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