Transcript Slide 1

Targeted therapy in Early
Breast Cancer
Paul Ellis
Guy’s Hospital, London
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?
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 ?
 Background
 HER2 positive EBC
Global Adjuvant trial update
Current UK practice
Application of targeted therapies
Neoadjuvant therapy
 Triple Negative EBC
 Summary
HER2+ EBC
Drugs to block HER Family Receptors
Monoclonal
antibodies
cetuximab, ABX-EGF,
EMD72000, h-R3,
trastuzumab, pertuzumab
Tyrosine kinase
inhibitors
EGFR: gefitinib, erlotinib
HER2: AEE-788, lapatinib
Pan-erb: CI-1033, HKI-569
Ligand
R
R
K
K
Signal Transduction
Adjuvant trastuzumab trials:
>13,000 patients
HERA (ex-USA)
BCIRG 006 (global)
Observation
IHC
IHC or
or
FISH
FISH
(n=5090)
(n=5090)
FISH
(n=3222)
1 year Herceptin
2 years Herceptin
Standard
chemotherapy
Herceptin 1 year
NCCTG N9831 (USA)
NSABP B-31 (USA)
IHC or
FISH
(n=2030)
IHC or
FISH
(n=3505)
Herceptin 1 year
Herceptin 1 year
Docetaxel
Docetaxel + carboplatin
Doxorubicin + cyclophosphamide
Paclitaxel
Piccart-Gebhart et al 2005;
Romond et al 2005;
Slamon et al 2006
ASCO 2007: Updated N9831/B-31 Joint
Analysis: DFS
100
92.3%
80
Alive and disease-free
(%)
86.4%
87.9
%
77.6
%
P < 0.00001
60
85.9%
73.1
%
AC  P+ H
(n=1,989; 222 events)
AC  P
(n=1,979; 397 events)
40
21% crossover
N=619 events
HR*adj = 0.48 (95% CI: 0.41-0.57)
*Nodes, receptor status, paclitaxel schedule, protocol
20
1,854
1,800
1,347
1,235
868
753
522
460
202
168
4
8
1
2
3
4
5
6
Number
at risk
0
0
Follow-up (yrs)
*Intent to treat events: recurrent disease, contralateral bc, 2nd primary, death
7
DFS benefit across 5 out of 6 trials
DFS benefit
Median follow-up, years
HERA CTxH 1 year
2
B-31 / N9831 ACPH
4
BCIRG 006 ACDH
3
BCIRG 006 DCarboH
3
FinHera VH / DHCEFb
3
PACS-04a CTxH 1 year
4
0
Favours
Herceptin
1
Favours no
Herceptin
2
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
Adjuvant trastuzumab trials:
proven OS benefit
Median follow-up,
years
2
HERA H 1 year
B-31 / N9831 ACPH
4
BCIRG 006 ACDH
3
BCIRG 006 DCarboH
3
FinHer VH / DHa
3
0
Favours
Herceptin
1
HR
Favours no
Herceptin
2
Joensuu et al 2006; Perez et al 2007;
Slamon et al 2006; Smith et al 2006
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 (p=0.03)
 Hypertensive medications (p=0.02)
 Baseline LVEF (p=0.0003)
 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
Incidence of trastuzumab-related
cardiac events in EBC trials
Severe
CHF, %
Cardiac
death, n
Arm
n
Asymptomatic
LVEF decline, %a
HERA
H 1 year
1,678
3.0
0.6
0
NSABP B-31
ACPH
947
NR
3.8cum (5
yr)
0
NCCTG N9831
ACPH
570
NR
BCIRG 006
0
ACDH
1,068
18.0
3.3cum (3
yr)
DCarboH
1,056
8.6
1.9
0
0
Slamon
et al 2006
0.4
Rastogi et al 2007
Suter et al 2007
Perez et al 2008
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?
Duration: Vast majority of evidence in
trials of 12 months
DFS benefit
Median follow-up, years
HERA CTxH 1 year
2
B-31 / N9831 ACPH
4
BCIRG 006 ACDH
3
BCIRG 006 DCarboH
3
FinHera VH / DHCEFb
3
PACS-04a CTxH 1 year
4
0
Favours
Herceptin
1
Favours no
Herceptin
2
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
What is the optimum scheduling of
Herceptin and chemotherapy?
Observation
1 year H
HERA
HR 0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
PACS-04
HR 0.012
0.010
HR=0.57
95% CI (0.30-1.09)
HR=1.04
0.008
0.006
0.004
Observation
1 year H
0.002
1-6
7-12 13-18 19-24 25-30 31-36
0
6
18
24
30
36
42
Months
Months since randomisation
Rate per 120
1,000
100
women/
80
year
60
12
NSABP B-31 / NCCTG N9831
AC→T
40
20
AC→TH
0
0
1
2
3
Years since randomisation
4
Romond et al 2005
Smith 2006
Spielmann et al 2007
48
Should we treat the “low risk”
HER2+patient?
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
10-year BCSS and RFS by HER2 and ER
in the pT1N0 cohort
HER2- (All)
HER2+ (All)
HER2+ER+
HER2+ER-
All cases
n = 3836
3336 (87%)
500 (13%)
204 (5.3%)
296 (7.7%)
10-year
BCSS
76.5
58.1
62%
55.4%
10-year RFS
68.5
49.5
52.2%
47.6%
T1pN0
n = 1245
1128 (90.6%)
117 (9.4%)
40 (3.2%)
77 (6.2)
10-year
BCSS
90.1
81.3
91.7
76.2
10-year RFS
78.7
71.6
77.5
68.3
BCSS, breast cancer-specific survival
RFS, relapse-free survival
Adapted from Norris et al. SABCS 2006. Poster 2031
Adjuvant Trastuzumab in ‘Low-Risk’
Patients:T1N0M0
 T1 (≤ 1 cm ) N0 excluded from adjuvant trials
 T1 (> 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 >1cm
Smith IE et al. Lancet 2007; 369: 29–36
Perez EA et al. ASCO 2007. Abstract #512
Slamon D. SABCS 2006
DFS benefit
across different tumour sizes
HERA
0-2 cm
>2-5 cm
>5 cm
N9831 / B-31
0-2 cm
>2-5 cm
>5 cm
BCIRG 006
ACDH
DCarboH
<2 cm
≥2 cm
<2 cm
≥2 cm
0.0
0.5
1.0
Favours Herceptin
HR
DFS, disease-free survival
1.5
2.0
Favours no Herceptin
2.5
Slamon et al 2006
Perez et al 2007; Smith et al 2007
Trastuzumab for Low Risk Breast Cancer
The 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)
HER2+ve ‘Low Risk’ Breast Cancer
Key Issues
 Should women with HER2+ve low risk breast cancer be
given CT and trastuzumab?
 Would women with HER2+ve low risk breast cancer
benefit from trastuzumab alone (or with endocrine therapy
if ER+ve?)
 If so would the gain from additional chemotherapy be
clinically worthwhile?
Anthracyclines – Do we need them in
HER2+ pts?
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)
BCIRG006: DFS and OS
Disease Free Survival - 2nd Interim Analysis
1.0
Absolute DFS benefits
(from years 2 to 4):
ACTH vs ACT: 6%
TCH vs ACT: 5%
0.8
92%
87%
87%
86%
83%
Overall Survival – 2nd Interim Analysis
82%
81%
0.7
1.0
77%
99%
98%
97%
Patients Events
2
3
4
5
0.9
91%
86%
0.7
Year from randomization
92%
93%
Patients Events
0.6
1
95%
1073
1074
1075
80
49
56
AC->T
AC->TH HR (AC->TH vs AC->T) = 0.60 [0.42;0.85] P=0.004
HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017
TCH
0.5
0
97%
0.8
192 AC->T
128 AC->TH HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001
HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003
142 TCH
% Survival
0.6
1073
1074
1075
0.5
% Disease Free
0.9
93%
0
1
2
3
Year from randomization
26
4
5
Cardiotoxicity and trastuzumab:
pivotal adjuvant trastuzumab trials
Trial
HERA1
NSABP B-312
Arm
Baseline
LVEF, %
Chemo
Chemo  H
>55
ACP
ACPH
LLN (typically >50)
NCCTG N98312 ACP
ACPH
ACPH
LLN (typically >50)
BCIRG 0063
LLN (typically >50)
ACD
ACDH
DCarboH
Severe
CHF, %
Contractile
dysfunction, %
0.6
3
3.8
15.9
2.5
3.5
14
17
1.9
0.4
18.1
8.6
CHF, congestive heart failure;
LLN, lower limit of normal
27Smith I et al. Lancet 2007;369:29–36; 2. Rastogi et al. ASCO 2007.
Abstract LBA513; 2. Perez et al. ASCO 2007. Abstract 512; 3. Slamon
D et al. SABCS 2006;Abstract 52
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
28
Combined Targeted agents in EBC
ALTTO Study Design
HER2+ invasive breast cancer
Centrally-determined HER2+
Surgery, complete (neo)adjuvant anthracycline-based
chemotherapy (approved list)
LVEF  50
1:1 RANDOMIZATION (N=8000)
*
Trastuzumab
for 1 yr
Lapatinib
for 1 yr
* = weekly paclitaxel x 12w;
as per investigator’s discretion.
Trastuzumab Trastuzumab
3-weekly +
for 3 mo
lapatinib
for 1 yr
6 wk break
Lapatinib x
7.5 mo
PIs. M Piccart, EA Perez
BETH: Study design
Early breast cancer,
HER2 +ve
(n=3600)
TH  FEC
or TCH
+ Avastin®
H + Avastin®
15 mg/kg/q3wk
to complete 1 year
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)
BEATRICE: BEvacizumab as adjuvant
treatment of triple negative breast cancer
Triple
negative
EBCa
(n=2530)
Chemo + bev
(1 year)
DFS
Efficacy
and
safety
follow-up
Chemo


aHER2−
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
& ER/PgR status confirmed centrally before randomisation; DFS, disease-free survival
Are taxane chemotherapy regimens better or worse
for “basal-like” cancers?
Sufficient Power
Formal test of
interaction HRs
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
Metastasis
Free
Survival
Randomise
FEC x 4Docetaxel x 4
Hypothesis taxane resistance
7 IHC markers
Nielsen “basal-like” definition
ER-ve
+ EGFr
And /or
CK5/6
P-Cadherin
CK14 CK17
Formal test of interaction
Sub-group and treatment effect
The Rest
The Rest of ER-ve
P Ellis, P Barrett-Lee, J Bliss
S Johnston - Trans-TACT TRICC
Neoadjuvant Trastuzumab
Neoadjuvant trial in HER2-positive
operable BC: pathCR rates
95% CI
90 (41–87%)
80 p=0.02
95% CI
(43–84%)
p=0.016
P + FEC alone
H + (P  FEC)
pCR (%)
70
60
50
40
66.7%
n=18
30
20
10
25.0%
n=16
65.2
%
26.3% n=23
n=19
0
DSMB reviewed data
(n=34)
Final results
(n=42)
Buzdar A, et al. Proc ASCO 2004;23:7
NOAH study:
neoadjuvant Herceptin for LABC
HER2-positive LABC
(IHC 3+ and/or FISH+)
HER2-negative LABC
(IHC 0/1+)
n=115
H + AP
q3w x 3
n=113
n=99
AP
q3w x 3
AP
q3w x 3
H+P
q3w x 4
P
q3w x 4
P
q3w x 4
H q3w x 4
+ CMF q4w x 3
CMF
q4w x 3
CMF
q4w 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
Neoadjuvant Herceptin significantly
improves pCR rates in the NOAH trial
pCR
(%)
90
80
70
Without Herceptin
With Herceptin
p=0.004
60
50
p=0.002
40
30
20
10
23
43
17
19
55
29
0
HER2 positive
(n=228)
HER2
negative
(n=99)
Total population
pCR, pathological complete response in the breast
IBC, inflammatory breast cancer
HER2 positive
(n=62)
HER2
negative
(n=14)
IBC population
Baselga et al 2007; Gianni et al 2007
pCR rate in context:
IBC irrespective
of
HER2
status
Study
FAC → mitoxantrone + C + melphalan + SCT
Viens et al 1998, n=17
Franco et al 2002, n=10
D + carboplatin (including non-IBC)
ET
Vandebroek et al 2003, n=19
E →T
Ditsch et al 2006, n=42
Chemotherapy
NOAH (trastuzumab)
ET
Ditsch et al 2006, n=51
Gonzales-Angulo et al 2004, n=48
FAC or FAC + T
FEC-HD
Veyret et al 2006, n=102
Baldini et al 2004, n=68
CAF or CEF
AT → T → CMF + H
Baselga et al 2007, n=31
0
10
20
30
40 50 60
pCR (%)
70
80
90
100
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 O#2030
NOAH: cardiac safety
Patients %
LVEF worst value
HER2 positive
+H
(n=114)
HER2 negative
(n=99)
-H
(n=113)
LVEF worst value
no change
75
absolute decrease ≥10%
or <20%
21
absolute decrease ≥20%
2
CHF responsive to treatment
2
84
87
15
12
1
1
0
0
LVEF, left ventricular ejection fraction
Two patients experienced LVEF declines to <45%: one patient
during H who withdrew from study and one patient after
Gianni et al ASCO Breast 2007, Abs 144
completing H as per protocol
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
2.5%1
 Trastuzumab treatment of HER2+
Adapted from Reference 1
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
“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
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