Targeted adjuvant systemic therapy: Current status and future directions of Trastuzumab

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Targeted adjuvant systemic therapy Current
status and future directions of Trastuzumab

• May 25th 2007
• Highlights in the Management of Breast Cancer
• Mediterranean School of Rome
• Giuseppe Tonini
• University Campus Bio-Medico of Rome

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Background

• Breast cancer is an heterogeneous disease with
  different tumor subtypes and different natural
  histories
• Overexpression of HER2/neu defines one of these
  subtypes
• The HER2/neu gene belongs to a family of genes
  which encode for transmembrane receptors and
  includes HER1-4

Slamon DJ et al Science. 1987 235.
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Background

• HER2/neu gene is a proto-oncogene located on
  17q21
• HER2/neu is a transmembrane glycoprotein
• The extracellular domain interacts with other HER
  proteins allowing the facilitation of signal
  transduction after ligand binding
• The intracellular domain has an intrinsic
  Tyrosine Kinase (TK) activity that regulates
  various important aspects of the growth and
  differentiation of cells
• There is no known ligand for HER2 itself

Slamon DJ et al Science. 1987 235
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The EGFR/HER Family
Valabrega G et al Ann Oncol 2007
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HER2 as a prognostic factor

• Amplification of HER2 occurs in about 20-25 of
  invasive breast cancers
• It has been shown to be associated with poorly
  differentiated cancers, high rates of cell
  proliferation and lymph node involvement
• Most clinical studies have shown that patients
  with HER2 positive tumors have a poorer prognosis
• The prognostic value is strongest in patients
  with node positive disease while there is no
  consensus in its value in node negative patients
• The prognostic impact appears to be related only
  to the first 3-4 years after surgery as indicated
  by the peak of early recurrences

Menard et al Oncogene. 2003 22, 6570
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HER2 as a prognostic factor
Nodes negative
Nodes positive
Menard et al Oncogene. 2003 22, 6570
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HER2 as a predictive factor

• Anthracycline based chemotherapy appears to be
  particularly beneficial
• HER2 overexpression may be associated with
  resistance to alkylator based therapy
• The influence of HER2 on response to taxanes is
  unclear
• HER2 may also predict response to endocrine
  therapy
• Roughly 50 of HER2 amplified tumors are hormone
  receptor positive (typically lower levels than
  HER2 negative tumors)
• A prospective neoadjuvant study showed that in
  the HER2 positive patients the RR to letrozole
  were 88 VS 21 for the tamoxifen arm

Ellis et al JCO 2006 24 (19) 3019-25
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Trastuzumab Humanized Anti-HER2 Antibody
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Mechanisms of Trastuzumab action and resistance
Valabrega G et al Ann Oncol 2007
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Adjuvant Trastuzumab

• The beneficial effects on morbidity and/or
  mortality are seen in patients with HER2-positive
  breast cancer with HER2 overexpression at the 3
  level (IHC analysis) and/or HER2 gene
  amplification (FISH- CISH-positive).
• Phase III trials in early breast cancer HER-2
  the addition of Trastuzumab in adjuvant therapy
  significantly improves DFS

Plosker GL and Keam SJ Drugs 2006
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Randomized Phase III Trials Adjuvant Trastuzumab
Trial HERA NSABP B-31 NCCTG N9831 BCIRG
006 FinHer
No. patients 5090 2030 3505 3222 232a
Reference Piccart-Gebhart et al 2005Smith et al
2007 Romond et al 2005 Romond et al 2005 Slamon
et al 2006 Joensuu et al 2006
aHER2-positive subgroup
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Pivotal adjuvant Herceptin trialspatient
characteristics

• HER2 positive (IHC 3 / FISH)
• Invasive breast cancer resected by
  lumpectomy/mastectomy
• Nodal status
• node positive (NSABP B-31)
• node positive or high-risk node negative (NCCTG
  N9831, HERA, BCIRG 006)
• Known hormone receptor status (ER / PgR or ER
  alone)
• No previous or current cardiac disease

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Randomized Phase III Trials
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Combined analysis of B31 and N9831
Romond et alN Engl J Med 2005 3531673-1684
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Combined analysis of B31 and N9831
Romond et alN Engl J Med 2005 3531673-1684
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Adding trastuzumab significantly improves DFS !!!
Romond et alN Engl J Med 2005 3531673-1684
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Adding trastuzumab significantly improves OS!!!
Romond et alN Engl J Med 2005 3531673-1684
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Combined analysis of B31 and N9831
Romond et alN Engl J Med 2005 3531673-1684
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Sequential trastuzumab does not add nothing !!!
Romond et alN Engl J Med 2005 3531673-1684
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Early trastuzumab is better than sequential
trastuzumab !!!
Romond et alN Engl J Med 2005 3531673-1684
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Cardiac Safety

• 31.4 of patients receiving trastuzumab
  discontinued radiotherapy before 52 weeks for
  cardiac events
• NSABP-31
• N9831

Control Group 0.8
Grade III-IV events
Trastuzumab Group 4.1
Control Group 0
Trastuzumab Group 2.9
Romond et alN Engl J Med 2005 3531673-1684
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Randomized Phase III Trials
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Design of the HERA Trial
Piccart et alN Engl J Med 2005 3531659-1672
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HERA Trial patient characteristics () well
balanced arms
Piccart et alN Engl J Med 2005 3531659-1672
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HERA Trial tumor characteristics () well
balanced arms
Piccart et alN Engl J Med 2005 3531659-1672
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HERA trial recent developments

• Median follow-up more than 2 years

Smith et al, 2007
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HERA Trial DiseaseFree Survival
Absolute DFS benefit favoring trastuzumab of 6.3
Smith et al, 2007
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HERA Trial Overall Survival
Absolute OS benefit favoring trastuzumab of 2.7
Smith et al, 2007
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HERA trial DFS subgroup analysis summary

• No evidence of any subgroup in which there is
  less efficacy (similar efficacy in each subgroup)
• No substantial influence of any baseline
  characteristic on the DFS benefit for Herceptin

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Summary of Cardiac Toxicity in Three Studies
P 0.001 0.001 lt0.002
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BCIRG 006 study design
4 x AC60/600 mg/m2
4 x Docetaxel 100 mg/m2
AC?T
Her2 (Central FISH) N or high risk N-
4 x AC60/600 mg/m2
4 x Docetaxel 100 mg/m2
AC?TH
1 Year Trastuzumab
6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6
N3,222
TCH
Stratified by Nodes and Hormonal Receptor Status
1 Year Trastuzumab
Slamon D., SABCS 2006
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BCIRG 006 Endpoints

• Primary
• Disease-free Survival
• Secondary
• Overall Survival
• Toxicity
• Pathologic Molecular Markers

Slamon D., SABCS 2006
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Patient characteristics well balanced arms
Randomized (n3,222) AC-Tn1,073 AC-THn1,074 TCHn1,075

Age lt 50 years 52 52 54
KPS 100 80 79 80
Mastectomy 60 63 60
Radiotherapy 63 61 63
Hormonotherapy 50 51 51
Enrollment April 2001 to March 2004
Slamon D., SABCS 2006
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Tumor Characteristics well balanced arms
Randomized (n3,222) AC-Tn1,073 AC-THn1,074 TCHn1,075
Number of nodes
0 29 29 29
1 3 39 38 39
4 10 22 24 23
gt 10 11 9 10
Tumor Size (cm)
? 2 41 38 40
gt 2 and ? 5 53 55 54
gt 5 6 7 6
ER and/or PR 54 54 54
Slamon D., SABCS 2006
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Recent developments

• Median follow-up more than 3 years

Slamon D., SABCS 2006
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Disease Free Survival (1st interim analysis)
Median follow-up time 23 months
Year from randomization
Slamon D., SABCS 2006
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Disease Free Survival(2nd Interim Analysis)
Median follow-up time 36 months
Significant difference between trastuzumab arms
and non trastuzumab arm
Slamon D., SABCS 2006
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Overall Survival(2nd Interim Analysis) Median
follow-up time 36 months
Year from randomization
Slamon D., SABCS 2006
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Grade 3/4 Non-Hematological toxicity
AC-Tn1,050 AC-THn1,068 TCH n1,056
Arthralgia 3.2 3.3 1.4
Myalgia 5.2 5.2 1.8
Fatigue 7.0 7.3 7.2
Hand-foot syndrome 1.9 1.4 0.0
Stomatitis 3.6 3.1 1.4
Diarrhea 3.0 5.7 5.5
Nausea 6.0 5.7 4.8
Vomiting 6.1 6.8 3.4
Irregular menses 27.1 24.2 26.4





Yellow numerically less events AC-TH or
TCH Statistically significant AC-TH or TCH
Slamon D., SABCS 2006
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Grade 3/4 Hematological Toxicity
AC-Tn1,050 AC-THn1,068 TCH n1,056
Neutropenia 63.3 71.3 66.2
Leucopenia 51.5 60.2 48.2
Febrile neutropenia 9.1 11.0 9.8
Neutropenic infection 11.3 12.0 11.0
Anemia 2.5 3.1 5.8
Thrombocytopenia 1.0 1.2 5.4




Leukemia () 3 pts (0.3) 1 pt (0.1) 0 pts
Yellow numerically less events AC-TH or
TCH Statistically significant AC-TH or TCH
Slamon D., SABCS 2006
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Safety analysis population cardiotoxicity
AC-T n1,050 AC-TH n1,068 TCH n1,056
Cardiac related death 0 / 0 0 / 0 0 / 0
Cardiac left ventricular function (CHF) Grade 3 / 4 3 / 4 17 / 20 4 / 4

first interim analysis
second interim analysis
P 0.0015
Statistically significant increase in cardiac
events in the AC-TH arm
Slamon D., SABCS 2006
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TOPO IIa Amplification as a Predictor of
Anthracycline Response in Breast Cancer
Since 2002, at least 6 studies have been
published demonstrating the association between
topo II alpha amplification and improved
anthracyline response.
Study Yr N
Park et al. 2006 284
Tanner et al. 2006 525
Knoop at al. 2005 805
Park et al. 2003 188
Coon et al. 2002 35
Di Leo et al. 2002 354
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DFS Topo II Co-Amplified vs.... Non Co-Amplified
(2nd Interim Analysis)
Year from randomization
Slamon D., SABCS 2006
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DFS Co-Amplified Topo II by Arm (2nd Interim
Analysis)
In co-amplified Topo II patients trastuzumab does
not add nothing in term of DFS to anthracycline
based therapy
Year from randomization
Slamon D., SABCS 2006
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DFS Non Co-Amplified Topo II by Arm (2nd Interim
Analysis)
Year from randomization
In NOT co-amplified Topo II patients trastuzumab
INCREASES DFS compared to anthracycline based
therapy
Slamon D., SABCS 2006
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Adjuvant Herceptin trialssummary of DFS data to
date
Romond et al 2005 Joensuu et al 2006 Slamon et
al 2006 Smith et al 2007
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St. Gallen guidelines update on adjuvant
treatments for Early Breast Cancer

• Herceptin provides substantial benefit to
  patients with HER2-positive tumours athigh risk
  of early recurrence
• Herceptin should be added either with or after
  chemotherapy for HER2-positive patients,
  irrespective of endocrine responsiveness and
  nodal status

Goldhirsch et al 2006
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Adjuvant Herceptin answering some key questions

• Optimal duration of Herceptin treatment?
• - HERA (1 year versus 2 years Herceptin)
• Effect of delayed switching to Herceptin?
• - HERA
• Is concurrent or sequential Herceptin
  administration optimal?
• - NCCTG N9831

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Future directions

• 1) EGFR family inhibitors associated with
  trastuzumab
• Because HER2 and EGFR coexpression occurs in 30
  of breast cancers, blockage of both receptors is
  a rational strategy which may improve RR to
  trastuzumab. Such combination may also be
  considered for trastuzumab-resistant tumours, in
  which compensatory signalling by EGFR may inhibit
  the response to trastuzumab.
• - Lapatinib, Gefitinib, Pertuzumab

Valabrega G et al Ann Oncol 2007
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Future directions

• 2) Association with agents targeting other
  pathways and modified anti-HER2 antibodies
• It is under early clinical investigation for
  breast cancer after promising results in a
  preclinical setting.
• - inhibitors of mTOR (kinase located downstream
  the PI3K-AKT pathway) CCI-779 and RAD001
• - trastuzumab bevacizumab (NCI-sponsored phase
  I/II trial ongoing in HER2-overexpressing
  metastatic breast cancer patients)
• - recombinant molecules in which the
  antibody-combining site is fused directly to the
  toxin have been developed and show strong
  selectivity for HER2 binding

Valabrega G et al Ann Oncol 2007
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Lapatinib (Tykerb) in early stage
HER2-overexpressing breast cancer

• Ongoing large clinical phase III trials
• 1) The TEACH trial (3,000 patients)
• - it compares lapatinib and placebo after
  completion of any chemotherapy (anthracycline,
  taxane or CMF regimen)
• 2) ALTTO (Adjuvant lapatinib and/or trastuzumab
  treatment optimization) (to begin)
• it will investigates the benefit of trastuzumab 1
  year vs lapatinib 1 year vs trastuzumab 12 ws
  ?lapatinib 34 ws vs combination
  trastuzumablapatinib 1 year (after chemotherapy)
• it expects an ultimate enrollment of 8,000
  patients

Ito Y et al Breast Cancer 2007
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Co-amplification of c-myc and HER2 benefit of
trastuzumab
C-MYC/HER2 Regimen Patients Events HR 2p
Non co-amplified AC T AC TH 540 538 82 55 0,63 0,007
Co-amplified AC T AC TH 234 237 51 13 0,24 0,0001
Relationship between amplification of HER2 and
c-myc in NSABP-B31 trial
Kim et al Breast Cancer Research Treat 2005
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Co-amplification of c-myc and HER2 benefit of
trastuzumab

• Patients with co-amplification of c-myc and HER2
  have worse outcome when treated with chemotherapy
  alone, whereas the addition of Trastuzumab
  reverses this trend
• Patients treated with trastuzumab achieved
  recurrence-free survival of over 90
• HER2 amplification could represent an
  antiapoptotic signal for the pro-apoptotic
  function of c-Myc
• Trastuzumab could promote the apoptotic function
  of c-myc

Kim et al Breast Cancer Research Treat 2005
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Take-Home Messages

• Results from four major randomised trials provide
  level 1 evidence for OS benefit of adjuvant
  Herceptin
• Adjuvant Herceptin greatly increases the chance
  of Survival for patients with HER2-positive Early
  Breast Cancer
• Adjuvant Herceptin should be considered for all
  patients with HER2-positive breast cancer
• Close cardiac monitoring is mandatory
• Sequential vs.... concurrent vs.... chemotherapy
  regimen?
• Role of Topo II a testing?
• Role of c-myc testing?

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Adjuvant Herceptin approval
Bosnia-Herzegovina
Ecuador
Iceland
Russia
EU
USA
Israel
Switzerland
Chile
Pakistan
Philippines
Norway
New Zealand
South Korea
Guatemala
Australia
Nicaragua
Dominican Republic
Mexico
Columbia
India