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