Are We About To Cure HER2Positive Breast Cancer?
Carlos L. Arteaga, M.D.
Departments of Medicine and Cancer Biology
Breast Cancer Research Program
Vanderbilt Ingram Comprehensive Cancer Center
Vanderbilt University School of Medicine
HER2/Neu (ErbB2) oncogene is associated
with poor prognosis in breast cancer
HER2 gene
amplification (Southern)
Median Survival
HER2 overexpression
HER2 normal
HER2 protein
overexpression (IHC)
3 yrs
6-7 yrs
Slamon et al. Science 237:177, 1987
HER2 (ErbB2) is Oncogenic
Control
HER2
HER2
Soft Agar
Ligands
Ligands and Receptors of the HER (ErbB) family
EGFR/ErbB1
HER1
EGF
TGFa
Amphiregulin
HB-EGF
Betacellulin
Epiregulin
ErbB2
HER2
?
ErbB3
HER3
Heregulin
(Neuregulin)
ErbB4
HER4
Heregulin
HB-EGF
Betacellulin
Epiregulin
EC
100
44
36
48
Ligand
binding
IC
100
82
59
79
Tyr-Kinase
100
33
24
28
C-terminus
Some facts about the HER2 receptor
network and HER2+ breast cancer
• HER2 is the most potent kinase and HER2HER3 the most potent signaling dimer of this
receptor network
• The main survival program activated by the
HER (ErbB) network is the PI-3 kinase/Akt
pathway
• The antibody trastuzumab and the tyrosine
kinase inhibitor lapatinib are approved by the
FDA for the treatment of HER2+ breast
cancer
EGF30001: Phase III trial of paclitaxel ± lapatinib
in first line or metastatic breast cancer
No benefit from lapatinib when analyzing the whole cohort
Benefit from the addition of lapatinib to paclitaxel
was significant in patients with HER2+ cancers
Adjuvant trastuzumab prolongs survival of
patients with HER2+ breast cancer
% Surviving disease-free
100
87.1%
90
80
Control
(261 events)
70
Trastuzumab
(133 events)
85.3%
75.4%
67.1%
60
p<0.0001
HR=0.48
0
0
50
1
2
3
4
5
Years after randomization
No. at risk
Control
Trastuzumab
3351
1679
1672
2379
1162
1217
1455
689
766
801
374
427
133
59
74
0
0
0
Romond, Perez, Bryant, et al. NEJM 2005
Lapatinib prolongs progression-free survival
after trastuzumab (Geyer et al. NEJM 2006)
% patients free from progression*
Lapatinib +
Capecitabine
Capecitabine
No. of pts
160
161
Progressed or died* 45 (28%)
69 (43%)
Median TTP, wks
19.7
36.9
Hazard ratio (95% CI)
0.51 (0.35, 0.74)
P-value (log-rank, 1-sided)
0.00016
100
90
80
70
60
50
40
30
20
10
0
0
1
0
2
0
3
0
4
0
5
0
6
0
Time (weeks)
* Censors 4 patients who died due to causes other than breast cancer
70
Processing of trastuzumab-DM1 conjugate
Linker: MCC
Derivative of
Maytansine
Trastuzumab
HER2
Targetdependent
cytotoxic
activity
• Normal-tissue
target expression
• Fc-mediated
uptake
• Non-specific
uptake
Trastuzumab-DM1 but not trastuzumab induces apoptosis
and cell lysis and works in trastuzumab-resistant tumors
Lewis Phillips et al. Cancer Res. 68:9280, 2008
Krop et al. SABCS 2009 (late breaking abstract 710)
Key eligibility criteria
•
•
•
•
•
•
•
•
•
HER2+ disease by FISH or 3+ IHC by local lab
Measurable disease by CT scan as per RECIST
Prior anthracycline, trastuzumab, taxane, capecitabine and
lapatinib therapy in any setting
Prior treatment with two HER2-directed regimens in the
metastatic setting
Documented progression on their most recent treatment
regimen
No history of significant cardiac disease; left ventricular
ejection fraction (LVEF) ≥50%
No history of Grade ≥3 hypersensitivity to trastuzumab or
toxicity requiring discontinuation
No Grade ≥3 peripheral neuropathy
No untreated or symptomatic brain metastases, or any
treatment for brain metastases within 3 months of first dose
Clinical activity of trastuzumab-DM1
(n=110)
Tumour response
IRF
(n=110)
Investigator
(n=110)
32.7
(24.1–42.1)
30.0
(22.0–39.4)
CR
0
1.8
PR
32.7
28.2
SD*
46.4
52.7
PD
18.2
13.6
UE
1.8
0.9
Missing
0.9
2.7
44.5
(35.1–54.3)
40.0
(31.1–49.3)
Objective response rate, %
(95% CI)
Clinical benefit rate, %
(95% CI)
IRF, independent review facility
Objective response – CR or PR determined by two consecutive tumour assessments at least 28 days apart
Clinical benefit – objective response or SD maintained for at least 6 months
Krop I et al. SABCS 2009 (late breaking abstract 710)
Implications
• Even in advanced stages, HER2+ tumors
remain HER2-dependent
• Single agent anti-HER2 therapies do not
inhibit the HER2 network completely
• Combinations of HER2-targeted drugs early in
the treatment of HER2+ breast cancers is
the rational way to go
• The optimal combination(s) of anti-HER2
agents up front may abrogate acquired
resistance, shorten the duration of therapy,
and dispense the need of chemotherapy
In order to induce an antitumor effect, anti-HER2
therapies should inhibit the PI3K/Akt pathway
Akt
BT474

+
HR5

250
160
+

lapatinib
P-Tyr
105
+
lapatinib
P-HER3
HER3
75
HER3
p85
p85 i.p.
P-Akt
Akt
Trastuzumab disrupts ligand-independent HER2/HER3/PI3K complexes
Yakes et al. Cancer Res. 62:4132, 2002; Junttila et al. Cancer Cell 15:429, 2009
Contributed by Jenny Chang (Baylor), SABCS 2008
300
250
Histoscore
Post-therapy (2 wks)
Pre-therapy
Inhibition of the HER2 with lapatinib is followed by
upregulation of HER3 in primary HER2+ tumors
200
150
100
50
p=0.01
0
HER3 pre
HER3 post
P-HER3 was also upregulated upon tx
No change in S473 P-Akt
Inhibition of P-HER2 was incomplete
Under review
In collaboration with Jenny Chang (Baylor)
BT474
lapatinib:
P-EGFR (Y1068)
EGFR
Upon inhibition of the HER2
kinase, HER2+ cells upregulate
total and activated HER3
P-HER2 (Y1248)
HER2
P-HER3 (Y1197)
P-HER3 (Y1222)
P-HER3 (Y1289) short
P-HER3 (Y1289) long
HER3
lapatinib
0
1 4
13 24 48
0
1 4 13 24 48
0
1 4 13 24 48
h
P-Akt (S473)
HER3
P-Akt (T308)
β-actin
Akt
BT474
SKBR3
SUM225
P-Erk
Erk
P-S6
Garrett J, Arteaga CL. Unpublished
S6
β-actin
0
1
4 13 24 48
SKBR3
0
1
4 13 24 48 h
Is compensatory upregulation of HER3
a possible mechanism of drug resistance?
Activation of Compensatory Pathways
IGF-IR
Met
ErbB3
P p85
P
lapatinib
PI3K
p110
Akt
p85 P IRS-1
PI3K
p110
P
Akt
Tyrosine kinases that can activate HER3: MET, EGFR, FGFR2,
Src, IGF-IR (?), BRK (?)
Implication: Upregulation of HER3 provides a mechanism
for maintenance of PI3K and escape from drug action
Inhibition of either HER2 or PI3K/Akt results in upregulation
of HER3 RNA and protein and P-HER3
BT474
normalized expression (ddCt)
qRT-PCR for HER3
SKBR3
15
12
9
6
3
0
0
1
4
13
24
48
hrs post-lapatinib treatment
BT474
BEZ235
0
1 4 13 24 48
SKBR3
0
1 4 13 24 48 h
P-HER3
(Y1289)
HER3
β-actin
Active Akt mutant limits lapatinib-induced
upregulation of HER3 mRNA and protein
Upregulation of HER3 upon inhibition of HER2 blockade
is dependent on PI3 kinase and FoxO3a
1 h lap
DMSO
2° Ab alone
FOXO3a
DMSO
13 h lap
24 h lap
C
C
C
N
N
FOXO3a
4 h lap
N
TO-PRO-3
Merge
RNAi of HER3 enhances lapatinib action against HER2+ br ca cells
BT474
ctrl
SKBR3
HER3
ctrl
HER3 siRNA
HER3
β-actin
0.33 µM lap
1.0 µM lap
1.2
mean area of acini (% of control)
siHER3
siCTRL
DMSO
*
ctrl siRNA
HER3 siRNA
1.0
0.6
* p<0.05
0.4
*
0.2
*
0.0
dmso
Lap 0.33
Lap 1.0
Neutralizing HER3 monoclonal antibody sensitizes
BT-474 xenografts to lapatinib
ctrl, n=9
1300
lap, n=8
tumor volume (mm3)
1100
AMG-888, n=8
lap+AMG-888, n=9
900
*
700
*
*
#
##
##
500
#
300
*
** **
**
**
23
27
34
37
100
7
9
Tx
13
16
20
days
30
* p<0.05, ** p<0.01 versus control
# p<0.05, ## p<0.01 versus lapatinib
Combination of lapatinib and AMG-888 inhibits FDG-PET
p=.00005
2 weeks
p=.006
p=.034
lap +
AMG-888
lapatinib
control
Pre-tx
p=.029
p=.000007
Biomarkers of combined HER2 and HER3 inhibition
lap
lap+AMG-888
membrane H-score
HER3
ctrl
3
2
1
*
0
ctrl
lap
lap+AMG
H-score
P-Akt
140
130
120
*
110
100
% positive nuclei
FoxO3a
ctrl
lap
lap+AMG
*
35
25
15
5
ctrl
lap
lap+AMG
Trastuzumab inhibits recovery of P-HER3 after lapatinib
lapatinib
1
4 13 24 48 1 4 13 24 48 h
BT474
0
lap + trast
P-HER3
β-actin
SKBR3
0 1
4
13 24 48
1 4 13 24 48 h
P-HER3
β-actin
Src, MET, FGFR2, IGF-IR,
EGFR inhibitors and pertuzumab
Did not block recovery of P-HER3
Garret J, …….., Arteaga CL, Unpublished
Phase III study to test if total HER2
blockade improves clinical outcome
Key Inclusion
• HER2+(FISH+/ IHC3+) MBC
• Progression on
• Anthracycline
• Taxane
• Trastuzumab
• Progression on most recent
trastuzumab regimen
Stratification Factors
• Visceral Disease
• Hormone Receptor
R
A
N
D
O
M
I
Z
A
T
I
O
N
Lapatinib 1500 mg/day PO
N=148
Crossover if PD after
4wk therapy (N=73)
Lapatinib 1000 mg/day PO
Trastuzumab 4 2 mg/kg IV qw
N=148
31
Study conducted and funded by GlaxoSmithKline
Lapatinib + trastuzumab improves OS compared to
lapatinib in patients progressing on or after trastuzumab
Blackwell KL, et al. J Clin Oncol 2010; 28;1124–1130
Neoadjuvant lapatinib randomized Phase III trial
neo-ALTTO (adjuvant lapatinib ± trastuzumab
treatment optimization) trial (n=450)
Summary
• Current therapeutic inhibitors of HER2 do
not inhibit output to HER3 and PI3K/Akt
completely
• Compensatory upregulation of HER3 function
occurs by transcriptional and posttranslational mechanisms
• To completely inhibit the HER2 network (and
the PI3K pathway), compensatory
upregulation of HER3 should be eliminated
• The best therapeutic strategy to eliminate
HER3 function remains to be determined
Anti-HER3 (ErbB3) strategies in
clinical development
• Human antibody (IgG1) AMG-888
(AMGEN-U3)
• Human antibody (IgG2) MM-121
(Merrimack-Sanofi)
• HER3 antisense EZN-3920 (Enzon
Pharmaceuticals)
PI3K/AKT pathway inhibitors in clinical development
Ansamycins bind the ADP/ATP
switch site in Hsp90
Protein Hsp70
Hip, etc
Hsp90
Protein
p23
ATP
IP
17AAG
Hsp90
Protein
ATP
p23 IP
Release of the
mature/refolded
protein
Protein
Hsp90
Protein
17-AAG
p23 IP
Ubiquination/
degradation
Proteins degraded:
EGFR/HER2
MET
Raf kinase
Steroid Receptors
Akt
CDK4
Hif1a
Tumour regressions only seen in heavily pretreated HER2+ patients
Best response and target lesion change (n=25)*
* One additional patient had complete regression of a single target lesion but overall response of progressive disease
based on non-target lesions. One patient withdrawn for clinical progression without radiological assessment
Response rates for novel HER2-targeting
agents after progression on trastuzumab
P<0.0001
90
Response rates (%)
80
70
60
50
40
30
N=31
N=66
17-AAG
Pertuzumab
N=45
N=112
20
10
0
Neratinib
T-DM1
Modi S et al, ASCO 2008; Gelmon KA et al, ASCO 2008; Swaby R et al, ASCO 2009; Burris HA et al, ESMO 2009
We have a good problem (many drugs) in HER2+ breast
cancer – we are just learning how to combine them now
• Pertuzumab (anti-HER2 antibody)
• Irreversible HER2 kinase inhibitors (neratinib)
• HER3 antibodies (AMG-888, MM-121)
• PI3K inhibitors (GDC-0941, XL-147, BKM120)
• Akt inhibitors (MK-2206)
• IGF-IR inhibitors (R1507, MK-0646, OSI-906)
• HSP90 inhibitors
• Trastuzumab-DM1 (fusion toxin)
• Bevacizumab and other angiogenesis inhibitors
• MET, Src, and TGFb inhibitors
Implications
• There are several 2-drug combinations that can aim
at completely inhibiting the HER2 network and its
output to PI3K
–
–
–
–
Lapatinib + trastuzumab
Trastuzumab + AMG-888
Trastuzumab + pertuzumab
Trastuzumab (or lapatinib) + a PI3K or a AKT inhibitor
– Trastuzumb-DM1 + a PI3K or a AKT inhibitor
• Neoadjuvant therapy provides a space where these
can be compared (using path CR as an endpoint)
• Some molecular phenotypes may be more sensitive to
some specific combinations (i.e., tumors with PI3K
pathway mutations)
• Although efficacy may be equivalent, toxicity and
cost will be major differentiating factors
Acknowledgements
Vanderbilt
Charles Manning
William Pao
Baylor (Houston)
Jenny Chang
Bhuvanesh Dave
Novartis
Carlos Garcia-Echeverria
Stanford
Anne Brunet
AMGEN-U3
Dan Freeman
Robert Radinsky
Thore Hetmann