Treatment of Early Stage HER2-positive
Breast Cancer
(One size does not fit all)
8 November 2014
Edward H. Romond, M.D.
Professor of Medicine
Lucille Parker Markey Cancer Center
University of Kentucky
Lexington, KY
Slamon, et al. Science 1987;235:177-182
Amplified
Not Amplified
Amplified
Not Amplified
Focal HER2 Amplified Clones
Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(A) Trastuzumab.
M X Sliwkowski, and I Mellman Science 2013;341:1192-1198
Published by AAAS
Large Phase III Adjuvant Trastuzumab Trials
B31/N9831 AC → T
AC → TH
CIRG 006
AC → T*
AC → T*H
T*C*H
HERA: Chemo
± XRT
Observation
H x 1 year
H x 2 years
A = doxorubicin
C = cyclophosphamide
T = paclitaxel
H = trastuzumab
T* = docetaxel
C* = carboplatin
(AC → T → H)
NSABP B-31
NCCTG N9831
Arm 1
Arm 2
Arm A
Arm B
Arm C
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4
= paclitaxel (T) 175 mg/m2 q 3 wk x 4
= paclitaxel (T) 80 mg/m2/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Control: AC→T
Investigational: AC→T+H
N9831/B-31 Disease-Free Survival
2028 1959 1848 1747 1675 1611 1514 1293 910 619 350
2018 1887 1689 1529 1423 1329 1232 1027 705 449 255
% E
ve
nt-
Fre
e
Years from Randomization No. at risk
AC P
AC P+H
N Events
AC→P 2018 680
AC→P+H 2028 473 HRadj=0.60 (95% CI: 0.53-0.68)
P<0.0001
62.2%
73.7%
64.9%
76.8% 81.4%
69.5%
11.5%
San Antonio Breast Cancer Symposium, December 4-8, 2012
Perez, E et al. , J Clin Oncol, 2014
B-31/N9831 Overall Survival
2028 1995 1959 1897 1843 1785 1709 1506 1085 735 439
2018 1962 1883 1806 1730 1640 1534 1336 944 604 353
Years from Randomization
% S
urv
iva
l
No. at risk
AC P
AC P+H
84.0% 87.0% 89.8%
75.2%
79.4% 84.3%
HRadj=0.63 (95% CI 0.54-0.73)
P<0.0001
N Events
AC→P 2018 418
AC→P+H 2028 286
90.3%
93.2%
∆=2.9% ∆=5.5% ∆=7.6% ∆=8.8%
8.8%
San Antonio Breast Cancer Symposium, December 4-8, 2012
Perez, E et al. , J Clin Oncol, 2014
OS According to Subgroups ACTH vs. ACT (reference group)
Factor N
No. of Events
ACT ACTH HR
<40 years
40-49
50-59
60+ years
ER- and PR-
ER+ or PR+
0-2cm
2.1-5.0cm
5.1cm+
LN 0
LN 1-3
LN 4-9
LN 10+
Good
Intermediate
Poor
654
1373
1336
683
1828
2215
1598
2096
345
282
2144
1084
536
76
1123
2801
65
121
129
103
212
206
129
239
50
11
161
133
113
8
108
299
45
87
90
64
149
137
67
176
42
9
104
103
70
1
59
219
0.67
0.65
0.68
0.51
0.65
0.61
0.51
0.68
0.58
0.94
0.59
0.72
0.56
0.11
0.52
0.67
HR with 95% CI
0.5 1 1.5 2
Age
Hormone
Receptor
Tumor Size
Nodal
Status
Histologic
Grade
0.0
ER and PR Negative
AC P
AC P+H
N Events
AC→P 911 175
AC→P+H 917 103
21.5%
11.9%
B-31/N9831 Cumulative Incidence of Distant Recurrence as a First Event
ER and/or PR Positive
AC P
AC P+H
Cu
mu
lati
ve
In
cid
en
ce
(%
)
N Events
AC→P 1105 216
AC→P+H 1110 124
22.3%
12.7%
Years from Randomization
Δ= 9.6%
San Antonio Breast Cancer Symposium, December 4-8, 2012
Δ=9.6%
Does the degree of HER2 amplification correlate
with the degree of benefit from trastuzumab?
Reinholz M, SABCS 2007, abstr 36
Hazard Ratio of Benefit to Trastuzumab by HER2 FISH Ratio in NCCTG N9831
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00
11.0-15.0 (328)
< 2.0 (156)
2.0-5.0 (253)
5.0-8.0 (515)
8.0-11.0 (473)
≥ 15.0 (70)
p = 0.12
p = 0.05
p = 0.03
p = 0. 04
p = 0.96
p = 0.004
Ratio (N) p-value
Hazard ratio
What is the benefit of using trastuzumab with a
non-anthracycline containing regimen?
4 x AC 60/600 mg/m2
4 x Docetaxel 100 mg/m2
6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6
1 Year Trastuzumab
N=3,222
1 Year Trastuzumab
ACT
ACTH
TCH
Her2+ (Central FISH)
N+
or high
risk N-
4 x AC 60/600 mg/m2
4 x Docetaxel 100 mg/m2
BCIRG 006
Stratified by Nodes
and Hormonal
Receptor Status
BCIRG 006 Disease Free Survival (median follow-up 65 months)
Slamon D, et al. NEJM 365:1273-1283, 2011
Patients Events HR P
AC-TH 1074 185 .64 <0.001
TCH 1075 214 .75 0.04
AC-T 1073 257
What is the benefit of using trastuzumab after
chemotherapy is finished?
OBSERVATION n=1698
Women with locally determined HER2-positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
Randomization
1 year Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule
n=1703
2 years Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule
n=1701
After ASCO 2005, option of switch to Trastuzumab
HERA TRIAL DESIGN Accrual 2001 – 2005 (n=5102)
CT, chemotherapy; RT, radiotherapy
HERA: Disease Free Survival
Goldhirsch A, et al. Lancet 382:1021-1028,2013 53% of Observation received trastuzumab
Median follow-up
(% follow-up time
after selective crossover)
No. of DFS events
1 year trastuzumab
vs observation
127 vs 220
P<0.0001
218 vs 321
P<0.0001
369 vs 458
P<0.0001
DFS benefit
Favours 1 year trastuzumab Favours observation 0 1 2
HR (95% CI)
SUMMARY OF DFS ITT ANALYSES FOR 1 YEAR
TRASTUZUMAB VS. OBSERVATION
ACROSS ANALYSIS TIME POINTS
2005
(0%)
2006
(4.3%)
2008
(33.8%)
1 yr MFU
4 yrs MFU
2 yrs MFU
0.54
0.64
0.76
471 vs 570
P<0.0001
2012
(48.5%) 8 yrs MFU
0.76
Goldhirsch A, et al. Lancet 382:1021-1028,2013
Favours 1 year trastuzumab Favours observation 0 1 2
HR (95% CI)
OS benefit
SUMMARY OF OS ITT ANALYSES FOR 1
YEAR TRASTUZUMAB VS. OBSERVATION
ACROSS ANALYSIS TIME POINTS
Goldhirsch A, et al. Lancet 382:1021-1028,2013
Median follow-up
(% follow-up time
after selective crossover)
No. of deaths
1 year trastuzumab
vs observation
29 vs 37
P=0.26
59 vs 90
P=0.0115
182 vs 213
P=0.1087
2005
(0%)
2006
(4.1%)
2008
(30.9%)
0.76
0.66
0.85
1 yr MFU
4 yrs MFU
2 yrs MFU
278 vs 350
P=0.0005
2012
(45.5%)
0.76
8 yrs MFU
So is it better to start trastuzumab sequentially
after completion of chemotherapy or concurrently
with taxane chemotherapy?
NCCTG N9831 Trial Incorporating
Trastuzumab in Adjuvant Therapy
R
A
N
D
O
M
I
Z
E
HER2 positive
(FISH ratio ≥2
or
IHC 3+ >10%)
Arm A
Arm C
Arm B
AC T
AC T
H
H
AC T
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 51)
n=3,505
N9831: Sequential (B) vs. Concurrent (C)
Perez EA et al. J Clin Oncol 29:4491-4497, 2011
Efficacy Summary
Randomized Adjuvant Trastuzumab Trials
TRIAL Pts TREATMENT
DFS
(%) HR P
OS
(%) HR P
B31/N9831 2028
2018
AC→TH
AC→T
74*
62 0.60 <0.001
84*
75 0.63 <.001
CIRG 006 1074
1075
1073
AC→TH
TCH
AC→T
84**
81
75
0.64
0.75
<0.001
0.04
92**
91
87
0.63
0.77
0.001
0.038
HERA 1703
1698
chemo→H
chemo→obs
71*
65 0.76 <0.0001
83*
77 0.76 0.0005
FinHER 115
116
V/T+H→FEC
V/T→FEC
89†
78 0.42 0.01
96†
90 0.41 0.07
PACS04 260
268
FEC/ET→H
FEC/ET
73*
73 0.86 0.42
92*
93 1.27 NR
† - at 3 years * - at 8 years ** - at 5.5years
How long should trastuzumab be given in the
adjuvant setting?
Current Trials Assessing
Duration of Trastuzumab
SOLD
(Finland)
Docetaxel + Trast (nine weeks) → FEC X 3
Docetaxel + Trast (nine weeks) → FEC X 3 → Trast (total 1
year)
PHARE
(France)
Chemotherapy + Trast X 12 months
Chemotherapy + Trast X 6 months
Short-HER
(Italy)
Docetaxel + Trast (nine weeks) → FEC X 3
AC/FEC X 4 → Taxane + Trast X 4 → Trast (18 weeks)
Hellenic
Group
(Greece)
FEC X 4 → Docetaxel + Trast → Trast (total 12 months)
FEC X 4 → Docetaxel + Trast → Trast (total 6 months)
Persephone
(Great Britain)
Chemotherapy + Trast X 12 months
Chemotherapy + Trast X 6 months
HERA Chemotherapy → Trast X 1 year
Chemotherapy → Trast X 2 years
Dis
ease-f
ree s
urv
ival
(%)
Years from randomization
89.1%
86.7% 81.0%
81.6%
75.8%
76.0%
HERA: DFS FOR 2 YEARS VS. 1 YEAR
TRASTUZUMAB AT 8 YRS MFU
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
No. at risk
Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194
Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 367 0.99 (0.85-1.14) 0.86
1 year 1552 367
Goldhirsch A, et al. Lancet 382:1021-1028,2013
PHARE* Study design
trastuzumab 6 months
trastuzumab up to 12 months
1690 patients
stop trastuzumab
1690 patients
Clinical exam
LVEF 3
Mammography
6 9 12 15 18 21 24 30 mos
…
0
R
Up to 60 mos…
Stratification
1. ER pos / neg
2. Chemo: concurrent/sequential
* Protocol of Herceptin Adjuvant with Reduced Exposure
Pivot X, et al, Lancet Oncol 14:741-748, 2013
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00
Pro
babili
ty
1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Disease Free Survival
95.5 91.2 87.8 84.9
97.0 93.8 90.7 87.8
Events HR 95%CI p-value H 12m 176 H 6m 219 1.28 (1.05 – 1.56) 0.29
Pivot X, et al, Lancet Oncol 14:741-748, 2013
Equivalent
6 month Superior
6 month Non Inferior
6 month Inferior
A
B
C
D
E
.85 1 1.15 1.3 1.45 1.6 HR
Primary endpoint scenarii
PHARE trial
Pivot X, et al, Lancet Oncol 14:741-748, 2013
Cardiac Risk Assessment with
Anthracycline based regimens
Control
AC x 4 Paclitaxel
Investigational
AC x 4 Trastuzumab + Paclitaxel
0 mo.
18 mos.
6 mos.
9 mos.
3 mos.
0 mo.
18 mos.
6 mos.
9 mos.
3 mos.
B-31/N9831 LVEF Evaluation Schedule
Cont.
Hold*
Hold*
Relationship of LVEF to LLN
Absolute decrease of < 10%
Absolute decrease of 10%–15%
Absolute decrease of 15%
Hold*
Hold*
Hold*
Cont.
Cont.
Cont.*
*Repeat LVEF assessment after 4 weeks
– If criteria for continuation is met then resume trastuzumab • If 2 consecutive holds (or a total of 3 holds occur) then
discontinue trastuzumab
LLN = lower limit of normal.
Asymptomatic Patients
Rules for Trastuzumab Continuation
Based on Serial LVEF
Within normal limits
1%–5% below LLN
≥ 6% below LLN
0 1 2 3 4 5 6 7
01
23
45
Years Post Day 1 Cyc 5
%
HR=3.30;P-value- =0.00038
ACPH arm; 4.0%
ACP arm; 1.3%
NSABP B-31: 7 year cumulative incidence of cardiac events
Romond et al. J Clin Oncol 30:3792-3799, 2012
Risk Factors No. of
Pts
No. with CHF
(%)
P
value
Relative risk
(95% CI)
Age
< 50 486 11 (2.3%)
0.03
Ref. group
50-59 313 16 (5.1%) 2.3 (1.1-4.9)
60+ 148 8 (5.4%) 2.4 (1.0-6.0)
B-31: Potential Risk Factors for Congestive Heart Failure
Hypertension
medications
No 732 22 (3.0%) 0.02 2.3 (1.2 - 4.6)
Yes 192 13 (6.8%)
Baseline
LVEF
<54 70 9 (12.9%)
0 .0003
Ref. group
55-64 452 17 (3.8%) 0.3 (0.1 – 0.6)
65+ 425 9 (2.1%) 0.2 (0.1 – 0.4)
Left-sided tumor
& radiation
No 587 23 (3.9%) 0.71 0.9 (0.4-1.8)
Yes 351 12 (3.4%)
Cardiac Risk Score (based on evaluable cohort in NSABP B-31)
[7.0 + (0.04 x Age in years) – (0.1 x Baseline percent LVEF)] x 100
4.76
Romond et al. J Clin Oncol 30:3792-3799, 2012
0 20 40 60 80 100
0.0
0.1
0.2
0.3
0.4
Cardiac Risk Score
Pre
dic
ted
Pro
ba
bili
ty o
f CE
0 %
1
0 %
2
0 %
3
0 %
4
0 %
NSABP B-31 Cardiac Risk Assessment
Romond et al. J Clin Oncol 30:3792-3799, 2012
Examples:
(a)age 45, LVEF=65%, CRS=48.3
(b)age 65, LVEF=55, CRS=86.1
0 20 40 60 80 100
0.0
0.1
0.2
0.3
0.4
Cardiac Risk Score
Pre
dic
ted
Pro
ba
bili
ty o
f CE
0 %
1
0 %
2
0 %
3
0 %
4
0 %
a
b
NSABP B-31: Examples of Cardiac Risk Assessment
Summary of Cardiac Dysfunction in the
Large Adjuvant Trastuzumab Trials
Trial
Median
Follow-up
(years) Treatment Arms
Class III/IV
CHF (%)
Cardiac
Deaths
NSABP B-
31 7
AC→P + Trast
AC→P
4.0
1.3
1
1
NCCTG
N9831 5
AC→P+Trast
AC→P→Trast
AC→P
3.3
2.8
0.3
1
0
0
HERA 8 Chemo→Trast
Chemo→Observation
0.8
0
0
1
BCIRG 006 5
AC→D+Trast
D+Carboplatin+Trast
AC→D
2.0
0.4
0.7
0
0
0
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel
Low Risk and Node Negative Cancers
British Columbia Tumor
Registry
HER2
status
n 10 yr
RFS (%)
HER2- 1128 78.7
HER2+ 117 71.6
Stage I Only (T1N0)
Chia S et al. J Clin Oncol 2008 26:5697-5704
P=0.21
Valero et al, ASCO 2011, Abstr 553
BCIRG 006 Node Negative Patients
BCIRG 006 Disease Free Survival
Valero et al, ASCO 2011, Abstr 553
US Oncology Phase II Adjuvant Trial
Docetaxel + Cyclophosphamide + Trastuzumab
• Open label, Phase II
• 493 patients registered
• “Low risk” HER2 positive operable breast cancer: T1-2, N0-1a
• LVEF ≥ 50% by MUGA or echo
• Treatment regimen: (4 chemotherapy cycles)
– Docetaxel 75 mg/m² day 1
– Cyclophosphamide 600 mg/m² day 1
– Trastuzumab 4 mg/kg (loading) then 2mg/kg day 1,8,15
– Following completion of chemo: trastuzumab 6mg/kg q 21 days
to complete 1 year targeted therapy
Jones SE, et al. Lancet Oncol 14:1121-1128, 2013
Baseline Patient Characteristics
Jones SE, et al. Lancet Oncol
14:1121-1128, 2013
Disease-free Survival Overall Survival
Jones SE, et al. Lancet Oncol 14:1121-1128, 2013
US Oncology Phase II Adjuvant Trial
Docetaxel + Cyclophosphamide + Trastuzumab
Study Design
(APT Trial)
Tolaney S, et al. SABCS 2013, abstr S1-04
HER2+
ER+ or ER-
Node Negative
< 3 cm
Enroll
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
T
P
PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12
T T T T T T T T T T T T T
FOLLOWED BY 13 EVERY 3 WEEK DOSES
OF TRASTUZUMAB (6 mg/kg)*
Planned N=400
*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks
** Radiation and hormonal therapy was initiated after completion of paclitaxel
Patient Characteristics N %
Age
<50
50-70
≥70
132
233
41
33
57
10
Size of Primary Tumor
T1a ≤0.5 cm
T1b >0.5-≤1.0
T1c >1.0-≤2.0
T2 >2.0-≤3.0
77
124
169
36
19
31
42
9
Histologic Grade
I Well differentiated
II Moderately differentiated
III Poorly differentiated
44
131
228
11
32
56
HR Status (ER and/or PR)
Positive
Negative
272
134
67
33
Tolaney S, et al. SABCS 2013, abstr S1-04
San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center--December 10-14, 2013
50%
50%
San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013
Time (Months)
Re
curr
en
ce-F
ree
Su
rviv
al (
Pro
ba
bili
ty)
0 12 24 36 48 60
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60
0.0
0.2
0.4
0.6
0.8
1.0
All patientsNumber at risk
406 390 382 307 126 27
Recurrence-Free Interval
Tolaney S, et al. SABCS 2013, abstr S1-04
3-year RFI 95% Conf. Interval
99.2% 98.3% to >99.9%
Recurrence Free Interval=
•Invasive Local/Regional Recurrence
•Distant Recurrence
•Death from Breast Cancer
What about really small node negative breast
cancers ≤ 1.0 cm (T1a/b)?
Subset DFS and OS results
US Oncology Phase II Trial of TC + Trastuzumab
Jones SE, et al. Lancet Oncol 14:1121-1128, 2013
T1abN0M0 HER2+ Breast Cancers
Kaiser Permanente Northern California
• 3.3 million members
• 16,975 new Breast Cancers diagnosed
from 1/1/2000 to 12/31/2006
• HER2, ER, PR IHC mandatory on all cases
• 2,168 HER2+ (IHC 3+ or FISH ratio >2.0)
• 237 T1a or T1b
Fehrenbacher L, et al. J Clin Oncol 32:2151-2158, 2014
Recurrences:T1a+bN0 HER2+
Median F/U 5.8 yrs
N#
T1aN0
116
T1bN0
121
T1abN0
237
Invasive Cancer Recurrence
(%)
(4)
3.5%
(11)
9.1%
(15)
6.3%
Invasive Cancer Local
Recurrence Only (%)
(3)
2.6%
(4)
3.3%
(7)
2.9%
Invasive Cancer Distant
Recurrence (%)
(1)
0.9%
(7)
5.8%
(8)
3.4%
5 year Relapse Free Interval
(K-M) 97.4%
(95% CI, 92.1.,99.1)
91.1% (95% CI ,83.2,95.3)
94.2% (95% CI, 89.9, 96.7)
5 year Distant Relapse Free
Interval (K-M) 99.1%
(95% CI,93.9, 99.9)
94.0% (95% CI, 87.1, 97.3)
96.5% (95% CI, 92.8, 98.3)
Fehrenbacher L, et al. J Clin Oncol 32:2151-2158, 2014
Treatments Received by T1abN0M0
Received
Chemo
Received
Trastuzumab
Distant Recur
No Chemo
Distant Recur
with Chemo
All T1abN0 59/237 (24.9%) 20/237(8.4%) 5/178 (2.8%) 3/59 (5.1%)
Pre 2005 4/153 (2.6%)
2005-2006 16/84 (19.0%)
T1aN0* 15/116 (12.9%) 8/116 (6.8%) 1/101 (1.0%) 0/15(0%)
T1bN0 44/121 (36.3%) 12/121 (9.9%) 4/77 (5.2%) 3/44(6.8%)
Fehrenbacher L, et al. J Clin Oncol 32:2151-2158, 2014
*Note:48% ER negative
NCCN Breast Cancer Guidelines (v.1.2011)
T1/N0, HER2-positive
Tumor Size Recommendation
> 1cm Chemotherapy + trastuzumab*
0.6-1.0 cm Consider chemotherapy +
trastuzumab*
≤ 0.5cm No adjuvant therapy*
* endocrine therapy if HR +
Recently Reported Adjuvant Trials
TCH ± B
Node-Positive or High Risk Node-
Negative Breast Cancer HER2 Positive by
Central Testing
STRATIFICATION
• Number of positive Nodes (0, 1-3 4+)
• Hormone Receptor Status
BETH TRIAL
FEC → TH ± B
NSABP/CIRG CONTACT
Does improved neo-adjuvant response predict
improved disease-free and overall survival?
Collaborative Trials in
Neoadjuvant Breast Cancer (CTNeoBC): Association of pCR with EFS in Her2+ Subtype
pCR=ypT0/is ypN0
HR=0.39, P* < 0.001 HR=0.58, P* = 0.001 HR=0.25, P* < 0.001
Cortazar P, et al. Lancet 384:164–72,2014
Lapatinib
• Works intracellularly
• Binds reversibly to the
cytoplasmic ATP-binding site of
the kinase, thereby preventing
receptor phosphorylation and
activation
Lapatinib is an oral small-molecule
dual inhibitor of ERBB1 and ERBB2
tyrosine kinase:
Downstream signaling
cascade
1 + 1 2 + 2 1 + 2
Phase III NeoALTTO Trial
Baselga J et al. Lancet 379: 633–40,2012
Eligibility criteria:
• Operable HER2+
breast cancer
• T > 2 cm
• LVEF ≥ 50%
Stratify by:
• Tumor size (≤ 5 cm vs.
> 5 cm)
• HR status (positive vs.
negative)
• N status (0/1 vs. ≥ 2)
R
A
N
D
O
M
I
Z
E
S
U
R
G
E
R
Y
Lapatiniba 1000 mg/day
Trastuzumab 2 mg/kg/week (4-mg/kg
loading dose) × 18 cycles
Paclitaxel 80 mg/m2/week × 12 cycles
starting at week 7
Lapatinib 1500 mg/day
Paclitaxel 80 mg/m2/week × 12 cycles
starting at week 7
Trastuzumab 2 mg/kg/week (4-mg/kg
loading dose) × 18 cycles
Paclitaxel 80 mg/m2/week × 12 cycles
starting at week 7 a 750 mg/day with paclitaxel
(n = 455)
NeoALTTO: Efficacy
All differences between lapatinib/trastuzumab and trastuzumab alone are significant (P < .05).
Baselga J et al. Lancet 379: 633–40,2012 .
Lapatinib/
Trastuzumab
(n = 152)
Lapatinib
(n = 154)
Trastuzumab
(n = 149)
Pathologic CR, Breast 51% 25% 29.5%
By hormone receptor status
Positive 42% 16% 23%
Negative 61% 34% 36.5%
(n = 145) (n = 150) (n = 145)
Total Pathologic CR,
Breast +Nodes 47% 20% 28%
Objective Response (n = 152) (n = 154) (n = 149)
At week 6 67% 53% 30%
At surgery 80% 74% 70.5%
WILL DUAL ANTI-HER2 BLOCKADE IMPROVE DISEASE-FREE AND OVERALL SURVIVAL IN THE ADJUVANT SETTING?
ALTTO Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization
All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
All (neo)adjuvant
chemo prior to
anti-HER2 therapy
Lapatinib + 3-weekly Trastuzumab
Lapatinib Weekly
Trastuzumab
wash out
DESIGN 1: SEQUENTIAL ANTI-HER2 THERAPY AFTER ALL CHEMOTHERAPY (N= 4,613)
52 weeks
34 weeks 6 wks 12 weeks
Tras alone: 8 mg/kg 6 mg/Kg iv, q21 days Lap alone: 1500 mg po qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 8 mg/kg 6 mg/Kg iv, q21 days; L 1000 mg po qd
Weekly
Trastuzumab
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
Anthracycline-
based chemo first
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DESIGN 2: CONCURRENT ANTI-HER2 THERAPY AFTER ANTHRACYCLINE-BASED CHEMOTHERAPY (N= 3,337)
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P: weekly paclitaxel (80 mg/m2); 3-w D: q3 weeks docetaxel (75-100 mg/m2) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
34 weeks 6 wks 12 weeks
Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd
Weekly
Trastuzumab
Lapatinib*
28 weeks 6 wks 18 weeks
3-weekly Trastuzumab
Non-
anthracycline-
based chemo with
anti-HER2 therapy
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DESIGN 2B: CONCURRENT ANTI-HER2 THERAPY WITH A NON-ANTHRACYCLINE CHEMOTHERAPY (N= 431)
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D: q3 weeks docetaxel (75 mg/m2); carbo: carboplatin (AUC 6) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
28 weeks 6 wks 18 weeks
Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd
DISTRIBUTION OF THE STRATIFICATION FACTORS BY TREATMENT ARM
L + T
(N = 2,093)
T → L
(N = 2,091)
T
(N = 2,097)
Hormone Receptor Status
Positive 1,203 (57%) 1,205 (58%) 1,200 (57%)
Negative 890 (43%) 886 (42%) 897 (43%)
Timing of chemotherapy
Sequential (Design 1) 1,155 (55%) 1,143 (55%) 1,147 (55%)
Concurrent (Design 2 and 2B) 938 (45%) 948 (45%) 950 (45%)
Lymph Node Status
Not applicable (neoadjuvant chemotherapy) 168 (8%) 170 (8%) 181 (9%)
Node negative 845 (40%) 842 (40%) 844 (40%)
1-3 positive nodes 617 (29%) 617 (30%) 603 (29%)
>=4 positive nodes 463 (22%) 462 (22%) 469 (22%)
DISTRIBUTION OF PATIENT CHARACTERISTICS BY TREATMENT ARM
76
L + T
(N = 2,093)
T → L
(N = 2,091)
T
(N = 2,097)
Menopausal Status
Premenopausal 908 (43%) 929 (44%) 908 (43%)
Postmenopausal or male 1,185 (57%) 1,162 (56%) 1,189 (57%)
Pathological primary tumor size - largest diameter of invasive component
Missing 27 41 38
≤ 2cm 937 (45%) 938 (46%) 942 (46%)
> 2cm to ≤ 5cm 1,002 (49%) 980 (48%) 990 (48%)
> 5cm 127 (6%) 132 (6%) 127 (6%)
Histologic grade
Missing 10 7 9
Gx: Differentiation cannot be assessed 79 (4%) 61 (3%) 59 (3%)
G1: Well differentiated 51 (2%) 59 (3%) 48 (2%)
G2: Moderately differentiated 774 (37%) 793 (38%) 744 (36%)
G3: Poorly differentiated/undifferentiated 1,179 (57%) 1,171 (56%) 1,237 (59%)
DISEASE-FREE SURVIVAL (DFS) ANALYSIS
MFU = 4.5 yrs
*
* 97.5% CI
**
**p-value ≤ 0.025 required for statistical significance Piccart-Gebhart M. ASCO 2014, LBA 4
Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(B) Pertuzumab.
M X Sliwkowski, and I Mellman Science 2013;341:1192-1198
Published by AAAS
Randomized Phase II Study of Neoadjuvant
Pertuzumab Plus Trastuzumab: NeoSphere
Gianni et al. SABCS 2010; abstract S3-2.
Eligibility criteria:
• Operable or
locally advanced/
inflammatory
HER2+ breast
cancer
• Chemonaive
• Primary tumors >
2 cm
Primary endpoint: pCR rates
Secondary endpoints including: clinical response
R
A
N
D
O
M
I
Z
E
S
U
R
G
E
R
Y
Docetaxel (T)
Trastuzumab (H)
FEC q 3 weeks × 3
H q 3 weeks, cycles
5-17
Docetaxel (T)
Trastuzumab (H)
Pertuzumab (P)
FEC q 3 weeks × 3
H q 3 weeks, cycles
5-17
Trastuzumab (H)
Pertuzumab (P)
T q 3 weeks × 4 →
FEC q 3 weeks × 3
H q 3 weeks, cycles
5-17 Docetaxel (T)
Pertuzumab (P) FEC q 3 weeks × 3
H q 3 weeks, cycles
5-21
All q 3 weeks × 4 FEC: 5-fluorouracil/epirubicin/
cyclophosphamide
(n = 107)
(n = 96)
(n = 107)
(n = 107)
NeoSphere: Efficacy of Neoadjuvant
Pertuzumab Plus Trastuzumab
Gianni et al. SABCS 2010; abstract S3-2.
Pathologic Complete
Response
TH
(n = 107)
THP
(n = 107)
HP
(n = 107)
TP
(n = 96)
pCR in Breast 29% 46% 17% 24%
By Hormone Receptor
Status
ER+/PgR+ 20% 26% 6% 17%
ER–/PgR– 37% 63% 29% 30%
By Nodal Status
Node negative 21.5% 39% 11% 18%
Node positive 7.5% 6.5% 6% 6%
CR + PR + SDa 107 (100%) 106 (99%) 99 (92.5%) 94 (98%)
a Investigator assessed
T = docetaxel H = trastuzumab P = pertuzumab
TRYPHAENA
HER2-positive
EBC
centrally confirmed
(n = 225)
FEC
Trastuzumab
to complete
1 year
S
u
r
g
e
r
y
• All 3 arms were experimental
• Study dosing q3w: − FEC: 500 mg/m2, 100 mg/m2, 600 mg/m2
− Carboplatin: AUC 6
− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
− Pertuzumab: 840 mg loading dose, 420 mg maintenance
− Docetaxel: 75 mg/m2 (escalating to 100 mg/m2 if tolerated, in Arms A and B only)
Docetaxel
Cycles 1‒3 4‒6
Pertuzumab + trastuzumab
Pertuzumab + trastuzumab
FEC Docetaxel
Carboplatin
Docetaxel
Pertuzumab + trastuzumab C
B
A
Schneeweiss, et al. Annals Onc 24:2278-2284,2013
TRYPHAENA: Pathologic complete response
FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab;
T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab
Path
olo
gic
co
mp
lete
resp
on
se (
%)
FEC+H+P x3
T+H+P x3
(n = 73)
FEC x3
T+H+P x3
(n = 75)
TCH+P x6
(n = 77)
50.7
45.3
51.9
ypT0/is ypT0 ypN0
61.6
66.2
57.3
Schneeweiss, et al. Annals Onc 24:2278-2284,2013
Pathologic complete response by hormone
receptor status
ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide;
H, trastuzumab; P, pertuzumab; PR, progesterone receptor; T, docetaxel;
TCH, docetaxel/carboplatin/trastuzumab
Path
olo
gic
co
mp
lete
resp
on
se (
%)
ER- and PR-negative ER- and/or PR-positive
79.4
65.0
46.2 48.6
83.8
50.0
ypT0/is
FEC+H+P x3
T+H+P x3
(n = 73)
FEC x3
T+H+P x3
(n = 75)
TCH+P x6
(n = 77)
Schneeweiss, et al. Annals Onc 24:2278-2284,2013
Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(D) T-DM1.
M X Sliwkowski, and I Mellman Science 2013;341:1192-1198
Published by AAAS
NSABP B-50-I/GBG 77/Roche BO27938 Katherine: Study Schema
Residual Invasive HER2 Positive Breast Cancer in Breast and/or Axillary Nodes after Neoadjuvant
Taxane/Trastuzumab ± Anthracycline
Randomization
T-DM1 3.6 mg/kg q3wk x 14 doses
Accrual goal - 1484 patients
Trastuzumab 6 mg/kg q3wk x 14 doses
Radiation per standard guidance; hormone therapy if ER or PgR pos
A Final Question: Does the standard definition of
HER2 positivity mean the same thing as a
predictor of response to trastuzumab +
chemotherapy in the adjuvant setting as it does
for metastatic breast cancer?
B-31: distribution of cases according
to central HER2 assay
IHC=0 IHC=1 IHC=2 IHC=3 unk
FISH- 25 87 62 31 2
FISH+ 9 32 84 1457 6
“Central assay negative”
Paik, ASCO 2007, abstr 511
N #Event HR p-value 92 25 0.64 0.16
81 19
0 1 2 3 4 5 6 7
020
4060
8010
0
NSABP B-31:FISH Negative, IHC 0,1+,2+
Time from Randomization
% D
isea
se-F
ree
ACT
ACTH
NSABP B-31 Updated 2009 Disease Free Survival
FISH Negative, IHC 0, 1+, 2+ Breast Cancer Pts.
HR=0.64, p=0.16
0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000
Case
6
7
8
9
10
11
12
13
14
15
HE
R2
by
RT
-PC
R (
rela
tive
to r
ef g
en
es;
log
2)
Cut-off
Based on
IHC/FISH
0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000
Case
6
7
8
9
10
11
12
13
14
15
HE
R2
by
RT
-PC
R (
rela
tive
to r
ef g
en
es;
log
2)
Cut-off
Based on
IHC/FISH
HER2 expression is a continuous variable
Hard to imagine that these two tumors
respond differently to trastuzumab
Slide courtesy of S Paik
Summary of take-home messages
• Virtually all invasive breast cancers should be tested for HER2.
HER2 testing must be done in laboratories with rigorous quality
controls.
• Addition of one year of trastuzumab to adjuvant chemotherapy
decreased the rate of breast cancer events by 25-40% in the large
adjuvant trials. Focally positive cancers also derive similar benefit.
• The inclusion of pertuzumab along with trastuzumab and
chemotherapy in pre-operative treatment of early stage disease is
now a FDA approved standard of care. NCCN 2014 guidelines also
provide for option to include pertuzumab concurrent with
chemotherapy and trastuzumab in the adjuvant AC-TH and TCH
regimens.
Summary of take-home messages
• Cardiac monitoring must be done in all patients treated with adjuvant
trastuzumab with appropriate holds when indicated. Most patients
recover normal ejection fractions if holding rules are followed.
• In B-31 the combination of age and baseline LVEF correlates with
risk of CHF when trastuzumab/paclitaxel is used following AC.
• Radiation and hormone therapy may be given after chemotherapy
concurrently with trastuzumab.
• Neo-adjuvant trials are appropriate for studying new targeted agents
for specific patient subsets but appropriate patient selection for
incorporating new agents in adjuvant trials is critical.
• The criteria of HER2 positivity for discerning adjuvant trastuzumab
benefit is being studied further in a prospective randomized trial
(NSABP B=47).
Thank you!