Welche Targets, welche Substanzen bleiben nach ?· Welche Targets, welche Substanzen bleiben nach GATSBY,…

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  • Welche Targets, welche Substanzen bleiben nach

    GATSBY, RAINFALL & Co. fr die Therapie

    fortgeschrittener, gastrosophagealer Tumoren?

    Prof. Salah-Eddin Al-Batran

    Krankenhaus Nordwest

    UCT- University Cancer Center Frankfurt

  • 1. Murad, et al. Cancer 1993; 2. Vanhoefer, et al. J Clin Oncol 20003. Al-Batran, et al. J Clin Oncol 2008; 4. Cunningham, et al. N Engl J Med 2008

    5. Van Cutsem, et al. J Clin Oncol 2006; 6. Kang, et al. Ann Oncol 2009

    Magenkarzinom: berleben nach Erstlinientherapie

    BSC1

    FAMTX2

    PLF3

    FLO3

    ECF4

    EOF4

    DCF5

    XP6

    ECX4

    EOX4

    Median OS (months)

  • Lordick, Lorenzen et al Gastric Cancer 2014; 17(2):213-25

    HER2: pos. bei jedem 5.-6. Patienten

    Trastuzumab wirksam

    Lapatinib nicht ausreichend effektiv

    TDM1 nicht ausreichend effektiv

    Pertuzumab Prfung (Jakob Studie)

    Anti VEGF (anti-angiogen)

    Bevacizumab-Studie (AVAGAST) negativ

    Ramucirumab: wirksam in 2nd-Line

    Bang et al. Lancet 2010; 376: 687-697Satoh et al. J Clin Oncol 2014; 32(19):2039-49

    Ohtsu et al. J Clin Oncol 2011; 29: 3968-76

    Magenkarzinom Zielgerichtete Therapie

    Kang YK et al. ASCO GI 2016;

    Wilke et al. Lancet Oncol 2014Fuchs et al. Lancet 2014

  • HER2

  • 1520% of gastroesophageal cancers are HER2 positive

    Median survival for HER2 IHC 3+ patients 18 months!

    1. Bang, et al. Lancet 2010

    Trastuzumab improved outcomes in patients with HER2-positive tumours

    ToGA1

    (n=584)

    Al-Batran. Data on file0

    0.2

    0.4

    0.6

    0.8

    1.0

    Su

    rviv

    al p

    rob

    abili

    ty

    0 4 8 12 16 20 24 28 32 36

    11.8 16.0

    Time (months)

    HR=0.65(95% CI: 0.510.83)

    Events

    Trastuzumab + XC/FC 120

    XC/FC 136

    HER2 IHC

    HER2 SISH

  • Pertuzumab: HER-2 Dimerisierungsinhibitor

    HER2

    HER1, 3, 4

    Pertuzumab

    Pertuzumab blockiert die HER2 Dimerisierung und verhindert die ber den HER Signalweg vermittelte Tumorzellproliferation und berleben16

    Pertuzumab fhrt zu ADCC 7

    1. Agus DB, et al. Cancer Cell 2002; 2:127137; 2. Hughes JB, et al. Mol Cancer Ther 2009; 8:18851892; 3. Herbst RS, et al. Clin Cancer Res 2007; 13:61756181;4. Baselga J. Cancer Cell 2002; 2:9395; 5. Citri A, et al. Exp Cell Res 2003; 284:5465; 6. Franklin MC, et al. Cancer Cell 2004; 5:317328; 7. Scheuer W, et al. Cancer Res 2009; 69:93309336.

  • Jakob-Phase III Studie : Pertuzumab plus Trastuzumab

    plus Chemotherapie in der Erstlinientherapie

    Ergebnisse werden 2017 erwartet

  • VEGF/VEGFR

  • Anti VEGFR Antikrper Ramucirumab

    Ramucirumab versus BSC Paclitaxel + /- Ramucirumab

    REGARD RAINBOW

    Fuchs et al. Lancet 2013

    Wilke et al. Lancet Oncology 2014

  • FOLFIRI + Ramucirumab

    Paclitaxel + Ramucirumab

    R

    2

    1n=101

    Primrer Endpunkt: OS Rate nach 6 Monaten, Statistik ausgelegt auf experimentellen Arm. Kein statistischer Vergleich

    Progression nach 1st-line Platin + Fluoropyrimidin (+/-Epirubicin; +/-Docetaxel;+/-Trastuzumab)

    RAMIRIS: 2nd-line, randomisierte

    Phase II, Ram-Folfiri (AIO Studie)

  • Metastatic Gastric Cancer

    HER2 positive disease HER2 negative disease

    1L

    Doublet + trastuzumab

    Platinum/FP/trastuzumab

    (XP/trastuzumab)

    1L*

    Triplet

    Platinum/FP/docetaxel

    (FLOT)

    1L

    Doublet

    Platinum/FP (FOLFOX)

    Irinotecan/FP (FOLFIRI)

    **Patients refusing chemotherapy

    Unfit for paclitaxel

    (Indolent disease)

    2L

    Ramucirumab/paclitaxel

    3L

    Irinotecan/FOLFIRI or

    taxanes

    *Young patient

    Good ECOG PS

    High remission pressure

    High motivation

    2L

    Irinotecan/FOLFIRI or

    taxanes

    2L

    Ramucirumab monotherapy**

    Adapted from:

    http://www.nccn.org/professionals/

    physician_gls/PDF/gastric.pdf

    ECOG, Eastern Cooperative Oncology Group; FP, fluorouracil, cisplatin; FLOT, fluorouracil,

    leucovorin, oxaliplatin, docetaxel; FOLFIRI, leucovorin, fluorouracil, irinotecan; FOLFOX,

    leucovorin, fluorouracil, oxaliplatin; PS, performance status; XP, capecitabine, cisplatin.

  • TCGA: Molekulare Klassifikation

    Cancer Genome Atlas Research Network. Nature 2014

    9%

    22%20%

    50%

    Mutations

    Mutations

    Mutations

    RTKIs(Immun-therapie) PIK3CA

    PTENImmuntherapie

    ImmuntherapieRTKIs

    Neu Anstze!Stammzellen etc.

  • Immuntherapie

  • PD-L1 in gastric cancer

    Expression rate about 40%1

    More pronounced in intestinal type1

    Associated

    with better outcome in operable disease1

    Worse outcome in metastatic disease

    PD-1/PD-L1 pathway

    PD-1 is a negative co-stimulatory receptor expressed primarily on activated T cells. Binding of its ligands (PD-L1 and PD-L2) inhibits effector T-cell function2

    1. Kim, et al. Gastric Cancer 20142. Keir, et al. Annu Rev Immunol 2008

  • KEYNOTE-012- Pembrolizumab

    Monotherapie

    Metastasierte, PD-L1 + sophagus-Ca und AEG (n=23)

    Metastasierte, PD-L1 + Magenkarzinome (n=36)

    Bang, et al. ASCO 2015Doi et al, ASCO GI 2016

  • KEYNOTE-012- Pembrolizumab

    Monotherapie (Magenkarzinom)T

    umorverkleinerung

    Bang, et al. ASCO 2015

    Fazit: PD-L1 Inhibition aktiv beim MagenkarzinomOptimale Patientenselektion: unklar!

  • Trial Design

    JAVELIN Gastric 100,

    Merck KGaA

    1th line

    Maintenance with Avelumab versus Continuation of First-line

    FOLFOX or XELOX

    1th Line

    N=666, 2018

    PE: OS

    JAVELIN Gastric 300

    Merck KGaA

    3d line

    Avelumab vs. Irinotecan or Paclitaxel

    PE: OS

    N=330, 2017

    MK-3475-062/KEYNOTE-

    062), MSD

    1th line

    Pembrolizumab vs. Pembrolizumab + Cisplatin/FP vs. Cisplatin/FP

    PD-L1+ patients, N=750, 2019

    PE: PFS and OS

    MK-3475-061/KEYNOTE-

    061, MSD

    2nd line

    Pembrolizumab vs. Paclitaxel after platinum/FP

    N=720, December 2017

    PE: PFS and OS in PD-L1+ patients

    CheckMate 577

    Bristol-Myers Squibb

    Adjuvant

    Nivolumab vs. Placebo for resected esophageal or GEJ after

    neoadjuvant chemoradiation therapy and resection (Stage II/III)

    N=760, 2020

    PE: DFS and OS

    Phase III immunotherapy trials

  • Immuntherapiekonzepte

    Tumour

    Lymph node

    Blood vessel

    Chen & Mellman. Immunity 2013

    Release of cancer cell antigensChemotherapy

    Radiation therapyTargeted therapy

    1

    Cancer antigen presentationVaccines

    IFN-GM-CSF

    Anti-CD40 (agonist)TLR agonist

    2

    Priming and activationAnti-PD1

    Anti-PDL1Anti-CTLA-4

    Anti-CD137 (agonist)Anti-OX40 (agonist)Anti-CD27 (agonist)

    IL-2IL-12

    3

    Infiltration of T cells into tumours

    Anti-VEGF

    5

    Recognition of cancercells by T cells

    CARs

    6

    Killing of cancer cellsAnti-PDL1Anti-PD1

    IDO inhibitors

    7

    Trafficking of T cellsto tumours

    4

  • + EOX Chemotherapy *

    (immunogenic cell death)

    T Cell Infiltration

    Induction of Adaptive T cell immunity***

    IMAB362-coated Tumour Cell Debris

    Pro-Inflammatory, Chemoattractant Environment

    Cross-presentation by APCs**

    *Kroemer et al, 2013; **Rogers, Veeramani and Weiner, 2014; ***Biachini and Gianni, 2014EOX: Epirubicine, Oxaliplatin, Capecitabine

    Chimeric IgG1 backbone antibody Highly specific for CLDN18.2 CLDN18.2: Component of tight junction

    protein

    Modes of action: Antibody-dependent cellular

    cytotoxicity (ADCC)

    Complement-dependent cytotoxicity (CDC)

    In Combination with chemotherapy: enhances T-cell infiltration induces pro-inflammatory

    cytokines

    Al-Batran et al. ASCO 2016; #LBA4001

    FAST Studie IMAB362 Antikrper

  • Centers in GER (10), CZE (2), LAT (3), RUS (18), UKR (12),

    pts Randomized: N = 252

    Arm 1EOX

    N = 84

    Arm 2EOX/IMAB362 800/600 mg/m

    N = 77

    Arm 3EOX/IMAB362 1000 mg/m

    N = 85

    Excluded (n = 478) 44 pts w/o tumor tissue sample 352 pts CLDN18.2 neg/low expressors 82 pts eligibility criteria not fulfilled (19

    WoC, 63 others)

    Not treated (n = 6) 1 pt in Arm 1 (Anemia G2) 2 pts in Arm 2 (SAE/Anemia G3, WoC) 3 pts in Arm 3 (AE/incr. liver enzymes,

    SAE/deep vein thrombosis, WoC)

    Safety Set = Full Analysis Set (Pts with 1 treatment of any study drug)

    CLDN18.2 assessable: N = 686

    pts Treated: N = 246

    Consented for CLDN18.2 screen: N = 730

    Al-Batran et al. ASCO 2016; #LBA4001

    FAST Studie Patient Distribution

  • mPFS 5.6 vs. 7.2 moHR 0.36p=

  • Zusammenfassung

    Her2+ Magenkarzinom: Pertuzumab/Trastuzumab/Cx vs. Trastuzumab/Cx Her2-Blockade + Immuntherapie (phase1/2)

    Immuntherapie PD-1/PD-L1 AK in Phase III, 1.-3. Linie + adjuvant

    Wirksam? Mit oder ohne Cx? Kombinationen: CTLA-4 AK + PD1/PD-L1 AK (ohne Cx) und

    VEGF/VEGR AK + PD1/PD-L1 AK

    Neue Anstze Z.B. IMAB362 (Phase 2)

    Sonstiges Weiterentwicklung Ramucirumab, MMP-9, Multitarget

    TKIs, STAT Inhibitor

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