ESMO Preceptorship Targeted Therapy for Gastric Cancer

Transcription

1 ESMO Preceptorship Targeted Therapy for Gastric Cancer Professor Dr. Florian Lordick Professor of Oncology Director University Cancer Center Leipzig (UCCL)

2 Disclosure Florian Lordick declares honoraria for advisory role, membership in data safety board or lectures within the last three years for Amgen, Astellas, Astra Zeneca, Biontech, BMS, Ganymed, Elsevier, Excerpta Medica, MSD, Roche, Servier, and Taiho. He receives research support from BMS 2

3 Systemic Treatment Options in GC Chemotherapy Molecular Targeted therapy Antiangiogenic therapy Immuno therapy 3

4 Targeted Therapy in GC Not a Success Story Compound Mechanism of action Treatment setting Reference Cetuximab Anti-EGFR mab 1 st -line metastatic Lordick et al Panitumumab Anti-EGFR mab 1 st -line metastatic Waddell et al Gefitinib Anti-EGFR TKI 2 nd -line metastatic Petty et al Trastuzumab Anti-HER2 mab 2 nd -line metastatic Makiyama et al Pertuzumab Anti-HER2 mab 1 st -line metastatic Tabernero et al Lapatinib Anti-EGFR/HER2 TKI 2 nd -line metastatic Satoh et al Rilotumumab Anti-HGF mab 1 st -line metastatic Catenacci et al Onartuzumab Anti-MET mab 1 st -line metastatic Shah et al Napabucasin Anti-STAT3 2 nd -line metastatic Shah et al Bevacizumab Anti-VEGF mab Perioperative Cunningham et al Bevacizumab Anti-VEGF mab 1 st -line metastatic Ohtsu et al Ramucirumab Anti-VEGFR-2 mab 1st-line metastatic Fuchs et al Olaparib PARP inhibitor 2 nd -line metastatic Bang et al Pembrolizumab PD-1-directed mab 2 nd -line metastatic Shitara et al. Lancet

5 Potential Molecular Targets in Gastric Cancer Deng N, et al. Gut 2012;61:

6 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 (?) HER2 positive phase-3: ToGA Bang et al. Lancet 2010 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 (Affymetrix, Santa Clara, California, USA) Deng N, et al. Gut 2012;61:

7 The EGFR Story mixed, 3+ intestinal, 0-3+ Expression bei Magenkarzinomen (Immunhistochemie) diffuse, 2+ diffuse, 1+ Gamboa et al. Mod Pathol 2004;17:

8 The EGFR Story n Response (%) mttp (Mon) FUFOX + Cetuximab Lordick F, et al. BJC % 95% CI, 50 79% 7,6 95% CI, Lordick F, et al. Br J Canc 2010; 102:

9 EXPAND Study R A N D O M Cisplatin 80mg/m 2 d1 Capecitabine 1000mg/m 2 2 x / day.; d1-14 q3w Until radiographic progression or toxicity-related end of treatment Primary endpoint: Progression-free survival (PFS) Cisplatin 80mg/m 2 d1 Capecitabine 1000mg/m 2 2 x tgl.; d1-14 q3w Cetuximab 400mg/m 2 loading dose, then 250mg/m 2 / week Lordick et al., Lancet Oncol. 2013; 14:

10 EXPAND Study Lordick et al., Lancet Oncol. 2013; 14:

11 Survival (%) Pre-EXPAND Study 100 EGFR FISH >4.0 Log-rank P= n=8 40 EGFR gene amplification: EGFR: 8.20 signals per nucleus EGFR/CEP7 ratio: 1.36 EGFR (red), chromosome 7 (green) 20 0 EGFR FISH < Overall survival time (days) n=28 Luber B, Lordick F. BMC Cancer 2011;11:509 11

12 EXPAND Study Lordick et al., Lancet Oncol 2012; 13:

13 What Can We Learn from the EGFR Lesson? A good study hypothesis is important: preclinical evidence Do not trust in overoptimistic phase II data Do correlative research and explore biomarkers! For rare subtypes of cancer - you need a strong network! 14

14 HER2-directed Therapy: ToGA Anti-HER2 Trastuzumab prolongs survival in stage IV gastric cancer Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016 Survival advantage with trastuzumab in HER2 + gastric cancer CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio. Bang Y, Lordick F. et al. Lancet 2010;376:

15 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 Jun;13(6):348-60

16 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:

17 Pertuzumab Trastuzumab JACOB Study Arm A (n=388) Arm B (n=392) HR (95%CI) mpfs, months (0.62, 0.86) Response rate (%) Difference 8.4 (0.9, 15.9) Tabernero J et al. Lancet Oncol Sep 11. [Epub ahead of print 18

18 Target Expression in Gastric Cancer Heterogenous / focal HER-2 expression in gastric cancer Signet ring type Intestinal (gland forming) type High Amplification No Amplification Lordick F, Janjigian YY. Nat Rev Clin Oncol Jun;13(6):

19 HER2-Testing Central and Local Lordick et al. AACR, Chicago, 2018 abstract

20 HER2-Testing Central and Local Deviation rate 23% Lordick et al. AACR, Chicago, 2018 abstract 21

21 HER2-Testing Central and Local Lordick et al. AACR, Chicago, 2018 abstract 22

22 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 Jun;13(6):348-60

23 2nd-line HER2-targeted treatment? Makiyama et al. ASCO 2018; #

24 2nd-line HER2-targeted treatment? Makiyama et al. ASCO 2018; #

25 2nd-line HER2-targeted treatment? PIK3CA WT PIK3CA E454K Mutation Janjigian Y et al.. Cancer Discovery 2018 Jan;8(1):

26 Tumor Heterogeneity and Evolution Tumor Heterogeneity Biological Evolution Treatment Resistance 27

27 Tumor Heterogeneity Pectasides et al. Cancer Discovery 2017; 8:

28 Tumor Heterogeneity in GC Pectasides et al. Cancer Discovery 2017; 8:

29 Tumor Heterogeneity in GC Pectasides et al. Cancer Discovery 2017; 8:

30 Tumor Heterogeneity and Evolution Aparicio & Caldas et al. N Engl J Med 2013; 368:

31 Tumor Size Tumor Heterogeneity and Evolution Time Baseline Sampling Relapse Progression Resection, adjuvant Drug A Drug B (Metastases) 32

32 Liquid Biopsy Diaz et al. J Clin Oncol 2014; 32:

33 Anti-Angiogenic Approach Dr. Judah Folkman, Boston Folkman s Hypothesis Folkman J, et al. N Engl J Med 1971;285:1182 6

34 Anti-Angiogenic Approach Clarke JM et al. Expert Opin Biol Ther 2013; 13:

35 Ramucirumab 2nd-line Mono (REGARD) RAM + BSC Placebo + BSC HR P-value Disease Control 49% 23% P< PFS (med, Mon) OS (med, Mon) HR 0.48 p < HR 0.78 p = FU, fluorouracil; CI, confidence interval; EGJ, oesophageal junction; HR, hazard ratio. Fuchs CS, et al. Lancet 2014;383:31 9

36 Ramucirumab 2nd-line Mono Median OS (months) by Study Arm REGARD: Ramucirumab vs PBO (BSC) (n=355) Ramucirumab vs BSC (n=355) UK: COUGAR-02: Docetaxel vs BSC 1 Docetaxel vs ASC (n=131) (n=131) CTX [Docetaxel or Irinotecan] vs BSC (n=202) Korea: CTX [Docetaxel or Irinotecan] vs BSC 2 (n=202) German: Irinotecan vs BSC 3 Irinotecan vs BSC (n=40) (n=40) Active Treatment BSC 1. Ford et al. Lancet Oncol Jan;15(1): Kang et al. J Clin Oncol 2012;30: Thuss-Patience et al. EUR J CANCER 2011;47:

37 Ramucirumab 2nd-line Combined (RAINBOW) RAM + Paclitaxel Placebo + Paclitaxel HR P-value Response Rate 28% 16% p = PFS (med, Mon) 6 months (%) % % HR p < OS (med, Mon) 6 months % % HR p = Wilke et al., Lancet Oncol 2014 Oct;15(11):

38 Ramucirumab 2nd-line Quality of Life (RAINBOW) 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 Apr;27(4):673-9

39 Is Ramucirumab Effective in HER2 Positive Cancers? Post-hoc analysis from Regard Fuchs C et al Brit J Cancer 2016 Oct 11;115(8):

40 Ramucirumab in the Elderly Population? REGARD STUDY RAINBOW STUDY Fuchs C et al Brit J Cancer 2016 Oct 11;115(8): Wilke et al., Lancet Oncol 2014 Oct;15(11):

41 Ramucirumab in the Peritoneal Carcinosis? REGARD STUDY RAINBOW STUDY Fuchs C et al Brit J Cancer 2016 Oct 11;115(8): Wilke et al., Lancet Oncol 2014 Oct;15(11):

42 Anti-Angiogenic Treatment in Early Gastric Cancer or 1st-Line Metastatic GC: not effective Study Setting Drug Control (C) Reference STO-3 Peri-operative BEV+C ECX 1 AVAGAST AVATAR NCT RAINFALL RAINSTORM 1st-line metastatic 1st-line metastatic 1st-line metastatic 1st-line metastatic 1st-line metastatic BEV+C CF 2 BEV+C XP 3 RAM+C FOLFOX 4 RAM+C CF 5 RAM+C SOX 9 1. Bev: Bevacizumab C: Control CF: Cisplati, 5-Fluorouracil ECX: Epirubicin, Cisplatin, Capecitabin FOLFOX: Folinic Acid, 5-Fluorozracil, Oxaliplatin SOX: S-1, Oxaliplatin XP: Capecitabine, Cisplatin Cunningham D et al. Lancet Oncol 2017; 18: Ohtsu A et al. J Clin Oncol 2011; 29: Shen L et al. Gastric Cancer 2015; 18: Yoon HH et al. Ann Oncol Dec;27(12): Fuchs C et al. ASCO-GI 2018; abstract # Muro K. Et al. ASCO 2018; abstract #4038

43 Anti-Angiogenic Treatment Among Treatment Lines Stomach Cancer Colorectal Cancer Disease setting Localized : Impact in OS : Impact in PFS : No Impact in OS/DFS/PFS Perioperative or Adjuvant Locally advanced Metastatic and Mostly Palliative 1 st 2 nd Advanced 3 rd - Yoon HH, ASCO-GI 2015, substantially modified by Muro K

44 2nd-line Treatment Algorithm for Gastric Cancer ECOG, Eastern Cooperative Oncology Group; PS, performance status. Lordick F, Janjigian YY. Nat Rev Clin Oncol Jun;13(6):348-60

45 Summary Gastric cancer is a heterogenous disease, which compromises - to a certain extent targeted treatment Trastuzumab plus chemo-doublet improves survival in firstline metastatic gastric cancer Other receptor tyrosine kinase directed treatments have failed thus far Ramucirumab alone and - even more - ramucirumab plus paclitaxel improves survival in 2nd-line gastric cancer Universitätsklinikum Leipzig AöR (2009): Thema, Autor 46

46 8 11 May 2019, Prague

47 Back-Up Slides 48

48 Perioperative anti-her2 Therapy TRIGGER study SP HER2 + GC, Bulky N SP / Tmab Surgery S-1 Surgery S-1 Sample size: 130 pts. Primary endpoint: Overall survival Secondary endpoint: Progression-free survival, response rate, completion of protocol treatment, adverse event Legend: SP, S-1 plus Cisplatin; Tmab, Trastuzumab 49

49 Perioperative INNOVATION study HER2-positive mgc or GEJ adenocarcinoma (N = 220) Centrally confirmed Stages IB-III R 1:2:2 XC or FLOT 3 / 4 cycles (N = 44) Chemo + T 3 cycles (N = 88) Chemo + TP 3 cycles (N = 88) Surgery XC or FLOT 3 / 4 cycles Chemo + T 3 cycles Chemo + TP 3 cycles T for up to 1 year TP for up to 1 year T: Trastuzumab; P: Pertuzumab Primary endpoint: histopathological near complete response (<10% viable tumour cells) after neoadjuvant therapy Stratification: histological subtype (intestinal/non-intestinal); Korea versus Europe; stage II versus III; node positive versus node negative 50