ESMO Preceptorship Targeted Therapy for Gastric Cancer

Professor Dr. Florian Lordick Professor of Oncology Director University Cancer Center Leipzig (UCCL) Disclosure

Personal financial interests (lecture honoraria, advisory boards, travel support) Amgen, Astellas, Astra Zeneca, Biontech, BMS, Eli Lilly, Elsevier, Infomedica, Medscape, MedUpdate, Merck, MSD, Roche, Promedicis, Servier, Springer-Nature, StreamedUp!, Zymeworks Institutional financial interests (research support) BMS Leadership roles German Cancer Society (Secretary), EORTC (Chairman of the GI Tract Cancer Group), ESMO (GI Faculty Coordinator, Director of Education Elect), International Gastric Cancer Association (President)

Molecular Anti- Immuno Chemotherapy Targeted angiogenic therapy therapy therapy

Compound Mechanism of action Treatment setting Reference

Cetuximab Anti-EGFR mAB 1st-line metastatic Lordick et al. 2013

Panitumumab Anti-EGFR mAB 1st-line metastatic Waddell et al. 2013

Gefitinib Anti-EGFR TKI 2nd-line metastatic Petty et al. 2017

Trastuzumab Anti-HER2 mAB 2nd-line metastatic Makiyama et al. 2018

Pertuzumab Anti-HER2 mAB 1st-line metastatic Tabernero et al. 2017

Lapatinib Anti-EGFR/HER2 TKI 2nd-line metastatic Satoh et al. 2014

Rilotumumab Anti-HGF mAB 1st-line metastatic Catenacci et al. 2017

Onartuzumab Anti-MET mAB 1st-line metastatic Shah et al. 2017

Napabucasin Anti-STAT3 2nd-line metastatic Shah et al. 2018

Bevacizumab Anti-VEGF mAB Perioperative Cunningham et al. 2017

Bevacizumab Anti-VEGF mAB 1st-line metastatic Ohtsu et al. 2011

Ramucirumab Anti-VEGFR-2 mAB 1st-line metastatic Fuchs et al. 2018

Olaparib PARP inhibitor 2nd-line metastatic Bang et al. 2017

Pembrolizumab PD-1-directed mAB 2nd-line metastatic Shitara et al. Lancet 2018

Deng N, et al. Gut 2012;61:673-84

Anti-EGFR negative phase-3: EXPAND, REAL3 Lordick et al. Lancet Oncol 2013 Waddell et al. Lancet Oncol 2013

Anti-MET negative phase-3: MetMab, RiloMet Shah et al. ASCO 2015 Cunningham et al. ASCO 2015

anti-FGFR preliminary phase-2: Shine Bang et al. ASCO 2015

KRAS

non druggable (?) Genomic DNA were extracted from flash-frozen tissues or cell pellets using a Qiagen genomic DNA extraction kit (Qiagen, Hilden, Germany), and profiled on Affymetrix SNP 6.0 arrays HER2 (Affymetrix, Santa Clara, California, USA) positive phase-3: ToGA Bang et al. Lancet 2010

Deng N, et al. Gut 2012;61:673-84

RTK gene copy number gains/losses in the patient cohort and cell models.

Secrier M et al. Nature Genetics 2017; 48: 1131-41.

diffuse, 2+ diffuse, 1+ Gamboa et al. Mod Pathol 2004;17:579-87

n Response mTTP (%) (Mon)

FUFOX + Cetuximab 65% 7,6 46 Lordick F, et al. BJC 2010 95% CI, 50–79% 95% CI, 5.0–10.1

Lordick F, et al. Br J Canc 2010; 102: 500-505

Cisplatin 80mg/m2 d1 R Capecitabine 1000mg/m2 2 x / day.; d1-14 q3w A N • Until radiographic progression or toxicity-related end of treatment • Primary endpoint: Progression-free survival (PFS) D Cisplatin 80mg/m2 d1 O Capecitabine 1000mg/m2 2 x tgl.; d1-14 q3w M Cetuximab 400mg/m2 loading dose, then 250mg/m2 / week

Lordick et al., Lancet Oncol. 2013; 14: 490-499

100 Log-rank P=0.011 EGFR FISH >4.0

n=8 60

40 Survival (%) Survival EGFR gene amplification: EGFR: 8.20 signals per nucleus EGFR FISH <4.0 EGFR/CEP7 ratio: 1.36 20

EGFR (red), chromosome 7 (green) n=28 0 0 200 400 600 Overall survival time (days)

Luber B,… Lordick F. BMC Cancer 2011;11:509

Lordick et al., Lancet Oncol 2012; 13: 33–42

• A good study hypothesis is important

• Preclinical evidence / biological plausibility is important

• Do not trust in overoptimistic phase II data

• Do correlative research and explore biomarkers!

• For rare subtypes of cancer - you need a strong network!

The Cancer Genome Atlas

Four subtypes - CIN: Chromosomal Instability - GS: Genomically stable - MSI: Microsatellite Instability - EBV: Epstein-Barr-Virus

TCGA Nature. 2014 Sep 11;513(7517):202-9

The Cancer Genome Atlas

Four subtypes - CIN: Chromosomal Instability - GS: Genomically stable - MSI: Microsatellite Instability - EBV: Epstein-Barr-Virus

Immunogenic

TCGA Nature. 2014 Sep 11;513(7517):202-9

Four subtypes - CIN: Chromosomal Instability - GS: Genomically stable - MSI: Microsatellite Instability - EBV: Epstein-Barr-Virus

TCGA Nature. 2014 Sep 11;513(7517):202-9

Anti-HER2 Trastuzumab prolongs survival in stage IV gastric cancer

▪ Therapeutically relevant HER2 overexpression: ~ 16% ▪ Intestinal > diffuse subtype ▪ Proximal > distal Tumors

Bang Y,…Lordick F. et al. Lancet 2010;376:687–97

HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridisation. Lordick F, Janjigian YY. Nat Rev Clin Oncol. 2016 Jun;13(6):348-60

The mechanism of action of pertuzumab and trastuzumab. Trastuzumab binds to the ECD IV of the HER2 receptor, preventing the spontaneous formation of homodimers (HER2–HER2) and ligand-independent heterodimers (HER2–HER3 and also HER2–HER1 and HER2–HER4). Pertuzumab binds to the dimerization domain of the HER2 receptor (ECD II), preventing the formation of ligand-induced HER2 heterodimers.

Metzger-Filho O, et al. Clin Cancer Res 2013; 19: 5552-5556

Arm A (n=388) Arm B (n=392) HR (95%CI) mPFS, months 8.5 7.0 0.73 (0.62, 0.86) Response rate (%) 56.7 48.3 Difference 8.4 (0.9, 15.9)

Tabernero J et al. Lancet Oncol. 2018 Sep 11. [Epub ahead of print

Heterogenous / focal HER-2 – expression in gastric cancer

Intestinal (gland forming) type Signet ring type

High Amplification

No Amplification

Lordick F, Janjigian YY. Nat Rev Clin Oncol. 2016 Jun;13(6):348-60

PIK3CA WT

PIK3CA E454K Mutation

Janjigian Y et al.. Cancer Discovery 2018 Jan;8(1):49-58

Makiyama et al. ASCO 2018; #4011

Aparicio & Caldas et al. N Engl J Med 2013; 368: 842-51

Tumor Heterogeneity

Biological Evolution

Treatment Resistance

Pectasides et al. Cancer Discovery 2017; 8: 1–12

Tumor Heterogeneity and Evolution Tumor Size Tumor

Time

Baseline Sampling Relapse Progression

Resection, adjuvant Drug A Drug B (Metastases)

Diaz et al. J Clin Oncol 2014; 32: 579-86

CtDNA follow-up in lapatinib treated GC patients in correlation to radiologic assessment

Kim ST et al. Annals of Oncology 29: 1037–1048, 2018

Lee J et al. Cancer Discov 2019;9:1388–405

Arm 4: savolitinib (MET inhibitor) monotherapy arm for patients with MET-amplified gastric cancer. * indicates newly developed lesion per RECIST 1.1.

Lee J et al. Cancer Discov 2019;9:1388–405

Claudin18.2 Immunohistological CLDN18.2 Labeling CLDN18.2

Any [%] ≥2+ [%] Tissue Total positivity 40%

Gastric 1205 977 81 603 50 adenocarcinomas

Diffuse 358 320 89 216 60 Intestinal 395 287 73 168 43 Mixed 64 49 77 30 47 Not specified 388 321 83 189 49

► Member of the claudin family ► Major structural component of tight junctions ► Seals intercellular space in epithelial sheets ► Not expressed in any healthy tissues, except: stomach mucosa, but with limited accessibility

Lordick F et al. ESMO Asia 2016; #2200

EOX +/- IMAB362 (Zolbetuximab) – Survival (PFS and OS)

EOX + IMAB362 EOX + IMAB362

EOX EOX

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

Lordick F et al. ESMO Asia 2016; #2200

Subgroup EOX + IMAB362 EOX Hazard Ratio (95% CI) (800/600 mg/m2)

No. of patients All patients 77 84 0.51 (0.36-0.73) Subsite of Tumor* Gastroesophageal Junction 13 12 0.68 (0.29-1.59) Stomach 62 68 0.51 (0.34-0.76)

Histopathology Diffuse 35 37 0.40 (0.23-0.75) Intestinal 26 27 0.67 (0.36-1.23) Mixed 10 11 0.49 (0.17-1.37) 0.75 (0.24-2.35) Other 6 9 Measurable Disease Yes 67 65 0.51 (0.35-0.76) No 17 12 0.48 (0.19-1.22) CLDN18.2 expression 2+ 25 35 0.40 (0.22-0.75) 3+ 52 49 0.56 (0.36-0.88) CLDN18.2 cellular staining rate 20 25 EOX+IMAB better EOX better 0.75 (0.40-1.43) <70% 57 59 0.44 (0.29-0.68) ≥70% Previous Gastrectomy No 56 61 0.40 (0.26-0.62) Yes 21 23 0.84 (0.43-1.65)

0 1 2

Lordick F et al. ESMO Asia 2016; #2200 E O X + IM A B E O X © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick B e tte r B e tte r 41

Claudin 18.2 – SPOTLIGHT randomized Ph-III

SPOTLIGHT: Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 as First-line Treatment of Subjects With Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Loading dose of zolbetuximab at Cycle 1 Day 1 followed by a lower dose in subsequent cycles every • 550 participants 3 weeks. Additionally 12 treatments of mFOLFOX6 • 1st line advanced GC • CLDN18.2 pos in R ≥ 75% of tumor cells • Her2 negative Placebo starting at Cycle 1 Day 1 and every 3 weeks thereafter. Additionally 12 treatments of mFOLFOX6

Primary endpoint: PFS; secondary: OS, ORR, DOR, HrQoL

Lordick F et al. ESMO Asia 2016; #2200

Dr. Judah Folkman, Boston 1933–2008

Folkman’s Hypothesis

http://3quarksdaily.blogs.com/3quarksdaily/images/12folkman_1.jpg

Folkman J, et al. N Engl J Med 1971;285:1182–6

Clarke JM et al. Expert Opin Biol Ther 2013; 13: 1187-1196

RAM + Placebo + HR BSC BSC P-value

Disease Control 49% 23% P<0.0001

HR 0.48 PFS (med, Mon) 2.1 1.3 p <0.0001

HR 0.78 OS (med, Mon) 5.2 3.8 p =0.047

5FU, fluorouracil; CI, confidence interval; EGJ, oesophageal junction; HR, hazard ratio. Fuchs CS, et al. Lancet 2014;383:31–9

Median OS (months) by Study Arm

RamucirumabREGARD: Ramucirumab vs BSC vs(n=355) PBO (BSC) 5.2 (n=355) 3.8

DocetaxelUK: COUGAR vs-02: ASC Docetaxel (n=131) vs BSC1 5.2 (n=131) 3.6

CTXKorea: [Docetaxel CTX [Docetaxel or or Irinotecan] Irinotecan] vs BSCvs 2 5.3 BSC (n=202) (n=202) 3.8

IrinotecanGerman: vs Irinotecan BSC (n=40)vs BSC3 4.0 (n=40) 2.4

0 1 2 3 4 5 6 Active Treatment BSC

1. Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86. 2. Kang et al. J Clin Oncol 2012;30:1513-1518 3. Thuss-Patience et al. EUR J CANCER 2011;47:2306-2314.

RAM + Placebo + HR Paclitaxel Paclitaxel P-value

Response Rate 28% 16% p =0.0001

PFS (med, Mon) 4.4 2.9 HR 0.635 6 months (%) 22% 10% p <0.0001

OS (med, Mon) 9.6 7.3 HR 0.807 6 months 40% 30% p =0.0169

Wilke et al., Lancet Oncol 2014 Oct;15(11):1224-35

Dyspnoea

Diarrhoea

Favours RAM+PTX Favours PBO+PTX

CI, confidence interval; HR, hazard ratio; PBO, placebo; PTX, paclitaxel; RAM, ramucirumab Al-Batran SE, et al. Ann Oncol. 2016 Apr;27(4):673-9

Post-hoc analysis from Regard

Fuchs C et al Brit J Cancer 2016 Oct 11;115(8):974-982

REGARD STUDY

RAINBOW STUDY

Fuchs C et al Brit J Cancer 2016 Oct 11;115(8):974-982 Wilke et al., Lancet Oncol 2014 Oct;15(11):1224-35

REGARD STUDY

RAINBOW STUDY

Fuchs C et al Brit J Cancer 2016 Oct 11;115(8):974-982 Wilke et al., Lancet Oncol 2014 Oct;15(11):1224-35

Study Setting Drug Control Reference (C) STO-3 Peri-operative BEV+C ECX 1 AVAGAST 1st-line BEV+C CF 2 metastatic AVATAR 1st-line BEV+C XP 3 metastatic NCT 1st-line RAM+C FOLFOX 4 01246960 metastatic RAINFALL 1st-line RAM+C CF 5 metastatic RAINSTORM 1st-line RAM+C SOX 9 metastatic

1. Bev: Bevacizumab

C: Control 1. 1. Cunningham D et al. Lancet Oncol 2017; 18: 357–70

CF: Cisplati, 5-Fluorouracil 2. 2. Ohtsu A et al. J Clin Oncol 2011; 29:3968-3976

ECX: Epirubicin, Cisplatin, Capecitabin 3. 3. Shen L et al. Gastric Cancer 2015; 18:168–176

FOLFOX: Folinic Acid, 5-Fluorozracil, Oxaliplatin 4. 4. Yoon HH et al. Ann Oncol. 2016 Dec;27(12):2196-2203

SOX: S-1, Oxaliplatin 5. 5. Fuchs C et al. ASCO-GI 2018; abstract #5

XP: Capecitabine, Cisplatin 6. 6. Muro K. Et al. ASCO 2018; abstract #4038

× △ × △ ○ ○ ○ Stomach Cancer

× × × ○ △ ○ ○ ○ ○ ○ ○ Colorectal Cancer

Disease setting Perioperative Metastatic and or Adjuvant Mostly Palliative Localized Locally 1st 2nd 3rd - advanced ○: Impact in OS Advanced △: Impact in PFS ×: No Impact in OS/DFS/PFS Yoon HH, ASCO-GI 2015, substantially modified by Muro K

3rd-line chemotherapy (TAS102, irinotecan)

ECOG, Eastern Cooperative Oncology Group; PS, performance status. Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016;13:348-60

• Gastric cancer is a heterogenous disease, which compromises - to a certain extent – targeted treatment • Trastuzumab plus chemo-doublet improves survival in first- line metastatic gastric cancer • Other receptor tyrosine kinase directed treatments have failed thus far in phase-III, but further research is ongoing • Claudin18.2 is a novel promising target for advanced GC treatment. Phase III studies are on the way • Ramucirumab alone and - even more - ramucirumab plus paclitaxel improves survival in 2nd-line gastric cancer

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