Download trastuzumab

CURRENT PARADIGMS
in
HER2-Positive Breast Cancer
Neoadjuvant, Adjuvant & Metastatic Settings
Gunter von Minckwitz, MD, PhD
Chairman of German Breast Group
Germany
NEOADJUVANT SETTING
von Minckwitz et al. J Clin Oncol 2010
Untch M,, J Clin Oncol 2010
Eligibility Criteria
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Unilateral or bilateral untreated breast
cancer
Tumour 2 cm (palpation) or 1 cm (US)
Given indication for chemotherapy, e.g.:
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cT3 or cT4 (including inflammatory)
cT1-3 and ER/PgR negative
cT1-3 and ER/PgR positive and cN+ (for cT2) or
pNSLN+(for cT1)
LVEF  55%
No significant cardiac co-morbidity
Untch M,, EBCC 2008 & J Clin Oncol 2010
Von Minckwitz G, J Clin Oncol 2010
ER, estrogen receptor; PgR, progesterone receptor
LVEF, left ventricular ejection fraction
Efficacy of Trastuzumab
pCR
45
40
35
30
%
25
41,4
20
15
10
17,8
5
0
HER-2 negative
Untch M,, J Clin Oncol 2010
HER-2 positive
pCR (ypT0/is ypN0)
Efficacy of Trastuzumab
according to central HER2 status
60
50
40
%
30
pCR (ypT0/is ypN0)
49,7
20
10
17,8
16,4
HER-2 negative
HER-2
equivocal
0
HER2 central
positive
Long-term LVEF in patients receiving
3xA60T150→3xT175CMFx4 ± Trastuzumab
Gianni L, et al. NOAH study Lancet 2010
PCR predicts survival in HER2-positive
disease treated with EC-P+trastuzumab
Results of the TECHNO-study
M. Untch, personal communication
Geparquinto – Decision Tree
HER2 positive?
no
yes
EC-Doc + Trastuzumab
vs.
EC-Doc + Lapatinib
EC vs. EC + Bev
Response assessment
after 4xEC+/-Bev
no
yes
Doc vs. Doc + Bev
2nd randomisation:
Pw vs. Pw + RAD001
M. Untch, SABCS 2011, G. von Minckwitz SABCS 2011
pCR
(no invasive/non-invasive residual in breast & nodes
based on central pathology report review)
M. Untch, SABCS 2011,
Study Design
Invasive operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450
Stratification:
• T ≤ 5 cm vs. T > 5 cm
• ER or PgR + vs.
ER & PgR –
• N 0-1 vs. N ≥ 2
• Conservative surgery
or not
lapatinib
lapatinib
paclitaxel
R
A
N
D
O
M
I
Z
E
trastuzumab
paclitaxel
lapatinib
S
U
R
G
E
R
Y
F
E
C
trastuzumab
X
3
lapatinib
trastuzumab
trastuzumab
paclitaxel
6 wks
+ 12 wks
34 weeks
52 weeks of anti-HER2 therapy
J. Baselga, SABCS 2011
Cumulative Incidence of Diarrhea Grade ≥ 3
J. Baselga, SABCS 2011
Safety Population
Efficacy – pCR and tpCR
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response
J. Baselga, SABCS 2011
Comparison of pCR-rates
Neo-Sphere
Neo-Altto
G5 HER2+
G5 TNBC
Duration
12
12+6
24
24
Mono-Tx
Doc+H
Pw+H
EC-Doc+H
EC-Doc+B
ypT0/is ypN0
21.5
27.6
45.0
40.1*
Combo-Tx
Doc+HP
Pw+HL
n.a.
n.a
ypT0/is ypN0
39.3
46.9
*without pCRs in non-responders
CALGB 40601: HER2+ Neoadjuvant Trial
Paclitaxel x 16 wks
Trastuzumab
N=400
HER2+
Stage
II-III
S
U
R
Trastuzumab x 1y
Dose-dense
G
(recommended)
AC
E
(recommended)
R
Y
Paclitaxel x 16 wks
Lapatinib
Endocrine Rx
and RT prn
Paclitaxel x 16 wks
Trastuzumab + lapatinib
Breast imaging
Blood
MUGA
Tumor Biopsy - required
Breast imaging Blood
MUGA
Planned cross-validation with NeoALTTO
GeparSixto
Effect of Carboplatin in HER2+/triple neg BC
T4 or
T3 or
T>1cm, R*
Triple neg. or
HER2 pos.
Paclitaxel weekly +
Myocet weekly
Paclitaxel weekly +
Myocet weekly +
Carboplatin
Trastuzumab+Lapatinib in HER2 positive pts.
Bevacizumab in TNBC pts.
*stratified according to HER2/ER and Ki-67
Surgery
N=600
18 weeks
Conclusions
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Trastuzumab (H) doubles pCR-rates
pCR after H is a surrogate for survival
Combination with anthracyclines appears to
be safe
Double blockage of HER2 combined with a
few CT cycles reaches comparable pCR rates
as longer CT+Trastuzumab
Double blockage of HER2 opens the window
for CT-free regimen.
Case 1 with Locally Advanced
Breast Cancer
Age
30
Menaposual Status
Premenaposual
Surgery
-
Tumour size
5.5 cm
Pathology
Diagnosis
Ductal-invasive BREAST CARCINOMA
Grade
Grade III
Lymphatic
Nodes
cN2
HR
ER ( + ) , PR ( - )
HER2
IHC +++
Stage
cT3 cN2 cM0
Treatment
???
Case 1 :
What is your treatment option?
1) Preop AC-T + trastuzumab (9 weeks)
2) Preop AC-T + trastuzumab (T completed up to
52 weeks including adjuvant)
3) Preop TCH
4) Preop AC-T with no trastuzumab
5) Preop trastuzumab without CT
6) Primary surgery
Case 1 with Locally Advanced
Breast Cancer

Treatment approach according to AGO’s
perspective:
AC-TH → Surgery → H (up to 1 year)
Any question or contribution?...
METASTATIC SETTING
Single-Institution Retrospective Analysis
on 2091 patients with MBC
Dawood et al. J Clin Oncol 2010
First Randomized Phase III Study to
Investigate Continuation of Trastuzumab
(n=78)
Capecitabine 2,500 mg/m² d 1–14 q3w
R
(n=78)
Capecitabine 2,500 mg/m² d 1–14 q3w
+
Continuation of trastuzumab 6 mg/kg q3w
von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009
R, randomization
Clinical Response (RECIST)
100,0
90,0
OR: 27.0%
CB: 54.1%
80,0
OR: 0.0115
CB: 0.0068
(2-sided p)
CR: 7.7%
% of pts
70,0
60,0
OR: 48.0%
CB: 75.3%
CR: 2.7%
50,0
40,0
PR: 24.3%
PR: 40.4%
30,0
20,0
10,0
NC: 27.1%
NC: 27.2%
X
XH
0,0
von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009
OR = Overall response = CR+PR
CB = Clinical benefit = CR+PR+NC>24wks
Time To Progression
at median Follow up of 15.6 months
X : 5.6 (4.2 - 6.3) mos
XH : 8.2 (7.3 - 11.2) mos
P<0.0467
HR=0.69 (two-sided p=0.034;
one-sided p=0.017)
Progression to CNS:
X: 8.3% XH: 13.8%
PFS
X: 5.6 mos XH: 8.2 mos
P=0.026 two sided
von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009
Capecitabine + Lapatinib vs Capecitabine
Lapatinib +
Capecitabine
Capecitabine
No. of pts
198
201
Progressed or died*
82 (41%)
102 (51%)
Median TTP, months
4.3
6.2
Hazard ratio (95% CI)
0.57 (0.43, 0.77)
p-value
0.00013
70
* due to breast cancer
Cameron et al, Breast Cancer Res Treat 2008
Final Overall Survival Analysis
(N=151)
X : 20.6 (18.6 – 27.4) mos
XH : 24.9 (20.3 – 30.7) mos
HR=0.94 (two-sided p=0.74)
von Minckwitz G, et al. SABCS 2010 poster presentation
Overall survival after 2nd progression
cont of trast vs not (N=140)
von Minckwitz G, et al. SABCS 2010 poster presentation
….Trastuzumab and lapatinib beyond trastuzumab
K. L. Blackwell et al, JCO Mar 2010: 1124–1130
Phase II Trastuzumab / Pertuzumab Study
(BO17929)
Baselga et al. J Clin Oncol 20010
3
Beyond trastuzumab…T-DM1
IRF
(N=110)
Investigator
(N=110)
Objective Response Rate, %
(95% CI)
CR
PR
SD*
PD
UE
Missing
32.7
(24.1–42.1)
0
32.7
46.4
18.2
1.8
0.9
30.0
(22.0–39.4)
1.8
28.2
52.7
13.6
0.9
2.7
Clinical Benefit Rate, %)
(95% CI)
44.5
(35.1–54.3)
40.0
(31.1–49.3)
Tumor Response
IRF - Independent Review Facility *including unconfirmed partial remissions
Conclusion
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ADCC is an antibody specific key mechanism
for the action of trastuzumab
Trastuzumab is synergistic to various other
agents
In vivo data and clinical evidence support the
concept of “trastuzumab beyond
progression”; representing a paradigm shift
HER2 blockade throughout all stages of MBC
should be considered !
Case 2 with Metastatic Breast Cancer
Age
56
Menaposual Status
Postmenaposual
Surgery
TM-AD
Tumour size
4 cm
Pathology
Diagnosis
INVASIVE LOBULAR CARCINOMA
Grade
Grade II
Lymphatic
Nodes
6/22
HR
ER 0%, PR 0%
HER2
IHC 2+, FISH pos.
Stage
T2 N2 M°
Previous Treatment
4xAC4xDocTrastuzumab  Trastuzumab
Liver metastases at 5th month after completion
of adjuvant Trastuzumab treatment
Treatment
???
Case 2:
What is your treatment of choice?
1) Trastuzumab + Paclitaxel
2) Trastuzumab + Vinorelbine
3) Trastuzumab + Capecitabine
4) Lapatinib + Capecitabine
5) Trastuzumab + Lapatinib
6) CT without anti-Her2-agent
Case 2 with Metastatic Breast Cancer
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Treatment approach according to AGO’s
perspective:
Paclitaxel + Trastuzumab
Case 3 with Metastatic Breast Cancer
Age
50
Menaposual Status
Postmenaposual
Surgery
mod. Rad mastectomy
Tumour size
3.5 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade
Grade III
Lymphatic
Nodes
7/21
HR
ER 60%, PR 30%
HER2
IHC 3+
Stage
T2 N2 M1 (lung)
1st line treatment
DocH trastuzumab
(liver metastases during trastuzumab
monotherapy at 9th months )
2nd line treatment
???
Case 3:
What is your treatment option in 2nd line?
1) Vinorelbine + Trastuzumab
2) Capecitabine + Trastuzumab
3) Capecitabine + Lapatinib
4) Trastuzumab + Lapatinib
Case 3 with Metastatic Breast Cancer

Treatment approach according to AGO’s
perspective:
Capecitabine + Trastuzumab
Option 1
2nd Line Treatment for Case 3
Stage
T² N² M¹ (lung)
1st line
treatment
DocH Trastuzumab
Liver metastases during Trastuzumab monotherapy at
9th months
2nd line
treatment
Capecitabine + Trastuzumab
CNS metastasis after 6 months
3rd line
treatment
???
Case 3:
What is your treatment option in 3rd line?
WBRT followed by
1) Vinorelbine +Trastuzumab
2) Cisplatin+ Trastuzumab
3) Lapatinib + Capecitabine (if not used as 2nd line)
4) Trastuzumab + Lapatinib
Case 3 with Metastatic Breast Cancer

Treatment approach according to AGO’s
perspective:
Trastuzumab + Lapatinib
Any question or contribution?...
ADJUVANT SETTING
Case 4 with Early Breast Cancer
Age
45
Menaposual Status
Premenopausal
Surgery
BCS-SNL
Tumour size
1,2 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade,
Ki-67
Grade I,
24%
Lymphatic
Nodes
0/2
HR
ER 60%, PR 60%
HER2
IHC +++
Stage
cT¹ cN° M°
Treatment
???
Case 4:
What is your treatment option?
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1) CT + HT + Trastuzumab (9 weeks)
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2) CT + HT + Trastuzumab (52 weeks)
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3) CT + HT

4) HT + Trastuzumab (9 weeks)
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5) HT + Trastuzumab (52 weeks)
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6) HT
Case 4 with Early Breast Cancer
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Treatment approach according to AGO’s
perspective:
CT+Trastuzumab 52 wks + HT
FEC x6 or EC x4-Pac x12
Case 5 with Early Breast Cancer
Age
38
Menaposual Status
Premenaposual
Surgery
BCT-SNL
Tumour size
2,3 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade
Grade III
Lymphatic
Nodes
0/1
HR
ER ( - ) , PR ( - )
HER2
IHC %100 (+++)
Stage
pT2 pN° M°
Treatment
???
Case 5:
What is your treatment option?
1) CT + Trastuzumab (9 weeks)
2) CT + Trastuzumab (52 weeks)
3) CT
4) Trastuzumab (9 weeks)
5) Trastuzumab (52 weeks)
Case 5 with Early Breast Cancer

Treatment approach according to AGO’s
perspective:
EC-Pac + Trastuzumab 52 wks + HT
Any question or contribution?...