Die Behandlung der Patientin mit HER2 positiven MACA J. Huober Brustzentrum, St. Gallen DESO 16.2.2012
Die Behandlung der Patientin mit HER2 positiven MACA
J. Huober
Brustzentrum, St. Gallen
DESO
16.2.2012
erb-b1
EGFR
HER1
neu
Erb-b2
HER2
Erb-b3
HER3 Erb-b4
HER4
HR
G
(NR
G1
)
Tyrosin
kinase
Domäne
Liganden
bindende
Domäne
Transmembranärer
Anteil
Die EGFR/ HER Familie
Paul Ehrlich Royal Society, London, 1900
"I refer here to the production of "Antikörper" against cells of the higher animal organization, e.g. ciliated epithelium, spermatozoa, kidney cells and leucocytes. These "Antikörper" are also of a complex nature. They obey the already described law of elective absorption, and their origin is in keeping with the side-chain theory. It is to be hoped that such immunizations as these, which are of great theoretical interest, may also come to be available for therapeutic application. The idea has already been mooted by v. Dungern, of attacking epithelial new formations, particularly carcinoma, by means of specific "anti-epithelial" sera,..... But even if in the immediate future no great practical success is attained, we must remember that we are only at the very beginning of a rational investigation of properties of cells which hitherto have been far too
lightly regarded"
Trastuzumab beim HER2 positiven MACA
Ist ein monoklonaler humanisierter Antikörper
Hat unterschiedliche Wirkungsweisen
- blockiert HER2 Signalweg
- fördert antikörperabhängige celluläre Toxizität
- verhindert HER2 shedding
Zulassung 1998 (metastasiert) und 2006 (adjuvant)
Verbessert das PFS (12 Mo) und OS (32 Mo) bei MBC
Verbessert das DFS (HR 0.54) und OS (HR 0.66)
in der adjuvanten Situation
Hat die Behandlung des HER2 positiven MACA grundlegend
verändert und als separate molekulare Entität etabliert
OFFENE FRAGEN – Trastuzumab
Therapiedauer adjuvant
Treatment beyond progression
Sequentiell – gleichzeitig zu CHT
Resistenzmechanismen
Integration neuer anti-HER2 Substanzen
OFFENE FRAGEN – Trastuzumab
Therapiedauer adjuvant 1 Jahr
Treatment beyond progression Ja
Sequentiell – gleichzeitig zu CHT eher gleichzeitig
Resistenzmechanismen viele Kandidaten
Integration neuer anti-HER2 Substanzen duale Blockade
Integration neuer Substanzen Pertuzumab und Lapatinib
HER2
Dimerisierungs- domäne
Pertuzumab
HER3
Trastuzumab
Subdomäne IV
Lapatinib Pertuzumab
Pertuzumab and Trastuzumab nach Progression unter Trastuzumab
PFS 6 Mo
OR 24%
CB 50%
Baselga et al. J Clin Oncol 2010;28:1138–1144
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR pos
ER and PR neg
NeoSphere: hohe pCR Raten mit Pertuzumab
20.0
26.0
17.4
36.8
29.1 30.0
63.2
5.9
pC
R, %
9
5%
CI
H, trastuzumab; P, pertuzumab; T, docetaxel
7
29%
46%
17% 24%
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San Antonio Breast Cancer Symposium – Cancer Therapy and
Research Center at UT Health Science Center – December 6-10, 2011
10
Docetaxel-Trastuzumab-Pertuzumab vs
Docetaxel-Trastuzumab-Plazebo
PFS
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
n at risk
402 345 267 139 83 32 10 0 0 Ptz + T + D
406 311 209 93 42 17 7 0 0 Pla + T + D
Time (months)
Ptz + T + D: median 18.5 months
Pla + T + D: median 12.4 months
HR = 0.62
95% CI 0.51‒0.75
p<0.0001
∆ = 6.1 months
Pro
gre
ss
ion
-fre
e s
urv
ival
(%)
Stratified by prior treatment status and region
Table 4. Best Overall Response (n=76)
Response Cohort 1 (n=36)
N (%)
Cohort 2 (n=40)
N (%)
Confirmed response
Complete response
Partial response
16 (44%; 95% CI 23-67%)
3
13
9 (23%; 95% CI 8-40%)
0
9
Unconfirmed response
Complete response
Partial response
3 (8%)
0
3
5 (13%)
0
5
Stable disease 5 (14%) 16 (40%)
Progressive disease 10 (28%) 10 (25%)
Unknown 2 (6%) 0 (0%)
Clinical Benefit Rate
(confirmed CR or PR +
SD > 24 weeks)
17 (47%) 14 (35%)
Table 4. Best Overall Response (n=76)
Response Cohort 1 (n=36)
N (%)
Cohort 2 (n=40)
N (%)
Confirmed response
Complete response
Partial response
16 (44%; 95% CI 23-67%)
3
13
9 (23%; 95% CI 8-40%)
0
9
Unconfirmed response
Complete response
Partial response
3 (8%)
0
3
5 (13%)
0
5
Stable disease 5 (14%) 16 (40%)
Progressive disease 10 (28%) 10 (25%)
Unknown 2 (6%) 0 (0%)
Clinical Benefit Rate
(confirmed CR or PR +
SD > 24 weeks)
17 (47%) 14 (35%)
Lapatinib (1000 mg) +Trastuzumab
DM1: - Hemmt Tubulin Polymerisation und Microtubulin
Dynamik
- ist 25–500-fach wirksamer als Taxane in cytotoxischen
Assays.
T: - behält Trastuzumab Wirkung
T-DM1: Konjugat von Trastuzumab und DM1
T-DM1 3.6 mg/kg q3w IV
(n=67)
Met MACA HER2 pos - First-line:
T-DM1 vs Docetaxel und Trastuzumab
1:1 HER2-
positives
Met MACA
(N=137)
Trastuzumab ;6 mg/kg q3w IV
+ Docetaxel 75 or 100 mg/m2 q3w
(n=70)
OR PFS
58% 9.2 Mo
64% 14.2 Mo
!!! Weniger Neutropenien, febrile Neutropenien, Diarrhoe, Alopezie
mit T-DM1
Trastuzumab + Pertuzumab
+ Chemotherapy (paclitaxel, vinorelbine) *
Trastuzumab + Pertuzumab*
HER2-positive metastatic or locally advanced breast cancer
first line Therapy
Progression
T-DM1 T-DM1
Progression
Physicians’ discretion Physicians’ discretion
*Patients with hormone receptor positive disease will receive endocrine treatment when treated without chemotherapy
SAKK 22/10
Zusammenfassung
Das HER2 positive MACA ist eine separate molekulare Entität
Trastuzumab hat die Behandlung der HER2 positiven Erkrankung
grundlegend verändert und die Prognose verbessert
Duale Blockade des HER2 Rezeptors
- Bestätigt sich als effektive Therapie
- Trastuzumab Basis der dualen Blockade
- Chemotherapie als upfront Behandlung verliert an Bedeutung
T-DM1 wirksame, neue, wenig toxische Substanz
Herausforderungen:
- Entwicklung von Therapiestrategien bei multiplen Therapieoptionen
- Resistenzgetriggerte Selektion der optimalen
anti-HER Substanz
Grosse Effektivität der dualen HER2 Blockade
Nr Prior adjuvant
Tra
Prior adjuvant
CHT
PFS (mo)
OAS (mo)
Ref
CHT + Tra
Pac + Tra
235
92
0 %
0 %
72%
97 %
7.4
6.9
25
22
Slamon et al NEJM 2001
Doc + Tra 92 0% 71% 11.7 31 Marty et al JCO 2005
Doc + Tra
Nav + Tra
143
141
1%
0%
41%
50 %
12.4
15.3
35.7
38.8
Andersson et al
JCO 2011
Tra (+ CHT) 72 3% 47 % 8.1 31 Huober et al Oncology
2011
Doc + Tra 406 10% 47 % 12.4 nr Baselga et al NEJM 2011
First-line Studien Trastuzumab
References:
Slamon DJ, NEJM 2001:344: 783-792; Marty M J Clin Oncol 2005; 23: 4265-4274;
Andersson M J Clin Oncol 2011; 29: 264-271; Huober J Oncology 2011 ;81:160-66; Baselga J 2011 NEJM
Nr Prior adjuvant
Tra
Prior adjuvant
CHT
PFS (mo)
OAS (mo)
Ref
CHT + Tra
Pac + Tra
235
92
0 %
0 %
72% 1
97 %
7.4
6.9
25
22
Slamon et al NEJM 2001
Doc + Tra 92 0% 71% 2 11.7 31 Marty et al JCO 2005
Doc + Tra
Nav + Tra
143
141
1%
0%
41% 3
50 %
12.4
15.3
35.7
38.8
Andersson et al
JCO 2011
Tra (+ CHT) 72 3% 47 % 4 8.1 31 Huober et al Oncology
2011
Proportion of pts with adjuvant taxanes: 1 not reported, 2 0%, 3 0.7% / 2.1%, 4 5%
First-line Studien Trastuzumab
References:
Slamon DJ et al. NEJM 2001:344: 783-792; Marty M et al. J Clin Oncol 2005; 23: 4265-4274
Andersson M et al J Clin Oncol 2011; 29: 264-271; Huober J et al Oncology 2011 in press
Duale HER2 Blockade mit Trastuzumab und Lapatinib
Homodimere Heterodimere
Aktivierung der Signalwege durch Homo und Heterodimerisierung
HER1:HER1
HER2:HER2 HER3:HER3
HER4:HER4 HER1:HER2 HER1:HER3
HER1:HER4
HER2:HER4
HER3:HER4
+ + + + +
+
+
+
+
+
HER2:HER3
+
+
+
+
+
+
+ Signalaktivität
Entwicklung von Trastuzumab rasche Entwicklung bis zur Zulassung
Phase III
Klonierung von HER2
25.09.1998: Zulassung met MACA durch FDA
Phase II Phase I für rhuMAk HER2
muMAk 4D5
1993 1997 1994 1995 1996 1992 1998 1985 1991 1990 2006
5/06 Zulassung
Adjuvanz durch
EMEA