12:71–80
Conclusions (1)
• 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 (2)
• 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
Research into HER2-positive metastatic
breast cancer has advanced, but that’s
no reason to stop……