Targeted therapy in Early Breast Cancer

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Targeted therapy in EarlyBreast Cancer

• Paul Ellis
• Guys Hospital, London

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Targeted therapy

• Key principles for targeted therapeutics
• the target must be relevant to the disease
• a clear scientific rationale must exist for the
  therapeutic
• patients can be selected for on basis of tumour
  expression of the target

• Questions for clinical trials of targeted
  therapeutics
• Are the most appropriate population of patients
  being treated?
• Has the trial been designed correctly, with most
  appropriate biological / clinical endpoints?

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Targeted Therapy of Breast Cancer 2008

• Molecular targets
• Hormone Receptors
• ER, PgR
• AR
• Cell Surface Receptors
• HER family (EGFR, HER2)
• IGFR-I
• Angiogenesis
• PARP
• Signal Transduction
• Src
• MEK
• PI3-Kinase / Akt
• mTOR
• HSP-90

• Treatment choices based on molecular features
• ER / PgR positive
• HER2 positive
• Basal type (triple negative) ?
• BRCA status ?

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• Background
• HER2 positive EBC
• Global Adjuvant trial update
• Current UK practice
• Application of targeted therapies
• Neoadjuvant therapy
• Triple Negative EBC
• Summary

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HER2 EBC
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Drugs to block HER Family Receptors
Monoclonal antibodies cetuximab, ABX-EGF,
EMD72000, h-R3, trastuzumab, pertuzumab
Ligand
R
R
Tyrosine kinase inhibitors EGFR gefitinib,
erlotinib HER2 AEE-788, lapatinib Pan-erb
CI-1033, HKI-569
K
K
Signal Transduction
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Adjuvant trastuzumab trialsgt13,000 patients
HERA (ex-USA)
BCIRG 006 (global)
IHC or FISH (n5090)
NCCTG N9831 (USA)
NSABP B-31 (USA)
Piccart-Gebhart et al 2005Romond et al
2005Slamon et al 2006
Docetaxel
Docetaxel carboplatin
Doxorubicin cyclophosphamide
Paclitaxel
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ASCO 2007 Updated N9831/B-31 Joint Analysis DFS
100
86.4
80
77.6
P lt 0.00001
73.1
60
AC ? P (n1,979 397 events)
Alive and disease-free ()
40
21 crossover
N619 events HRadj 0.48 (95 CI
0.41-0.57) Nodes, receptor status, paclitaxel
schedule, protocol
20
Numberat risk
168
460
8
753
1,235
1,800
0
0
1
2
3
4
5
6
7
Follow-up (yrs)
Intent to treat events recurrent disease,
contralateral bc, 2nd primary, death
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DFS benefit across 5 out of 6 trials
Median follow-up, years
DFS benefit
2
HERA CTx?H 1 year
4
B-31 / N9831 AC?PH
3
BCIRG 006 AC?DH
3
BCIRG 006 DCarboH
3
FinHera VH / DH?CEFb
PACS-04a CTx?H 1 year
4
0
1
2
FavoursHerceptin
Favours noHerceptin
HR
aBased on small subgroups of patients with
HER2-positive breast cancer brelapse-free
survival V, vinorelbine CEF, cyclophosphamide,
epirubicin, 5-fluorouracil
Joensuu et al 2006 Slamon et al 2006 Perez et
al 2007 Smith et al 2007 Spielmann et al 2007
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Adjuvant trastuzumab trialsproven OS benefit
Median follow-up,years
HERA H 1 year
2
B-31 / N9831 AC?PH
4
BCIRG 006 AC?DH
3
BCIRG 006 DCarboH
3
FinHer VH / DHa
3
0
1
2
FavoursHerceptin
Favours noHerceptin
HR
Joensuu et al 2006 Perez et al 2007Slamon et
al 2006 Smith et al 2006
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Cumulative incidence of cardiac events
N9831/NSABP B31 updated analysis

• Longer follow-up showed no additional concerns
  regarding the cardiac safety profile
• Cardiac events occurred early
• No evidence of increased toxicity or late
  toxicity
• In NSABP B 31 the following factors were shown to
  be predictive for CHF
• Age (p0.03)
• Hypertensive medications (p0.02)
• Baseline LVEF (p0.0003)
• The incidence of cardiac events reach a plateau
  at around 1 year
• Cardiac effects of trastuzumab were largely
  reversible

Perez et al Abs 512 ASCO 2007
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Incidence of trastuzumab-related cardiac events
in EBC trials
Asymptomatic LVEF decline, a
Severe CHF,
Cardiac death, n
Arm
n
3.0 NR NR 18.0 8.6
H 1 year AC?PH AC?PH AC?DH DCarboH
HERA NSABP B-31 NCCTG N9831 BCIRG 006
1,678 947 570 1,068 1,056
0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4
0 0 0 0 0
Slamon et al 2006 Rastogi et al 2007 Suter et
al 2007 Perez et al 2008
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Ongoing Trial Questions

• Duration
• Greater than 1 yr (HERA 1 v 2 yr awaited - ? SA
  08 )
• Shorter 6 v 12 months (Separate UK French
  trials)
• Concurrent or Sequential
• N 9831 update - ? SA 09
• Older / Lower risk patients
• Herceptin needed in addition to AI?
• Can we do without anthracyclines?
• Translational Biology
• How do we Identify subgroups that gain most
  benefit?

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Duration Vast majority of evidence in trials of
12 months
Median follow-up, years
DFS benefit
2
HERA CTx?H 1 year
4
B-31 / N9831 AC?PH
3
BCIRG 006 AC?DH
3
BCIRG 006 DCarboH
3
FinHera VH / DH?CEFb
PACS-04a CTx?H 1 year
4
0
1
2
FavoursHerceptin
Favours noHerceptin
HR
aBased on small subgroups of patients with
HER2-positive breast cancer brelapse-free
survival V, vinorelbine CEF, cyclophosphamide,
epirubicin, 5-fluorouracil
Joensuu et al 2006 Slamon et al 2006 Perez et
al 2007 Smith et al 2007 Spielmann et al 2007
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What is the optimum scheduling of Herceptin and
chemotherapy?
HERA
PACS-04
HR
HR
HR0.5795 CI (0.30-1.09)
HR1.04
Observation
0.002
1 year H
0.00
1-6
7-12
13-18
19-24
25-30
31-36
Months since randomisation
Months
NSABP B-31 / NCCTG N9831
Rate per1,000 women/year
AC?T
AC?TH
Romond et al 2005Smith 2006 Spielmann et al 2007
Years since randomisation
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Should we treat the low risk HER2patient?
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Poor 10-year Breast Cancer Specific Survival
(BCSS) and RFS for HER2 pT1N0 tumours

• 3836 tissue microarray cohort of ebc diagnosed in
  British Columbia 1986-92, confirmed invasive with
  ER and HER2
• 1245 cases T1pN0 (952 of these no adjuvant
  therapy)
• HER2 ve defined as IHC 3 or FISH
• 13 of total were HER2 ve
• 9.4 of TIpN0 were HER2 ve

Norris et al. SABCS 2006. Poster 2031
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10-year BCSS and RFS by HER2 and ER in the
pT1N0 cohort
BCSS, breast cancer-specific survival RFS,
relapse-free survival
Adapted from Norris et al. SABCS 2006. Poster 2031
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Adjuvant Trastuzumab in Low-Risk PatientsT1N0M0

• T1 ( 1 cm ) N0 excluded from adjuvant trials
• T1 (gt 1 cm) were recruited into HERA, N9831, and
  BCIRG 006
• - 32 (HERA)
• - 29 (BCIRG006)
• - 11 (N9831), patients had node-negative
  disease
• In HERA 994 of 1099 N0 pts had tumours gt1cm

Smith IE et al. Lancet 2007 369 2936 Perez EA
et al. ASCO 2007. Abstract 512 Slamon D. SABCS
2006
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DFS benefit across different tumour sizes
0-2 cm
HERA
gt2-5 cm
gt5 cm
N9831 / B-31
0-2 cm
gt2-5 cm
gt5 cm
BCIRG 006
AC?DH
lt2 cm
2 cm
DCarboH
lt2 cm
2 cm
0.0
0.5
2.5
1.0
1.5
2.0
Favours Herceptin
Favours no Herceptin
HR
Slamon et al 2006 Perez et al 2007 Smith et al
2007
DFS, disease-free survival
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Trastuzumab for Low Risk Breast CancerThe
Contradiction

• St Gallen and NCCN guidelines
• Adjuvant CT plus trastuzumab is indicated for
  patients with N0 tumours if 2 cm.
• HERA Conclusions
• We were unable to identify a subgroup for which
  the potential absolute benefit of trastuzumab was
  small enough to indicate that treatment might not
  be clinically beneficial
• (Based on 510 pts randomised with T1(1.1-2cm)N0
  tumours)

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HER2ve Low Risk Breast CancerKey Issues

• Should women with HER2ve low risk breast cancer
  be given CT and trastuzumab?
• Would women with HER2ve low risk breast cancer
  benefit from trastuzumab alone (or with endocrine
  therapy if ERve?)
• If so would the gain from additional chemotherapy
  be clinically worthwhile?

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Anthracyclines Do we need them in HER2 pts?
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Anthracyclines Do we need them?

• Increasing concern re potential long term
  morbidity cardiac tox/leukeamia risk
• Adjuvant anthracyclines are effective in patients
  whose tumors have topo II alpha amplification (7
  of total)
• However, almost all of those tumors have
  simultaneous amplification of Her2
• We now have very effective targeted therapies for
  these tumors (trastuzumab) (BCIRG 006 - TCH)

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BCIRG006 DFS and OS
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Cardiotoxicity and trastuzumab pivotal adjuvant
trastuzumab trials
CHF, congestive heart failure LLN, lower limit
of normal
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Patients should receive Trastuzumab upfront

• In the joined analysis 5-7 of patients receiving
  AC have cardiac dysfunction that they never
  receive Trastuzumab
• 15 receive less than 1 year of Herceptin
• In the BCIRG006, 23 pts in the AC?TH arm never
  got Herceptin due to unacceptable declines in
  LVEF following AC

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Combined Targeted agents in EBC
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ALTTO Study Design
HER2 invasive breast cancer
Centrally-determined HER2
Surgery, complete (neo)adjuvant
anthracycline-basedchemotherapy (approved list)
LVEF ? 50
11 RANDOMIZATION (N8000)

Trastuzumabfor 1 yr
Lapatinibfor 1 yr
Trastuzumabfor 3 mo
Trastuzumab3-weekly lapatinibfor 1 yr
6 wk breakLapatinib x7.5 mo
weekly paclitaxel x 12w as per
investigators discretion.
PIs. M Piccart, EA Perez
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BETH Study design
TH ? FEC or TCH Avastin
H Avastin 15 mg/kg/q3wk to complete 1 year
Early breast cancer, HER2 ve (n3600)
TH ? FEC or TCH
H to complete 1 year
Primary Endpoint Invasive Disease-Free Survival

• Randomized, open label trial TCH docetaxel
  carboplatin (q3w x 6 cycles) Herceptin (q3w x
  1 year)
• TH?FEC?H docetaxel Herceptin (q3w x 3 cycles)
  ? 5-FU, epirubicin, and cyclophosphamide (q3w x 3
  cycles) ? Herceptin (q3w x 43 weeks)

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BEATRICE BEvacizumab as adjuvant treatment of
triple negative breast cancer
Chemo bev (1 year)
Efficacy and safety follow-up
DFS
Triple negative EBCa (n2530)
Chemo

• BEATRICE includes patients with early triple
  negative breast cancer (basal phenotype)
• End points
• primary end point disease-free survival
• secondary end points overall survival,
  recurrence-free survival, distant disease-free
  survival, time to recurrence, and time to distant
  recurrence

aHER2- ER/PgR status confirmed centrally
before randomisation DFS, disease-free survival
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Are taxane chemotherapy regimens better or worse
for basal-like cancers?
UK TACT Adjuvant study
Effect of being Basal-like
Basal-like Triple Negative
FEC x 8 or Epi/CMF
4162 women (3610 TMA) 800 predicted ER/PR/HER2
-ve
FEC x 4?Docetaxel x 4
The Rest The Rest of ER-ve
P Ellis, P Barrett-Lee, J Bliss S Johnston -
Trans-TACT TRICC
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Neoadjuvant Trastuzumab
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Neoadjuvant trial in HER2-positive operable BC
pathCR rates
95 CI(4187)p0.02
95 CI(4384)p0.016
pCR ()
65.2n23
66.7n18
26.3n19
25.0n16
(n34)
(n42)
Buzdar A, et al. Proc ASCO 2004237
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NOAH study neoadjuvant Herceptin for LABC
HER2-positive LABC(IHC 3 and/or FISH)
HER2-negative LABC(IHC 0/1)
n113
n115
n99
H AP q3w x 3
APq3w x 3
APq3w x 3
H Pq3w x 4
Pq3w x 4
Pq3w x 4
H q3w x 4 CMF q4w x 3
CMFq4w x 3
CMFq4w x 3
Surgery followed by radiotherapya
Surgery followed by radiotherapya
Surgery followed by radiotherapya
H continued q3w to Week 52
aHormone receptor-positive patients receive
adjuvant tamoxifen AP, doxorubicin 60 mg/m2,
paclitaxel 150 mg/m2 H, Herceptin 8 mg/kg
loading then 6 mg/kg P, paclitaxel 175 mg/m2
CMF, cyclophosphamide 600 mg/m2, methotrexate 40
mg/m2, 5-fluorouracil 600 mg/m2 LABC, locally
advanced breast cancer q3w, every 3 weeks q4w,
every 4 weeks
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Neoadjuvant Herceptin significantly improves pCR
rates in the NOAH trial
pCR ()
90
Without Herceptin With Herceptin
80
70
p0.004
60
p0.002
50
40
30
20
10
23
43
17
19
55
29
0
HER2 positive (n228)
HER2 positive (n62)
HER2 negative (n99)
HER2 negative(n14)
Total population
IBC population
pCR, pathological complete response in the
breastIBC, inflammatory breast cancer
Baselga et al 2007 Gianni et al 2007
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pCR rate in context IBC irrespective of HER2
status
Study
FAC ? mitoxantrone C melphalan SCT
D carboplatin (including non-IBC)
ET
E ?T
Chemotherapy
NOAH (trastuzumab)
ET
FAC or FAC T
FEC-HD
CAF or CEF
AT ? T ? CMF H
Baselga et al 2007, n31
pCR ()
A, doxorubicin C, cyclophosphamide D,
docetaxel E, epirubicin F, 5-fluorouracil HD,
high-dose 5-fluorouracil (750 mg/m2) SCT, stem
cell transplantation
Baselga J et al ECCO 2007 Abs O2030
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NOAH cardiac safety
Patients
HER2 negative(n99)
LVEF worst value
HER2 positive

• H(n114)
• 75
• 21
• 2
• 2

- H(n113) 84 15 1 0

• LVEF worst value
• no change
• absolute decrease 10
• or lt20
• absolute decrease 20
• CHF responsive to treatment

87 12 1 0
LVEF, left ventricular ejection fraction Two
patients experienced LVEF declines to lt45 one
patient during H who withdrew from study and one
patient after completing H as per protocol
Gianni et al ASCO Breast 2007, Abs 144
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Trastuzumab for EBC has changed approaches to
treating breast cancer1

• During the first 10 years, it is predicted that
  the use of trastuzumab will result in an annual
  decline in MBC patients of 2.51
• Trastuzumab treatment of HER2 EBC is expected to
  prevent almost 28,000 women from developing
  metastases over a 10-year period in five EU
  countries alone, including the UK, which may
  result in a similar number of breast cancer
  deaths being avoided1

Adapted from Reference 1
According to our model, trastuzumab will be
one of the rare examples of current drugs
actually changing the epidemiology of a disease
Weisgerber-Kriegl et al. 20081
Weisgerber-Kriegl et al. ASCO 2008 Abs 6589
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Summary

• Trastuzumab remains the cornerstone of adjuvant
  systemic therapy
• 12 months remains current standard but duration
  question remains important eg HERA 1 v 2 yrs
  shorter duration therapy 3-6months being tested
• Real alternatives to anthracyclines now available
  TCH
• Addition of novel therapeutics (e.g. Bevacizumab,
  Lapatinib) may offer more patients the potential
  for cure
• Adjuvant trastuzumab is changing the natural
  history of the disease
• Neoadjuvant trastuzumab promising safe and
  effective