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%

Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

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