Current Standard of Care of Gastro- Esophageal Cancer

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2 Current Standard of Care of Gastro- Esophageal Cancer Andrés Cervantes Professor of Medicine

3 Classical approach to localised gastric cancer Surgical resection Pathology assessment and estimation of risk Treatment based upon classical TNM stage Postoperative chemotherapy of limited value Postoperative chemoradiation in US

4 Meta-analysis of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer Meta-analysis Year No. trials No. pts Odds Ratio 95% CI Conclusions Hermanns (1) J Clin Oncol No benefit Earle (2) Eur J Cancer Small survival benefit In N+ patients Mari (3) Ann Oncol Small survival benefit Janunger (4) Eur J Surg Very heterogeneous group of trials Western Asian Gastric Group (5) JAMA P< Hermanns J et al. J Clin Oncol, 1993, vol11, no 8, Earle CC et al. Eur J Cancer 1999; 35 (7): Mari e et al. Ann Oncol 2000; 11(7): Janunger KG et al. Eur J Surg 2002; 168(11): The Gastric Group. Jama 2010: 303:

5 The Gastric Group. JAMA 2010;303: Meta-analysis of individual data of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer

6 Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow-up of a randomised phase III trial Noh SH, et al. Lancet Oncol 2014;15: , (2014), with permission from Elsevier

7 Study design The role of radiation in the postoperative setting: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial SURGERY NO TREATMENT STRATIFICATION T 1 4 NODES 0, 1 3, >3 CT+ CT-RT + CT MacDonald JS, et al. N Engl J Med 2001;345:

8 Smalley S, et al. J Clin Oncol 2012;30: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: Long term data of a randomised Phase III Trial

9 ARTIST: The role of Radiation in the Postoperative Setting Adjuvant Cisplatin and Capecitabine versus Chemoradiation for Gastric Cancer after Surgery: A Randomized phase III Trial Park SH, et al. J Clin Oncol 2015; 33:

10 CRITICS TRIAL Design: 788 pts: 393 CT and 395 CRT Preoperative chemotherapy 3x EC/OC q 3 wks D1 + surgery 3x EC/OC q 3 wks R QoL Tissue banking Preoperative chemotherapy 3x EC/OC q 3 wks D1 + surgery Chemoradiation Stratified for: - Center - Histological type - Localisation of tumor 45 Gy/25 fx + / capecitabine cisplatin Verheij M, et al. ASCO 2016; Abstract

11 Final Results from the CRITICS study Verheij M, et al. ASCO 2016; Abstract 4000

12 MAGIC: Study design Eligible patients: Adenocarcinoma of the stomach or lower third of the oesophagus (from 1999), suitable for curative resection Non-metastatic disease Stage II or greater Study entry and randomisation S arm N=253 CSC arm N=250 Primary Overall survival Secondary Progression-free survival Surgical resectability Quality of Life Chemotherapy (ECF): Epirubicin 50 mg/m 2, IV day 1 Cisplatin 60 mg/m 2, IV day 1 5-FU 200 mg/m 2 /day, continuous infusion, days 1-21 (cycles repeated every 3 weeks) Recruitment: July 1994-April 2002 Cunningham D, et al. N Engl J Med 2006;355:11 20 Surgery Pre-operative chemotherapy: ECFx3 Surgery 3-6 weeks 6-12 weeks Post-operative chemotherapy: ECFx3

13 MAGIC Trial results PFS* Overall Logrank p-value = Hazard Ratio = 0.66 (95% CI ) Logrank p-value = Hazard Ratio = 0.75 (95% CI ) EventsTotal CSC S Months from randomisation EventsTotal CSC S Months from randomisation 2 year survival 5 year survival Median survival CSC 50% 36% 24 mo S 41% 23% 20 mo Benefit to CSC arm 9% 13% 4 mo On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender Hazard ratio for death Adjusted: 0.74 (95%CI: ) Unadjusted: 0.75 Cunningham D, et al, N Engl J Med 2006;355: Copyright (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

14 Regression grade after neoadjuvant ECF and Overall Survival in Oesophagogastric Cancer in MAGIC Smyth EC, et al, J Clin Oncol 2016; 34:

15 Summary of trials of perioperative chemotherapy for localized Oesophagogastric cancer Trial CT No. pts control No. pts CT 5-year survival control 5-year survival CT HR (CI at 95%) Cunningham N Eng J Med 2006 ECF 253 No CT % 36 % p=0.009 Ychou J Clin Oncol 2011 CDDP 5-FU 111 No CT % 38% p=0.021 Allum J Clin Oncol 2009 CDDP FU 402 No CT ,6% 25.5% P= Cunningham D, et al, N Engl J Med 2006;355: Ychou M, et al. J Clin Oncol 2011;29: Allum W, et al. J Clin Oncol 2009; 27: Only esophageal cancer

16 FLOT-4 Study Randomized, multicenter, Phase II/III Study Gastric or EGJ cancer typ I-III Medically and anatomically operable ct2-4/cn-any/cm0 or ct-any/cn+/cm0 R n=716 Stratification: ECOG (0 or 1 vs. 2), localization (GEJ Type I vs. Type II/III vs. Gastric), age (< 60 vs vs. 70 years) and nodal status (cn+ vs. cn-). S T R A T I F I K A T I O N FLOT x4 - RESECTION - FLOT x4 FLOT: Docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; Leucovorin 200 mg/m², d1; Oxaliplatin 85 mg/m², d1, q2w ECF/ECX x3 - RESECTION - ECF/ECX x3 ECF/ECX: Epirubicin 50 mg/m2, d1; Cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or Capecitabin 1250 mg/m² p.o. geteilt in 2 doses d1-d21), q2w 23% had Siewert type I 33% had Siewert type II/III

17 Survival ECF/ECX versus FLOT ECF/ECX FLOT mos 35 months 50 months [27-46] [38-na] HR 0.77 [0,63 0,94] p=0.012 (log rank) OS rate* ECF/ECX FLOT 2y. 59% 68% 3y. 48% 57% 5y. 36% 45% *projected OS-rates Median follow-up time: 43 months Al-Batran et al. J Clin Oncol 2017; 35(suppl): #4004

18 Summary of trials of perioperative chemotherapy for localized Oesophagogastric cancer Trial CT No. pts control No. pts CT 5-year survival control 5-year survival CT HR (CI at 95%) Cunningham N Eng J Med 2006 ECF 253 No CT % 36 % p=0.009 Ychou J Clin Oncol 2011 CDDP 5-FU 111 No CT % 38% p=0.021 Allum J Clin Oncol 2009 CDDP FU 402 No CT ,6% 25.5% P=0.03 Al-Batran ASCO 2017 FLOT 360 ECF 356 FLOT 36% 45% P= Cunningham D, et al, N Engl J Med 2006;355: Ychou M, et al. J Clin Oncol 2011;29: Allum W, et al. J Clin Oncol 2009; 27: Only esophageal cancer 4. Al-Batran SA, et al 2017; 35(suppl): #4004

19 Perioperative chemotherapy for localized Oesophago-gastric cancer: a new standard Trial CT Experimental No. pts pcr Control vs Experimental 5-year survival Control vs Exp HR (CI at 95%) Cunningham N Eng J Med 2006 Al-Batran ASCO 2017 Alderson + Lancet Oncol 2017 ECF 503 0% vs 8% 23% vs 36 % FLOT 716 5,8% vs 15,6% 36% vs 45% ECX 897 3% vs 11% 39% vs 42%* p= P= Cunningham Lancet Oncol 2017 BEV-ECX % vs 11% 50% vs 48%* 1. Cunningham D, et al, N Engl J Med 2006;355: Al-Batran SA, et al 2017; 35(suppl): # Alderson D. et al Lancet Oncol 2017 on line +Only Esophageal, *3 year OS 4. Cunningham D, et. Lancet Oncology 2017; 18:

20 Perioperative chemotherapy: Induces downstaging Neoadjuvant chemotherapy in gastric cancer: Conclusions May increase the R0 resection rate Prolongs disease free survival Improves overall survival Evidence level I based upon 2 well designed and properly conducted randomised trials. FLOT is current standard of care Preoperative therapy is better tolerated than postoperative Localised gastric cancer requires a multidisciplinary team approach Further research on biological predictive factors is needed

21 Currently recommended approach to localised gastric cancer Clinical assessment and staging Multidisciplinary team discussion FLOT preoperative treatment in clinical stage II and III patients Surgical resection after FLOT chemotherapy Pathology assessment and estimation of risk Postoperative chemotherapy if tolerated Radiotherapy still experimental No biological agents (Bevacizumab) to be used in this setting

22 Treatment for localised gastric cancer: What is standard of care? ESMO guidelines Gastric Cancer (Adenocarcinoma) Operable Stage T1N0 Operable Stage > T1N0 Preferred pathway Consider endoscopic / limited resection Preoperative chemotherapy Surgery Surgery Adjuvant chemoradiation Adjuvant chemotherapy Post-operative chemotherapy

23 Treatment for advanced gastric cancer: What is standard of care? ESMO guidelines Inoperable or metastatic Surgery Re-assess Palliative chemotherapy Best supportive care if unfit for treatment HER-2 negative Platinum+ fluorpyrimidinebased doublet or triplet regimen HER-2 positive Trastuzumab + CF/CX Consider clinical trials of novel agents 2 nd line chemo Clinical trials if adequate PS Smyth EC, et al. Ann Oncol 2016;27(Suppl 5): By permission of the European Society of Medical Oncology

24 Based upon superiority trials: 5-FU Cisplatin Docetaxel Trastuzumab Treatment for metastatic/unresectable gastric cancer: Active agents in first line Based upon non-inferiority trials Oxaliplatin Capecitabine S1 Irinotecan Cervantes A, et al. Cancer Treat Rev 2012; 39:60-67

25 Have we made any progress in the treatment of advanced gastric cancer? Transtuzumab + CDDP+ FU or Cape months EOX 5 5-FU + LV + Oxaliplatin (FLO) 4 Capecitabine + Cisplatin (XP) months 10.7 months 10.5 months Docetaxel +Cisplatin + 5-FU months 5-FU monotherapy 1 7 months Best supportive care 1 4 months MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER 1. Wagner A, et al. JCO van Cutsem E, et al. J Clin Oncol 2006;24: Kang YK et al, Ann Oncol 2009; 20: Al Batran SE, et al. J Clin Oncol 2008;26: Cunningham D, et al. N Engl J Med 2008;358: Bang YJ, et al. Lancet 2010;376: EOX: Epirubicin/Oxaliplatin/Capecitabine.

26 FFCD-GERCOR-FNCLCC Phase III Study. FOLFIRI vs ECF in advanced gastric cancer Objective II: Response Rate (RR), PFS and OS ECF N=209 FOLFIRI n=207 p value TTF (months) 4.2 5, RR 1 st 39.2% RR 2 nd 10.1% PFS (months) Median range OS (months) Median range % 13.7% n.s Guimbaud R, et al. J Clin Oncol 2014;32:

27 Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer Stratification: Measurable or not Gastric vs GEJ Center R A: modified DCF B: standard DCF plus G-CSF Objective : 6 months-pfs Objectives II: RR, OS, Toxicity Shah MA, et al. J Clin Oncol 2015;33:

28 Shah MA, et al. J Clin Oncol 2015;33: Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer

29 Shah MA, et al. J Clin Oncol 2015;33: Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer

30 Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine TE vs TEF vs TEX Van Cutsem E, et al. Ann Oncol 2015;26:

31 Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine TE vs TEF vs TEX Treatment Patients nr RR % 95% CI PFS months 95% CI OS months 95% CI TE 79 23,1 14,3-34,0 4,50 3,68-5,32 8,97 7,79-10,9 TEX 86 25,6 16,6-36,6 5,55 4,30-6,37 11,30 8,08-14,0 TEF ,9-57,5 7,66 6,97-9,40 14,59 11,7-21,8 Van Cutsem E, et al. Ann Oncol 2015;26:

32 Targeted therapies in first-line treatment for advanced gastric cancer: Summary of Phase III Trials Trial Chemotherapy Biological ToGA 1 AVAGAST 2 EXPAND 3 REAL-3 4 RILOMET-1 5 Cisplatin+5-FU/ capecitabine Cisplatin+ capecitabine Cisplatin+ capecitabine Oxaliplatin+ epirubicin + capecitabine Cisplatin+ epirubiicin+ capecitabine HR OS P value Increase in median survival Trastuzumab months Bevacizumab months Cetuximab months Panitumumab months Rilotumumab Stopped in futility analysis METGASTRIC 6 FOLFOX6 Onartuzumab months 1. Bang YJ, et al. Lancet 2010;376: Van Cutsem E, J Clin Oncol 2012;30 (17): Lordick F, Lancet Oncol 2013;14: Waddell T, Lancet Oncol 2013;14: Cunigham ASCO Shah M. J Clin Oncol 2015;33(15)

33 Targeted therapies against HER2 in advanced gastric cancer: Summary of Phase III Trials on tratuzumab, lapatinib, TDM-1 and pertuzumab TRIAL Chemotherapy backbone Line of therapy number HR OS P value Response rate Increase in median survival ToGA 1 Cisplatin+5-FU/ capecitabine First % vs 37% p= months LOGiC 2 Oxaliplatin/ capecitabine +/- Lapatinib First % vs 39% p= months TyTAN 3 Paclitaxel+/- Lapatinib Second % vs 9% p= months GATSBY 4 TDM-1 vs Taxane Second NP - 0,7 months JACOB 5 Cisplatin+5-FU/ cap/trastu +/- Pertuzumab First % vs 48% 3.3 months 1. Bang YJ, et al. Lancet 2010;376: Hecht JR, et al. ASCO abstract 2013 LBA Satoh N, et al. J Clin Oncol 2014; 32: Kang YK et al. ASCO GI Tabernero j, et al. ESMO

34 Trial author Gastric cancer: Second line chemotherapy. Trials comparing BSC versus active treatment Year Patients random (n) Treatment Response rate (%) HR OS P value Gain in median survival Thuss-Patience, et al :1 Irinotecan NR SD 58% months Kang, et al :1 Irinotecan Docetaxel NR months Ford, et al :1 Docetaxel NR months 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15:78 86.

35 Ford HE, et al. Lancet Oncol 2014;15: Gastric cancer second line chemotherapy: Docetaxel vs BSC (COUGAR-02 Trial) is improving survival

36 Gastric cancer: Second line chemotherapy trials comparing BSC versus active treatment 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15: Otshu A. et al. J Clin Oncol 2013;31: Fuchs CS, et al. Lancet 2014;383: Trial author Year Patients random (n) Treatment HR OS P value Gain in median survival Thuss-Patience, et al Kang, et al Ford, et al Otshu, et al Fuchs, et al : : : : :1 Irinotecan months Irinotecan Docetaxel months Docetaxel months Everolimus months Ramucirumab months

37 Gastric cancer second line treatment: Ramucirumab vs BSC (REGARD Trial) is improving survival Reprinted from Fuchs CS, et al. Lancet Oncol 2014;383:31 39 (2005) with permission from Elsevier

38 Gastric cancer: Second line chemotherapy trials comparing two active treatments Trial author Year Patients (n) Hironaka, et al Wilke et al Treatment Irinotecan vs paclitaxel Paclitaxel+/- ramucirumab HR OS P value Gain in median survival 0.9 months for irinotecam months 1. Hironaka S, et al. J Clin Oncol 2013;31: Wilke H, et al. Lancet Oncol 2014;15:

39 Gastric cancer second line treatment: Addition of ramucirumab to paclitaxel improves overall survival (Rainbow Trial) Wilke HJ, et al. Lancet Oncol 2014;15: (2005) with permission from Elsevier

40 Pembrolizumab induces responses in chemorefractory gastric cancer Central review N = 36 a Investigator review N = 39 ORR, % (95% CI) 22.2 (10.1, 39.2) 33.3 (19.1, 50.2) Best overall response, n (%) Complete response b 0 0 Partial response b 8 (22.2) 13 (33.3) Stable disease 5 (13.9) 5 (12.8) Progressive disease 19 (52.8) 21 (53.8) No assessment c 1 (2.8) Not determined d 3 (8.3). Muro K, et al. Lancet Oncol 2016; 17:

41 Nivolumab (ONO-4538/BMS ) as Salvage Treatment After Second- or Later-Line Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer (AGC): A Double-Blinded, Randomized, Phase 3 Trial Yoon-Koo Kang, 1 Taroh Satoh, 2 Min-Hee Ryu, 1 Yee Chao, 3 Ken Kato, 4 Hyun Cheol Chung, 5 Jen-Shi Chen, 6 Kei Muro, 7 Won Ki Kang, 8 Takaki Yoshikawa, 9 Sang Cheul Oh, 10 Takao Tamura, 11 Keun-Wook Lee, 12 Narikazu Boku, 4 Li-Tzong Chen 13 1 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 2 Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan; 3 Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 4 Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; 5 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Song Dang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea; 6 Division of Hematology/Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; 7 Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 8 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 9 Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan; 10 Division of Hematology/Oncology, Internal Medicine Department, College of Medicine, Korea University, Seoul, Korea; 11 Medical Oncology, Kindai University, Faculty of Medicine, Osakasayama, Japan; 12 Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; 13 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

42 Study Design and Endpoints Key eligibility criteria: Age 20 years Unresectable advanced or recurrent gastric or gastroesophageal junction cancer Nivolumab 3 mg/kg IV Q2W Primary endpoint: OS Histologically confirmed adenocarcinoma Prior treatment with 2 regimens and refractory to/intolerant of standard therapy R 2:1 Stratification based on: Country (Japan vs Korea vs Taiwan) ECOG PS (0 vs 1) Number of organs with metastases (< 2 vs 2) Secondary endpoints: Efficacy (PFS, BOR, ORR, TTR, DOR, DCR) Safety ECOG PS of 0 or 1 Exploratory endpoint: Biomarkers Placebo Patients were permitted to continue treatment beyond initial RECIST v1.1 defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV; intravenous; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response.

43 Overall Survival Probability of Survival (%) Patien ts, n Event s, n Median OS [95% CI], months Nivolumab [ ] Placebo [ ] Hazard ratio, 0.63 (95% CI, ) P < Month OS Rate [95% CI], % 26.6 [ ] 10.9 [ ] At risk: Time (months) Nivolumab Placebo

44 Classification of gastric adenocarcinoma: Pathology Intestinal versus diffuse subtypes Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31 49

45 50% 9% 20% 22% Cancer Genome Atlas Research Network. Nature 2014;513:

46 Advanced Gastric cancer: Conclusions I Her2 status to be determined in all patients with advanced disease Trastuzumab to be added if HER2 positive (+++) Platinum-based chemotherapy as first option, with FOLFIRI as an alternative Second line chemotherapy also prolongs survival in good PS patients Ramucirumab as single agent prolongs survival versus BSC Ramucirumab in combination with paclitaxel improves outcomes over paclitaxel These statements could also be valid for junctional and lower third esophageal adenocarcinoma

47 Advanced Gastric cancer: Conclusions II Most targeted therapies failed in molecularly unselected trials Immunotherapy (Pembrolizumab/Nivolumab) under development with interesting data to be confirmed Better selection of patients needed in clinical trials Validation of molecular classification in trials International cooperation

48 Oesophageal cancer: Specific features Squamous histology in upper and middle third location Adenocarcinoma histology in lower third location Lower third located tumours treated frequently as gastric cancer Different diseases according to histology, biology and epidemiological factors PET scanning of value in apparently localized tumours, detecting metastatic disease in up to 15-20% of cases Staging based in TNM (endoscopy, EUS, CT-scan, Pet-CT)

49 Localized Oesophageal cancer: Principles of Therapy Single modality (Surgery or Radiation) not adequate for locally advanced disease (T3 or N+) Low prevalence of early stages Assessment of comorbidities related to etiological factors such as tobacco and alcohol: respiratory failure due to COPD and chronic liver disease Multimodality treatment provides better results in randomised trials Preoperative treatment strategy preferred to postoperative

50 Localized Oesophageal cancer: Principles of Therapy Current validated options are: Preoperative Chemotherapy Preoperative Chemoradiation Definitive Chemoradiation

51 1. Sjoquist KM, et al. Lancet Oncol 2011;12: Preoperative Chemotherapy in Localized Oesophageal cancer

52 Preoperative Chemo-Radiotherapy in Localized Oesophageal cancer Sjoquist KM, et al. Lancet Oncol 2011;12:

53 Preoperative Chemo-Radiotherapy in Localized Oesophageal cancer: Long term data of the CROSS trial Median OS: 24.0 vs 48.6 months HR: 0.68 (CI at 95%: ) p: Shapiro KM, et al. Lancet Oncol 2015;16:

54 Keblebro F, et al. Ann Oncol 2016; 27: :8. Preoperative Chemotherapy versus Chemo- Radiotherapy in Localized Oesophageal cancer

55 Definitive Chemo-Radiotherapy in Localized Oesophageal cancer Al Sarraf M, et al. J Clin Oncol 1997;15:

56 Localized Oesophageal cancer: Conclusions Most patients do present with locally advanced tumors Multimodality approach is mandatory Multimodality approach does benefit both squamous and adenocarcinoma histologies Preoperative chemotherapy and preoperative chemoradiation are better that surgery alone Comparisons between both strategies are underway Definitive chemoradiation is better than radiation as single arm in squamous tumours located at cervical and middle third who are not operable