Gastric cancer:

Andrés CervantesProfessor of Medicine

DECLARATION OF INTEREST DISCLOSURE

Employment: None; Stock Ownership: None

Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas.

Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD

Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. Grant support: Merck Serono, Roche.

Others: Executive Board member of ESMO, Chair of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.

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

The Gastric Group. JAMA 2010;303:1729–37

Meta-analysis of individual data of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer

Noh SH, et al. Lancet Oncol 2014;15:1389–1396, © (2014), with permission from Elsevier

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow-up of a randomised phase III trial

SURGERYNO TREATMENT

STRATIFICATION

T 1–4NODES CT+ CT-RT + CT0, 1–3, >3

MacDonald JS, et al. N Engl J Med 2001;345:725–730

The role of radiation in the postoperative setting: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial

Study design

Smalley S, et al. J Clin Oncol 2012;30:2327–2333

Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: Long term data of a randomised Phase III Trial

CRITICS TRIALDesign: 788 pts: 393 CT and 395 CRT

Tissuebanking

QoL

Chemoradiation

3x EC/OC q 3 wks

D1 + surgery

D1 + surgeryPreoperative chemotherapy3x EC/OC q 3 wks

Preoperative chemotherapy3x EC/OC q 3 wks

R

45 Gy/25 fx + / capecitabine

cisplatin-

Stratified for:- Center- Histological type- Localisation of tumor

Cats A, et al. Lancet Oncol 2018; 19:616-628.

Final Results from the CRITICS study

Cats A, et al. Lancet Oncol 2018; 19:616-628.

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

Chemotherapy (ECF):Epirubicin 50 mg/m2, IV day 1Cisplatin 60 mg/m2, IV day 15-FU 200 mg/m2/day, continuous infusion, days 1-21(cycles repeated every 3 weeks)

PrimaryOverall survival

SecondaryProgression-free survivalSurgical resectabilityQuality of Life

Recruitment: July 1994-April 2002

Study entry and randomisation

S armN=253

CSC armN=250

3-6 weeks

6-12 weeks

Cunningham D, et al. N Engl J Med 2006;355:11–20

MAGIC: Study design

Pre-operative chemotherapy:ECFx3

Post-operative chemotherapy:ECFx3

Surgery

Surgery

MAGIC Trial results

Logrank p-value = 0.0001Hazard Ratio = 0.66

(95% CI 0.53 - 0.81)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomisation0 12 24 36 48 60 72

163 250190 253

EventsTotalCSCS

Logrank p-value = 0.009Hazard Ratio = 0.75

(95% CI 0.60 - 0.93)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomisation0 12 24 36 48 60 72

149 250170 253

EventsTotalCSCS

2 year survival

5 year survival

Median survival

CSC 50% 36% 24 moS 41% 23% 20 moBenefit to CSC arm 9% 13% 4 mo

PFS* Overall

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: 0.59-0.93) Unadjusted: 0.75

Cunningham D, et al, N Engl J Med 2006;355:11–20. Copyright © (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Adjuvant CAPOX and PFS in CLASSIC according to MSI status

Response to Adjuvant Chemotherapy According to MSI Status The benefit from adjuvant chemotherapy was not clear in MSI-H gastric

cancer In sharp contrast, the prognosis of patients treated with chemotherapy

was significantly better than that of patients treated with surgery only in the MSS gastric cancer group

Choi YY, et al Ann Surg 2018; on line first 10.1097/SLA.0000000000002803

85.7

54.1

83.9

66.8

0

20

40

60

80

100

MSI-H MSS

Surgery only Surgery + CTx

Est

imat

ed 5

-yea

r DFS

(%) p=0.931

p=0.002

FLOT-4 Study

FLOT x4 - RESECTION - FLOT x4

ECF/ECX x3 - RESECTION - ECF/ECX x3

• Gastric or EGJ cancer typ I-III

• Medically and anatomically operable

• cT2-4/cN-any/cM0 or cT-any/cN+/cM0

R

n=716

STRATIFIKATION

FLOT: Docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; Leucovorin 200 mg/m², d1; Oxaliplatin 85 mg/m², d1, q2w

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

Stratification: ECOG (0 or 1 vs. 2), localization(GEJ Type I vs. Type II/III vs. Gastric), age (< 60 vs. 60-69 vs. ≥70 years) and nodal status (cN+ vs. cN-).

Randomized, multicenter, Phase II/III Study

23% had Siewert type I33% had Siewert type II/III

5-FU, Leucovorin, Oxaliplatin and Docetaxel vsECF/ECX as preoperative chemotherapy for Gastro-Esophageal Adenocarcinoma: The FLOT-4 StudyResults on Overall Survival

ECF/ECX FLOT

mOS 35 months 50 months[27-46] [38-na]

HR 0.77 [0,63 – 0,94] p=0.012 (log rank)

2y. 59% 68% 3y. 48% 57% 5y. 36% 45%

OS rate* ECF/ECX FLOT

*projected OS-rates

Reprinted from The Lancet, 393(10184), Al-Batran SE, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial, 1948–57. Copyright 2019, with permission from Elsevier

TrialCT

ExperimentalNo. pts

pCRControl vs

Experimental

5-year survival

Control vsExp

HR(CI at 95%)

CunninghamN Eng J Med 2006

ECF 503 0% vs 8% 23% vs 36 %0.75

0.60-0.93p=0.009

Al-BatranASCO 2017

FLOT 716 5,8% vs 15,6% 36% vs 45%0.77

0.63-0.94P=0.012

Alderson +Lancet Oncol 2017

ECX 897 3% vs 11% 39% vs 42%*0.90

0.77-1.050.19

CunninghamLancet Oncol 2017

BEV-ECX 1063 8% vs 11% 50% vs 48%*1.09

0.91-1.290.36

Perioperative chemotherapy for localized Oesophago-gastric cancer: a new standard

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Al-Batran SA, et al 2017; 35(suppl): #40043. Alderson D. et al Lancet Oncol 2017 on line +Only Esophageal, *3 year OS4. Cunningham D, et. Lancet Oncology 2017; 18:357-370

Neoadjuvant chemotherapy in gastric cancer: Conclusions

Perioperative chemotherapy: Induces downstaging 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

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

Participation in trials

Treatment for localised gastric cancer: What is standard of care? ESMO guidelines

Gastric Cancer (Adenocarcinoma)

Operable Stage > T1N0

Preoperativechemotherapy

Consider endoscopic /

limited resection

Operable Stage T1N0

Surgery Adjuvantchemotherapy

Adjuvantchemoradiation

Surgery

Post-operative chemotherapy

Preferred pathway

Treatment for advanced gastric cancer: What is standard of care? ESMO guidelines

Waddell T, et al. Ann Oncol 2013;24(Suppl 6):57–63. By permission of the European Society of Medical Oncology

SurgeryRe-assess

HER-2 negativePlatinum+

fluorpyrimidine-based doublet or

triplet regimen

HER-2 positive

Trastuzumab+ CF/CX

Consider clinical trials of

novel agents

2nd line chemoClinical trials ifadequate PS

Palliative chemotherapy

Best supportivecare if unfit for

treatment

Inoperable ormetastatic

Treatment for metastatic/unresectablegastric cancer: Active agents in first line

Based upon superiority trials: 5-FU Cisplatin Docetaxel Trastuzumab

Based upon non-inferiority trials Oxaliplatin Capecitabine S1 Irinotecan

Cervantes A, et al. Cancer Treat Rev 2012; 39:60-67

Bestsupportive

care1

5-FU monotherapy1

Transtuzumab + CDDP+ FU or Cape6

EOX5

5-FU + LV + Oxaliplatin (FLO)4

Capecitabine + Cisplatin (XP)3

Docetaxel +Cisplatin + 5-FU2

4 months

7 months

9.2 months

10.5 months

10.7 months

11.2 months

13.8 months

MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER1. Wagner A, et al. JCO 2006. 2. van Cutsem E, et al. J Clin Oncol 2006;24:4991–4997. 3.Kang YK et al, Ann Oncol 2009; 20:666–73. 4. Al Batran SE, et al. J Clin Oncol 2008;26:1435–1442. 5. Cunningham D, et al. N Engl J Med 2008;358:36-46. 6. Bang YJ, et al. Lancet 2010;376:687–697EOX: Epirubicin/Oxaliplatin/Capecitabine.

Have we made any progress in the treatment of advanced gastric cancer?

1. Bang YJ, et al. Lancet 2010;376:687–697. 2. Van Cutsem E, J Clin Oncol 2012;30 (17):2119–2127. 3. Lordick F, Lancet Oncol2013;14:490–499. 4. Waddell T, Lancet Oncol 2013;14:481–489. 5. Cunigham ASCO 2015.. 6. Shah M. J Clin Oncol 2015;33(15)

Trial Chemotherapy Biological HROS

P value

Increase in median survival

ToGA1 Cisplatin+5-FU/ capecitabine Trastuzumab 0.74 0.04 +2.8 months

AVAGAST2 Cisplatin+ capecitabine Bevacizumab 0.87 0.10 +2.0 months

EXPAND3 Cisplatin+capecitabine Cetuximab 1.00 0.95 -1.3 months

REAL-34 Oxaliplatin+ epirubicin + capecitabine

Panitumumab 1.37 0.013 -2.5 months

RILOMET-15Cisplatin+

epirubiicin+capecitabine

Rilotumumab -- -- Stopped in futility analysis

METGASTRIC6 FOLFOX6 Onartuzumab 1.06 0.83 -0.6 months

Targeted therapies in first-line treatment for advanced gastric cancer: Summary of Phase III Trials

23

1. Bang YJ, et al. Lancet 2010;376:687–697.2. Hecht JR, et al. ASCO abstract 2013 LBA4001.3. Satoh N, et al. J Clin Oncol 2014; 32:2039–2049.4. Kang YK et al. ASCO GI 2016

Targeted therapies against HER2 in advanced gastric cancer: Summary of Phase III Trials on tratuzumab, lapatinib and TDM-1

TRIAL Chemotherapybackbone

Line of therapynumber

HROS

P value

Response rate

Increase in median survival

ToGA1 Cisplatin+5-FU/ capecitabine

First584 0.74 0.04 51% vs 37%

p=0.0017 +2.8 months

LOGiC2 Oxaliplatin/capecitabine

First545 0.91 0.35 53% vs 39%

p=0.031 +1.7 months

TyTAN3 Paclitaxel Second261 0.84 0.20 27% vs 9%

p=0.001 +2.1 months

GATSBY4 TDM-1 vs Taxane

Second228vs

117 1.15 0.85 NP - 0,7 months

1. Thuss-Patience PC, et al. Eur J Cancer 2011;47:2306–2314. 2. Kang JH, et al. J Clin Oncol 2012;30:1513–1518. 3. Ford HE, et al. Lancet Oncol 2014;15:78–86.

Trialauthor Year

Patients random

(n)Treatment Response

rate (%)HR OS

Pvalue

Gain in median survival

Thuss-Patience,et al.1 2011 40

1:1 Irinotecan NRSD 58% 0.48 0.0023 2.4

months

Kang, et al.2 2012 1932:1

IrinotecanDocetaxel NR 0.65 0.004 1.3

months

Ford, et al.3 2014 1681:1 Docetaxel NR 0.67 0.01 1.6

months

Gastric cancer: Second line chemotherapy. Trials comparing BSC versus active treatment

Ford HE, et al. Lancet Oncol 2014;15:78-86.

Gastric cancer second line chemotherapy: Docetaxel vs BSC (COUGAR-02 Trial) is improving survival

1. Thuss-Patience PC, et al. Eur J Cancer 2011;47:2306–2314. 2. Kang JH, et al. J Clin Oncol 2012;30:1513–1518. 3. Ford HE, et al. Lancet Oncol 2014;15:78–86. 4. Otshu A. et al. J Clin Oncol 2013;31:3935–3943. 5. Fuchs CS, et al. Lancet2014;383:31–39.

Trial author Year Patients random (n) Treatment HR

OSP

valueGain in median

survival

Thuss-Patience,et al.1 2011 40

1:1 Irinotecan 0.48 0.0023 2.4 months

Kang, et al.2 2012 1932:1

IrinotecanDocetaxel 0.65 0.004 1.3 months

Ford, et al.3 2014 1681:1 Docetaxel 0.67 0.01 1.6 months

Otshu, et al4 2013 6562:1 Everolimus 0.90 0.124 0.9 months

Fuchs, et al5 2014 3552:1 Ramucirumab 0.77 0.047 1.4 months

Gastric cancer: Second line chemotherapy trials comparing BSC versus active treatment

Reprinted from Fuchs CS, et al. Lancet Oncol 2014;383:31–39 © (2005) with permission from Elsevier

Gastric cancer second line treatment: Ramucirumab vs BSC (REGARD Trial) is improving survival

1. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444. 2. Wilke H, et al. Lancet Oncol 2014;15:1224–1235.

Trial author Year Patients (n) Treatment HR

OSP

valueGain in median

survival

Hironaka, et al.1 2013 223 Irinotecanvs paclitaxel 1.13 0.38 0.9 months

for irinotecam

Wilke et al.2 2014 665 Paclitaxel+/-ramucirumab 0.80 0.017 2.2 months

Gastric cancer: Second line chemotherapy trials comparing two active treatments

Gastric cancer second line treatment: Addition of ramucirumab to paclitaxel improves overall survival (Rainbow Trial)

Wilke HJ, et al. Lancet Oncol 2014;15:1224–1235© (2005) with permission from Elsevier

IMMUNOTHERAPY IN ADVANCEDGASTRO-OESOPHAGEAL ADENOCARCINOMAS

PEMBROLIZUMAB INDUCES RESPONSES IN CHEMOREFRACTORYGASTRIC CANCEREfficacy in evaluable patients in KEYNOTE-012

Central reviewN = 36a

Investigator reviewN = 39

ORR, % (95% CI) 22.2 (10.1, 39.2) 33.3 (19.1, 50.2)

Best overall response, n (%)

Complete responseb 0 0

Partial responseb 8 (22.2) 13 (33.3)

Stable disease 5 (13.9) 5 (12.8)

Progressive disease 19 (52.8) 21 (53.8)

No assessmentc 1 (2.8) —

Not determinedd 3 (8.3) —

Muro K, et al. Lancet Oncol 2016;17:717-726.

PEMBROLIZUMAB INDUCES RESPONSES IN CHEMOREFRACTORY GASTRIC CANCEREfficacy in evaluable patients in KEYNOTE-059Cohort 1

Fuchs CS, et al JAMA Oncol 2018;4:2180013.

Best overall responsea Participants (n=259)No. % (95% CI)

Objective response (CR+PR) 30 11.6 (8.0-16.1)Disease control (CR+PR+SD ≥2 mo) 70 27.0 (21.7-32.9)

CR (Complete response) 6 2.3 (0.9-5.0)PR (Partial response) 24 9.3 (6.0-13.5)SD (stable disease) 42 16.2 (11.9-21.3)Progressive disease 145 56.0 (49.7-62.1)Non evaluable 7 2.7 (1.1-5.5)No assessment 35 13.5 (9.6-18.3)

Duration of response, median (range), mo 8.4 (1.6+ to 17.3+)

Objective tumour response

a) Only confirmed responses are included.

A PHASE III STUDYPembrolizumab vs. weekly paclitaxel in second line for advanced gastroesophageal adenocarcinoma (KEYNOTE-061)

Objective I: PFS and OS as co-primary end-points in PDL1 Combined Positive Score ≥ 1 patientsObjectives II:

Toxicity Response rate Duration of response Time to progression

Shitara, K. et al. Lancet 2018; 392:123–133.

Stratification: Geographical

region PS 0 vs. 1

Arm A: Paclitaxel 80 mg/m2 days 1, 8 and 15 every 4 weeks

Arm B: Pembrolizumab 200 mg every 3 weeks

R1:1

PEMBROLIZUMAB NOT SUPERIOR TO WEEKLY PACLITAXELIn second line for advanced gastroesophageal adenocarcinoma in KEYNOTE-06

Time since randomisation (months)

Reprinted from The Lancet, 392(10142), Shitara, K. et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial, 123–133. Copyright 2018, with permission from Elsevier.

A PHASE III STUDYNivolumab vs. BSC in second line advanced gastroesophageal adenocarcinoma: The ATTRACTION-2 Trial

Shitara, K. et al. Lancet 2018; 392:123–133.

Objective I: OS Objectives II:

PFS Response rate, duration of response, disease control rate Time to progression Safety

Stratification: Geographical

region PS 0 vs. 1 No. of organs

with metastases (<2 or ≥2)

Arm A: Nivolumab 3 mg/kg/ IV every 2 weeks

Arm B: Placebo and BEST SUPPORTIVE CARE

R2:1

OVERALL SURVIVAL NIVOLUMAB VS. BSC IN ATTRACTION-2 TRIAL

Time (months)

Prob

abilit

y of s

urviv

al (%

)

22181614121086420

0

10

20

30

40

50

60

70

80

90

100

Hazard ratio, 0.63 (95% CI, 0.50–0.78) P<0.0001

0351019395795142

275

330 013341016325312

1163

NivolumabPlacebo

At risk:

20

19382

Patients, n

Events, n

Median OS [95% CI], months

12-Month OS Rate [95% CI],

%Nivolumab 330 225 5.32 [4.63–

6.41]26.6 [21.1–

32.4]Placebo 163 141 4.14 [3.42–

4.86]10.9 [6.2–17.0]

Reprinted from The Lancet Oncol, 390 (10111), Kang YK, Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial, 2461-2471. Copyright 2017, with permission from Elsevier.

9%

22%20%

50%

Cancer Genome Atlas Research Network. Nature 2014;513:202–209 This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported licence. Available under the Creative Commons CC-BY-NC-SA license .

PEMBROLIZUMAB INDUCES RESPONSES MAINLY IN MSI OR EBV+ GASTRIC CANCER

Reprinted by permission from Springer Nature, Nature Med, Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer, Kim ST, et al.;24:1449–1458. Copyright 2018.

Waterfall plot according to MSI/EBV status

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

Advanced Gastric cancer: Conclusions II

Most targeted therapies failed in molecularly unselected trials Immunotherapy (Pembrolizumab/Nivolumab) under development

with interesting data to be confirmed Nivolumab superior to BSC in a placebo controlled study Pembrolizumab not superior to weekly Paclitaxel in second line Avelumab not superior to third line chemotherapy EBV and MSI predictive factors to sensitivity for checkpoint inhibitors Understanding the mechanisms of primary resistance to checkpoint inhibitors will

lead us to precision immunotherapy in GEA First line trials underway Better selection of patients needed in clinical trials Validation of molecular classification in trials International cooperation