Die Behandlung der Patientin mit HER2 positiven .Die Behandlung der Patientin mit HER2 positiven

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  • 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

    Domne

    Liganden

    bindende

    Domne

    Transmembranrer

    Anteil

    Die EGFR/ HER Familie

  • Paul Ehrlich Royal Society, London, 1900

    "I refer here to the production of "Antikrper" against cells of the higher animal organization, e.g. ciliated epithelium, spermatozoa, kidney cells and leucocytes. These "Antikrper" 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 Antikrper

    Hat unterschiedliche Wirkungsweisen

    - blockiert HER2 Signalweg - frdert antikrperabhngige cellulre Toxizitt

    - 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

    verndert und als separate molekulare Entitt 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- domne

    Pertuzumab

    HER3

    Trastuzumab

    Subdomne IV

    Lapatinib Pertuzumab

  • Pertuzumab and Trastuzumab nach Progression unter Trastuzumab

    PFS 6 Mo

    OR 24%

    CB 50%

    Baselga et al. J Clin Oncol 2010;28:11381144

  • 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 0.510.75

    p

  • 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 25500-fach wirksamer als Taxane in cytotoxischen

    Assays.

    T: - behlt 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 Entitt

    Trastuzumab hat die Behandlung der HER2 positiven Erkrankung

    grundlegend verndert und die Prognose verbessert

    Duale Blockade des HER2 Rezeptors

    - Besttigt 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 Effektivitt 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

    +

    +

    +

    +

    +