Exploring new and future standards of
care in HER2 positive breast cancer:
Improving efficacy in the adjuvant /
neoadjuvant setting
•Harold Burstein, MD
•Assistant Professor of Medicine
•Dana-Farber Cancer Institute
•Boston, MA
Studies of adjuvant trastuzumab therapy:
Summary
Patients (n)
BCIRG 006
NSABP B31 /
NCCTG N9831
HERA
FinHer
4,045
5,081
1,010
0.61
(0.5–0.75)
Year 2;
0.66 (0.47–0.91)
0.41
HR 0.63
HR 0.77
0.001
<0.0001
ns
0.001
0.04
0.52
(0.45–0.60)
0.54
(0.43–0.67)
0.42
(0.21–0.83)
0.64
0.75
<0.001
<0.001
=0.01
<0.001
=0.04
ACT vs
ACT + H
ACT vs
TCH
3,222
OS
HR
(95% CI)
P
DFS
HR
(95% CI)
P
 Interim analysis of the ALLTO trial (L, T, L+T, or TL) has reported L
is inferior to T in this setting; this arm has been discontinued
Romand et al, N Engl J Med. 2005;353:1673-84.
Perez et al, J Clin Oncol. 2011;29:3366-73.
Piccart-Gebhart et al, N Engl J Med. 2005;353:1659-72.
Smith et al, Lancet. 2007;369:29-36.
Joensuu et al, N Engl J Med. 2006;354:809-20.
Slamon et al, N Engl J Med. 2011;365:1273-83.
http://www.alttotrials.com/patients.php
1 year of adjuvant trastuzumab appears
optimal: Results from PHARE and HERA
 PHARE1
 3382 patients randomized to 6 or 12 months’ adjuvant
trastuzumab, median follow-up 47.2 months
 DFS 12 vs 6 months’ therapy:
HR = 1.28 (95% CI, 1.05–1.56)
 HERA2
 Target DFS events reached in April 2012 (725),
8 years median FU
 DFS: 2 vs 1 year therapy:
HR = 0.99 (95% CI, 0.85–1.14)
 OS: 2 vs 1 year therapy:
HR = 1.05 (95% CI, 0.86–1.28)
1. Pivot et al, Ann Oncol. 2012; 23(Suppl 9):ixe2#LBA5_PR.
2. Goldhirsch et al, Ann Oncol. 2012; 23(Suppl 9):ixe2#LBA6_PR.
NeoALLTO – Effect of dual HER2 blockade:
Study design
Lapatinib 1000 mg +
trastuzumab
4 mg/kg  2 mg/kg
(n=152)
HER2 +
≥2 cm
Lapatinib
1500 mg
(n=154)
R
Primary
endpoint:
pCR
Trastuzumab
4 mg/kg  2 mg/kg
(n=149)
Paclitaxel 80 mg/m2/wk
(6 weeks)
(12 weeks)
Baselga et al, Lancet. 2012;379:633-40.
NeoALLTO – Effect of dual HER2 blockade:
Pathologic CR
pCR (%)
75
Lapatinib + trastuzumab
(n=152)
***
51.3
Lapatinib
(n=154)
29.5
Trastuzumab
(n=149)
24.7
0
***p=0.0001 vs trastuzumab alone
Baselga et al, Lancet. 2012;379:633-40.
NeoSphere – Neoadjuvant pertuzumab +
trastuzumab: Study design
Trastuzumab + pertuzumab +
docetaxel
(n=107)
Trastuzumab + pertuzumab
(n=107)
HER2 +
≥2 cm
R
Pertuzumab + docetaxel
(n=96)
Primary
endpoint:
pCR
Trastuzumab + docetaxel
(n=107)
Docetaxel 75 mg/m2 q3w
Trastuzumab 8 mg/kg  6 mg/kg
Pertuzumab 840 mg/kg  420 mg/kg
(4 cycles)
Gianni et al, Lancet Oncol. 2012;13:25-32.
NeoSphere – Neoadjuvant pertuzumab +
trastuzumab: Pathologic CR
pCR (%)
50
*
45.8
Pertuzumab + trastuzumab
+ docetaxel
(n=107)
29
24
Trastuzumab + pertuzumab
(n=107)
Pertuzumab + docetaxel
(n=96)
16.8
Trastuzumab + docetaxel
(n=107)
0
*p=0.0141 vs trastuzumab + docetaxel
Gianni et al, Lancet Oncol. 2012;13:25-32.
APHINITY: Combined HER2 inhibition with
trastuzumab + pertuzumab – Study Design
Anthracycline based chemotherapy
3.4 cycles
3.4 cycles
A
T
Arm 1
S
U
R
G
E
R
Y
Central
confirmation
of HER2
status
Non-anthracycline based chemotherapy
Trastuzumab*
6 mg/kg 3-weekly
Pertuzumab**
420 mg IV 3-weekly*
R
6 cycles
F
O
L
L
O
W
TC
Arm 1
S
U
R
G
E
R
Y
U
P
3.4 cycles
3.4 cycles
A
T
Placebo
IV 3-weekly*
Start
treatment
within 1
week
KEY
U
P
6 cycles
10
TC
Arm 2
Y
E
A
R
S
Trastuzumab*
6 mg/kg 3-weekly
Placebo
IV 3-weekly*
Anti-HER2 therapy for a total of
1 year (52 weeks)
Randomization
within 7 weeks of
surgery
Pertuzumab**
420 mg IV 3-weekly*
R
10
Trastuzumab*
6 mg/kg 3-weekly
Arm 2
Central
confirmation
of HER2
status
Trastuzumab*
6 mg/kg 3-weekly
F
O
L
L
O
W
Y
E
A
R
S
Anti-HER2 therapy for a total of
1 year (52 weeks)
Randomization
within 7 weeks of
surgery
Radiotherapy and/or endocrine
therapy may be started after the
end of adjuvant chemotherapy
and in accordance with the
protocol recommendations
A
3-4 cycles of anthracycline
containing chemotherapy
Trastuzumab
T
3-4 cycles of taxane
containing chemotherapy
Pertuzumab
TC
Start
treatment
within 1
week
Radiotherapy and/or endocrine
therapy may be started after the
end of adjuvant chemotherapy
and in accordance with the
protocol recommendations
6 cycles of docetaxel +
capecitabine
Placebo
*Site personnel, patients, study
management teams and sponsor will
be blinded as to treatment assignment
* Trastuzumab must be given at a 8mg/kg loading dose at the trastuzumab cycle
** Pertuzumab mus tbe given at a 40 mg loading dose at the first pertuzumab cycle
http://www.ibcsg.org/Public/Health_Professionals/Open_Trials/IBCSG_39-11/Pages/IBCSG39-11BIG4-11_APHINITY.aspx
Summary
 Adjuvant trastuzumab has been demonstrated to improve DFS
and OS in patients with early stage HER2 positive breast
cancer
 1 year therapy appears to be optimal
 Dual HER2 inhibition with lapatinib and trastuzumab in the
neoadjuvant setting is superior to trastuzumab or lapatinib
alone
 The combination of the dimerization inhibitor pertuzumab and
trastuzumab has promising activity in the neoadjuvant setting
when combined with docetaxel
 The APHINITY trial is addressing the role of pertuzumab in the
adjuvant setting