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ESMO Preceptorship Targeted Therapy for Gastric Cancer

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ESMO Preceptorship Targeted Therapy for Gastric Cancer 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) © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 2 Systemic Treatment Options in GC Molecular Anti- Immuno Chemotherapy Targeted angiogenic therapy therapy therapy © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 3 Targeted Therapy in GC – Not Always a Success Story 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 4 Potential Molecular Targets in Gastric Cancer Deng N, et al. Gut 2012;61:673-84 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 5 Potential Molecular Targets in Gastric Cancer 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 6 RTK Co-Amplifications RTK gene copy number gains/losses in the patient cohort and cell models. Secrier M et al. Nature Genetics 2017; 48: 1131-41. © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 7 The EGFR Story mixed, 3+ intestinal, 0-3+ Expression bei Magenkarzinomen (Immunhistochemie) diffuse, 2+ diffuse, 1+ Gamboa et al. Mod Pathol 2004;17:579-87 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 8 The EGFR Story 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 9 EXPAND Study 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 10 EXPAND Study Lordick et al., Lancet Oncol. 2013; 14: 490-499 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 11 Pre-EXPAND Study 100 Log-rank P=0.011 EGFR FISH >4.0 80 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 12 EXPAND Study Lordick et al., Lancet Oncol 2012; 13: 33–42 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 13 What Can We Learn from the EGFR Lesson? • 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! © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 14 Biology of Gastric Cancer 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 15 Biology of Gastric Cancer 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 16 Biology of Gastric Cancer ? 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 17 HER2-directed Therapy: ToGA 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 18 HER2-directed Therapy: ToGA Bang Y,…Lordick F. et al. Lancet 2010;376:687–97 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 19 Gastric Cancer Therapy in Stage IV 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick HER2 Combined Therapy: Pertuzumab - Trastuzumab 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 21 Pertuzumab – Trastuzumab – JACOB Study 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 22 Target Expression in Gastric Cancer 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 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 23 Loss of Target Expression PIK3CA WT PIK3CA E454K Mutation Janjigian Y et al.. Cancer Discovery 2018 Jan;8(1):49-58 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 24 2nd-line HER2-targeted treatment? Makiyama et al. ASCO 2018; #4011 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 25 Tumor Heterogeneity and Evolution Aparicio & Caldas et al. N Engl J Med 2013; 368: 842-51 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 26 Tumor Heterogeneity and Evolution Tumor Heterogeneity Biological Evolution Treatment Resistance © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 27 Tumor Heterogeneity in GC Pectasides et al. Cancer Discovery 2017; 8: 1–12 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 28 Tumor Heterogeneity in GC Pectasides et al. Cancer Discovery 2017; 8: 1–12 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 29 Tumor Heterogeneity and Evolution Tumor Size Tumor Time Baseline Sampling Relapse Progression Resection, adjuvant Drug A Drug B (Metastases) © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 30 Liquid Biopsy Diaz et al. J Clin Oncol 2014; 32: 579-86 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 31 Liquid Biopsy – Follow-up of HER2 CtDNA follow-up in lapatinib treated GC patients in correlation to radiologic assessment Kim ST et al. Annals of Oncology 29: 1037–1048, 2018 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 32 VIKTORY Trial Lee J et al. Cancer Discov 2019;9:1388–405 © University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 33 VIKTORY Trial Lee J et
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