ADVANCES IN GASTRO- OESOPHAGEAL ADENOCARCINOMAS · GASTRO-OESOPHAGEAL ADENOCARCINOMA IHC score 0/1...

ADVANCES IN GASTRO-OESOPHAGEAL ADENOCARCINOMAS Biology and treatment for advanced disease

Valentina Gambardella and Andrés Cervantes

Dept. Medical Oncology

Biomedical Research institute INCLIVA

University of Valencia, Spain

OUTLINE

Molecular classification

◆ Pathology

◆ Classification after gene expression

◆ The Cancer Genome Atlas Research Network

Treatment for advanced disease

◆ First line

◆ Second line

◆ Third line

Immunotherapy

CLASSIFICATION OF GASTRIC ADENOCARCINOMA:

PATHOLOGY

Intestinal versus diffuse subtypes

Lauren P, et al. Acta Pathol Microbiol Scand 1965;64:31–49.

CLASSIFICATION OF GASTRIC ADENOCARCINOMA:

PATHOLOGY

Papillary carcinomas

Tubular carcinomas

Mucinous carcinomas

Poorly cohesive carcinomas (including signet ring cell carcinoma)

WHO Classification of Tumours of the Digestive System 4th Ed.2010 (International Agency for Cancer Research)

COMPREHENSIVE MOLECULAR CHARACTERISATION

OF GASTRIC ADENOCARCINOMA

Molecular platforms

Array-based somatic copy number analysis

Whole exome sequencing

Array-based DNA methylation profiling

Messenger RNA sequencing

RNA sequencing

Reverse Phase Protein Array (RPPA)

The Cancer Genome Atlas Research Network. Nature 2014;513:202–209.



Molecular platforms

Cancer Genome Atlas Research Network. Nature 2014;513:202–9. Available under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence (https://creativecommons.org/licenses/by-nc/4.0/. Accessed June 2019.

https://creativecommons.org/licenses/by-nc/4.0/

9%

22%20%

50%

Cancer Genome Atlas Research Network. Nature 2014;513:202–9. Available under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence (https://creativecommons.org/licenses/by-nc/4.0/. Accessed June 2019.

THE MOLECULAR CLASSIFICATION OF GASTRIC

CANCER ACCORDING TO THE CANCER GENOME ATLAS




The ACRG approach

Reprinted by permission from Springer Nature: Nature Medicine, Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes, Cristescu R, et al. 21:449–56, copyright 2015.



The ACRG approach predicts survival

Reprinted by permission from Springer Nature: Nature Medicine, Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes,,Cristescu R, et al. 21:449–456, copyright 2015.

INTEGRATED GENOMIC CHARACTERISATION OF

OESOPHAGEAL CANCERS

Cancer Genome Atlas Research Network. Nature 2017;541;169–75. Available under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence (https://creativecommons.org/licenses/by-nc/4.0/. Accessed June 2019)


INTEGRATED GENOMIC CHARACTERISATION OF

OESOPHAGEAL CANCERS

Squamous cell cancers

Vs.

Adenocarcinomas

Cancer Genome Atlas Research Network. Nature 2017;541;169–75. Available under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence (https://creativecommons.org/licenses/by-nc/4.0/. Accessed June 2019)


TREATMENT FOR METASTATIC/UNRESECTABLE

GASTRIC 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.

BSC1

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 CANCER

HAVE WE MADE ANY PROGRESS IN THE TREATMENT

OF ADVANCED GASTRIC CANCER?

1. Wagner AD, et al. J Clin Oncol 2006;24:2903–9. 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;376:687–697.

BSC: Best supportive care; CDDP, cisplatin; EOX: Epirubicin/Oxaliplatin/Capecitabine; 5-FU, 5-fluorouracil.

5-FU monotherapy vs. BSC1

Transtuzumab +

CDDP + FU/Cape6

EOX5

FLO4

XP3

DCF2

HR: 0.39 p<0.00001

HR: 0.77 p=0.02

HR: 0.85 p=0.008

HR: Not shown p=0.506

HR: 0.80 p=0.02

HR: 0.74 p=0.0046

RISK OF DEATH REDUCTION IN ADVANCED GASTRIC CANCER

Combination vs. monotherapy1 HR: 0.83 p=0.001

HAVE WE MADE ANY PROGRESS IN THE TREATMENT

OF ADVANCED GASTRIC CANCER?

1. Wagner AD, et al. J Clin Oncol 2006;24:2903–9. 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;376:687–697.

EOX: Epirubicin/Oxaliplatin/Capecitabine; FLO: 5-FU/leucovorin/Oxaliplatin; XP: Capecitabine/CDDP. CDDP, cisplatin; DCF: Docetaxel/CDDP/5-FU; BSC: Best supportive care.

FFCD-GERCOR-FNCLCC 03-07 PHASE III STUDY.

FOLFIRI VS. ECF IN ADVANCED GASTRIC CANCER

Time between randomisation and:

1/ progression

Or 2/ TT discontinuation

Or 3/ death

Objective I: 1st line Time-to-Treatment Failure (TTF)

Objectives II:

◆ PFS, OS, (TTF 2nd line)

◆ Toxicity

◆ Response rate, QoL

Guimbaud R, et al. J Clin Oncol 2014;32:3520–3526.

ECX: D1 = Epirubicin 50 mg/m² (15 min.), Cisplatin 60 mg/m² (1 h); D2 to 15: Capecitabine 1 g/m² x 2/d. D1 = D21. Cumulated dose of Epirubicin < 900 mg/m² (max 18 cures)

FOLFIRI: D1 = Irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2h), 5FU b 400 mg/m², 5FU c.i. 2400 mg/m² (46h). D1 = D14.

Stratification:

◆ Measurable or not

◆ PS WHO 0-1 or 2

◆ Adj (R)CT or not

◆ Linitis or not

◆ Cardial or gastric

◆ Center

A: ECX until progression;

then FOLFIRI 2nd line

B: FOLFIRI until progression;

then ECX 2nd line

R

FFCD-GERCOR-FNCLCC 03-07 PHASE III STUDY

FOLFIRI vs. ECF in advanced gastric cancer

Objective I: 1st line Time-to-Treatment Failure (TTF)

0.4

0.2

0.6

0.8

1.0

TT

F (

prop

ortio

n)

02 4 60 8 10

Time (months)No. at risk

ECX 209 145 108 61 33 14 8 5 4

FOLFIRI 207 157 123 81 50 28 19 9 6

12 14 16

ECX

FOLFIRI

HR, 0.77; 95% CI, 0.63 to 0.93; P=0.008

ECX arm: Epirubicin, cisplatin, and

capecitabine as the first-line treatment.

FOLFIRI arm: Irinotecan, leucovorin,

fluorouracil bols, and continuous infusion as

the first-line treatment.

ECX: D1 = Epirubicin 50 mg/m² (15 min.), Cisplatin 60 mg/m² (1 h); D2 to 15: Capecitabine 1 g/m² x 2/d. D1 = D21. Cumulated dose of Epirubicin < 900 mg/m² (max 18 cures)

FOLFIRI: D1 = Irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2h), 5FU b 400 mg/m², 5FU c.i. 2400 mg/m² (46h). D1 = D14.

Guimbaud R, et al. J Clin Oncol 32(31), 2014:3520–26. Reprinted with permission. © 2014. American Society of Clinical Oncology. All rights reserved.

FFCD-GERCOR-FNCLCC 03-07 PHASE III STUDY

FOLFIRI vs. ECF in advanced gastric cancer

Objective II: Response Rate (RR), PFS and OS

ECF

N=209

FOLFIRI

n=207p value

RR 1st

RR 2nd

39.2%

10.1%

37.8%

13.7%n.s.

PFS (months)

Median range

5.29

4.53-6.31

5.75

5.19-6.740.96

OS (months)

Median range

9.49

8.77-11.14

9.72

8.54-11.270.95

Guimbaud R, et al. J Clin Oncol 2014;32:3520–3526.

PHASE III STUDY OF CF VS. DCF

Showing improved survival by the addition of docetaxel in first line for

advanced gastric cancer

HR: 1.29 (95% CI, 1.0–1.6)

Van Cutsem E, et al. J Clin Oncol 33, 2006:3874–9. Reprinted with permission. © 2006 American Society of Clinical Oncology. All rights reserved.

PHASE II STUDY OF MODIFIED DCF VS. DCF PLUS

G-CSF IN ADVANCED GASTRIC CANCER

Shah MA, et al. J Clin Oncol 2015;33:3874–3879.

Stratification:

◆ Measurable or not

◆ Gastric vs. GEJ

◆ Centre

A: modified DCF

B: standard DCF plus G-CSF

R

Objective: 6 months-PFS

Objectives II: RR, OS, Toxicity



Randomly assigned treatment

Shah MA, et al. J Clin Oncol 2015;33:3874–3879.

Drug Dose (mg/m2) Schedule

Arm A (mDCF)

Docetaxel 40 Day 1 IVPB (60 minutes)

Leucovorin 400 Day 1 IVPB (30 minutes)

Fluorouracil 400 Day 1 IVP

Fluororacil 1,000 (per day) IVCI daily x2 days

Cisplatin 40 Day 2 or 3 IVPB (30 minutes)

Arm B (parent DCF plus G-CSF)

Docetaxel 75 Day 1 IVPB (60 minutes)

Cisplatin 75 Day 1 IVPB (60 minutes)

Fluorouracil 750 (per day) IVCI daily x5 days

Neulasta* 6 mg Subcutaneous on day 8, 9, or 10

Neupogen* 300 or 480 μg† Subcutaneous x7 days (days 10 to 17)

DOCETAXEL + OXALIPLATIN + 5FU-LV/CAPECITABINE

TE VS. TEF VS. TEX

Van Cutsem E, et al. Ann Oncol 2015;26:149–156, by permission of Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved..

DOCETAXEL + OXALIPLATIN + 5FU-LV/CAPECITABINE

TE VS. TEF VS. TEX

Treatment Patients

(n)

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 89 46.6 35.9–57.5 7.66 6.97–9.40 14.59 11.7–21.8

Van Cutsem E, et al. Ann Oncol 2015;26:149–156.

TREATMENT FOR ADVANCED GASTRIC CANCER:

WHAT IS STANDARD OF CARE?

ESMO Guidelines

Surgery

Re-assess

HER-2 negative

Platinum+

fluorpyrimidine-

based doublet or

triplet regimen

HER-2 positive

Trastuzumab

+ CF/CX

Consider clinical

trials of

novel agents

2nd line chemo

Clinical trials if

adequate PS

Palliative

chemotherapy

Best supportive

care if unfit for

treatment

Inoperable or

metastatic

Smyth E, et al. Ann Oncol 2016. By permission of Oxford University Press/ on behalf of ESMO.

Adapted with permission © Lordick, F. Nat. Rev. Clin. Oncol 2015;12:7–8.

ASSESSMENT OF HER2 AMPLIFICATION IN ADVANCED

GASTRO-OESOPHAGEAL ADENOCARCINOMA

IHC score 0/1 IHC score 2

Treatment of advanced gastro-oesophageal cancer

Molecular stratification according to HER2 status

IHC score 3

ISH-test HER2

Platin-fluoropyrimidine

+/- docetaxel or epirubicin

Cisplatin-fluoropyrimidine +

trastuzumab

ISH– ISH+

Progression: evaluation of ECOG performance status, efficacy and tolerability of first-line

chemotherapy, patient preferences and the need for remission

ECOG PS 0-1 need for remission ++ ECOG PS 0-2 need for remission +/- ECOG PS 2-4 or patient preference

Paclitaxel + ramucirumab Ramucirumab monotherapy or irinotecan

monotherapy or taxane monotherapy Active symptom control

PHASE III STUDY ON THE ADDITION OF TRASTUZUMAB

TO CISPLATIN-BASED CHEMOTHERAPY

In first-line for HER2 amplified gastro-oesophageal adenocarcinomas

Reprinted from The Lancet, 376 (9742), Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer

(ToGA): a phase 3, open-label, randomised controlled trial; 687–697. Copyright 2010, with permission from Elsevier.

Trial Chemotherapy Biological HR OS P value Increase in median survival

ToGA1 Cisplatin+5-FU/

capecitabineTrastuzumab 0.74 0.04 +2.8 months

AVAGAST2 Cisplatin+ capecitabine Bevacizumab 0.87 0.10 +2.0 months

AVATAR3 Cisplatin+ capecitabine Bevacizumab 1.11 0.55 -0.9 months

RAINFALL4 Cisplatin+5-FU/ capecitabine Ramucirumab 0.96 0.68 0.5 month

EXPAND5 Cisplatin+

capecitabineCetuximab 1.00 0.95 -1.3 months

REAL-36 Oxaliplatin+ epi- +

capecitabinePanitumumab 1.37 0.013 -2.5 months

RILOMET-17 Cisplatin+epi+

capecitabineRilotumumab -- -- Stopped in futility analysis

METGASTRIC8 FOLFOX6 Onartuzumab 1.06 0.83 -0.6 months

PHASE III TRIALS WITH TARGETED THERAPIES IN

FIRST-LINE TREATMENT

For advanced gastro-oesophageal adenocarcinomas

1. Bang YJ, et al. Lancet 2010;376:687–697. 2. Van Cutsem E, J Clin Oncol 2012;30 (17):2119–2127. 3. Shen L, et al. Gastric Cancer 2015. 4. Fuchs CS, et al. Lancet Oncol 2019

5. Lordick F, Lancet Oncol 2013;14:490–499. 6. Waddell T, Lancet Oncol 2013;14:481–489. 7. Catenacci DVT, et al. Lancet Oncol 2017; 18:1467-1482.

8. Shah M. JAMA Oncol 2016; 3:620-627.

PHASE III TRIALS ON HER2 BLOCKADE

For HER2 amplified advanced gastro-oesophageal adenocarcinomas

TRIALChemotherapy

backbone

Line of

therapy

number

HR

OSP value Response rate

Increase in median

survival

ToGA1 Cisplatin+5-FU/

capecitabine

First

5840.74 0.04

51% vs. 37%

p=0.0017+2.8 months

LOGiC2 Oxaliplatin/

capecitabine +/-Lapatinib

First

5450.91 0.35

53% vs. 39%

p=0.031+1.7 months

TyTAN3 Paclitaxel+/-LapatinibSecond

2610.84 0.20

27% vs. 9%

p=0.001+2.1 months

GATSBY4 TDM-1

vs. Taxane

Second

3451.15 0.85 NP - 0,7 months

JACOB5

Cisplatin+5-FU/

cap/Trastu

+/- Pertuzumab

First

7800.84 0.056

56% vs. 48%

P=0.0263.3 months

HETEROGENEITY FOR HER2 STAINING IN GEA

Gambardella V, et al. Towards precision oncology for anti-HER2 blockade in gastroesophageal adenocarcinoma, Annals of Oncology, mdz143, https://doi.org/10.1093/annonc/mdz143

Published: 02 May 2019. by permission of Oxford University Press on behalf of the European Society for Medical Oncology.

Trial author YearPatients

random (n)Treatment

Response

rate (%)

HR

OS

P

value

Gain in median

survival

Thuss-Patience PC, et al.1 201140

1:1Irinotecan

NR

SD 58%0.48 0.0023 2.4 months

Kang JH, et al.2 2012193

2:1

Irinotecan

DocetaxelNR 0.65 0.004 1.3 months

Ford HE, et al.3 2014168

1:1Docetaxel NR 0.67 0.01 1.6 months

GASTRO-OESOPHAGEAL ADENOCARCINOMAS

Second line chemotherapy trials comparing BSC versus active treatment

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.

Trial author YearPatients

random (n)Treatment

HR

OS

P

value

Gain in median

survival

Thuss-Patience PC, et al.1 201140

1:1Irinotecan 0.48 0.0023 2.4 months

Kang JH, et al.2 2012193

2:1

Irinotecan

Docetaxel0.65 0.004 1.3 months

Ford HE, et al.3 2014168

1:1Docetaxel 0.67 0.01 1.6 months

Otshu A, et al.4 2013656

2:1Everolimus 0.90 0.124 0.9 months

Fuchs CS, et al.5 2014355

2:1Ramucirumab 0.77 0.047 1.4 months


Second line chemotherapy and targeted agent trials comparing BSC

versus active treatment

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. Lancet 2014;383:31–39.

Trial author Year Patients (n) TreatmentHR

OS

P

value

Gain in median

survival

Hironaka S, et al.1 2013 223Irinotecan

vs. paclitaxel1.13 0.38

0.9 months

For Irinotecam

Wilke H, et al.2 2014 665Paclitaxel+/-

ramucirumab0.80 0.017 2.2 months

Shitara K, et al.3

KEYNOTE-061 2018592

1:1

Pembrolizumab vs.

wk Paclitaxel0.82 0.084

0.8 months

for Pembrolizumab


Second line trials comparing two active treatments

1. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444. 2. Wilke H, et al. Lancet Oncol 2014;15:1224–1235. 3. Shitara K, et al. Lancet 2018; 392:123–133

Tyrosine kinase inhibitors (TKIs)

(Apatinib, regorafenib, SU5416, SU6668,

sunitinib, vatalanib, sorafenib, cediranib,

AEE788, AMG-706, KRN-951)

Anti-VEGFR MAbs

(IMC-1C11, Ramucirumab)

Signal transduction

R R

K K

LigandsAnti-VEGF MAbs

(Bevacizumab)Soluble receptors

(VEGF Trap, aflibercept)

Ribozymes

Anti-PlGF MAbs (TB-403)

CLINICAL ANTI-VEGF PATHWAY THERAPIES

Modified from Tabernero J, et al. Ann Oncol 2005;16:1740–1748, by permission of the European Society of Medical Oncology.

GASTRIC CANCER SECOND LINE TREATMENT

Paclitaxel+/-ramucirumab (Rainbow Trial)

Wilke HJ, et al. Lancet Oncol 2014;15:1224–1235.

Main aim: Overall survival

Stratification by:

◆ Measurable vs. non-measurable

◆ Time to progression after first line: < or > 6

month

◆ Geographic region

663 patients needed to show a HR of 0.75 in favour of

paclitaxel + ramucirumab with two-sided alfa 0.05 and

90% power

Arm A: Paclitaxel 80 mg/m2 day 1, 8, 14 every 28 days

plus Placebo

Arm B: Paclitaxel 80 mg/m2 day 1, 8, 14 every 28 days

Ramucirumab 8 mg/kg every 2 weeks

R

1:1


SECOND LINE TREATMENT

Addition of ramucirumab to paclitaxel improves overall survival (Rainbow Trial)

Reprinted from The Lancet Oncol, 15(11), Wilke HJ, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma

(RAINBOW): a double-blind, randomised phase 3 trial, 1224–1235; © 2014 with permission from Elsevier.


SECOND LINE TREATMENT

Addition of ramucirumab to paclitaxel is tolerable (Rainbow Trial)

Ramucirumab plus paclitaxel

(n=327)

Placebo plus paclitaxel

(n=329)

Grades 1-2 Grade 3 Grade 4 Grade 5 Grades 1-2 Grade 3 Grade 4 Grade 5

Bleeding or

haemorrhage123 (38%)

12

(4%)

1

(<1%)

1

(<1%)51 (16%)

4

(1%)

2

(<1%)

2

(<1%)

Proteinuria 51 (16%)4

(1%)0 0

20

(6%)0 0 0

Liver injury or failure 39 (12%)12

(4%)

3

(<1%)0

28

(9%)

11

(3%)

2

(<1%)0

Hypertension 34 (10%) 48 (15%) 0 010

(3%)

9

(3%)0 0

Gastrointestinal

haemorrhage

21

(6%)

10

(3%)

1

(<1%)

1

(<1%)

15

(5%)

3

(<1%)

1

(<1%)

1

(<1%)

Wilke HJ, et al. Lancet Oncol 2014;15:1224–1235.

NEW ANTI-ANGIOGENETICS

Background of apatinib

Apatinib (YN968D1)1

◆ A new small molecular tyrosine kinase inhibitor that highly and selectively inhibits the VEGFR2

◆ The MTD is determined to be 850 mg/day administered orally

Phase I / IIa study (N=65)1

◆ CR: 1.54%, PR: 12.31%, SD: 66.15%

◆ DCR: 80.00%

◆ PD: 20.00%

Li J, et al. J Clin Oncol 2013; 31:3219-3225.

CN

N

NH

O

N

NH .CH3SO3H

Li J, et al. J Clin Oncol 2013;31:3219–3225.

APATINIB IN ADVANCED GASTRIC CANCER:

Phase III study design vs. placebo

Design: Multicenter, randomised, double-blind, placebo-controlled clinical trial

1 treatment cycle = 28 days

Stratification factor: Number of metastatic sites (≤ 2 vs. >2)

Advanced gastric cancer previously

failed with the 2nd chemotherapy

(N=273)R

Apatinib

850 mg po. QD 28 days as 1 cycle

(N=181)

Placebo

po. QD 28 days as 1 cycle

(N=92)

Crossover

(N=14)

2:1

Ji L, et al. J Clin Oncol 2016:34:1448-1454.

Group n mOS (95% CI), months P value HR (95%CI)

Apatinib 176 6.5 (4.8–7.6)0.0149

0.709(0.537–0.937)Placebo 91 4.7 (3.6–5.4)

APATINIB IMPROVES SURVIVAL OVER PLACEBO IN

THIRD LINE FOR ADVANCED GASTRIC CANCER

Jin Li, et al. J Clin Oncol 34(13), 2016:1448-1454. Reprinted with permission. © 2016. American Society of Clinical Oncology. All rights reserved..

Trial author YearPatients random

(n)Treatment

HR

OS

P

value

mOS and

Gain in median survival

Li J, et al.1

Apatinib

Third line

2016273

2:1Apatinib vs. placebo 0,70 0,0149

6.5 vs. 4.7

1.8 months

Shitara K, et al.2

TAGS

Third line

2018507

2:1

Trifluridine/tipiracil vs.

BSC0.69 0.0003

5.7 vs. 3.6

2.1 months

Bang YJ, et al.3

JAVELIN 300

Third or further lines

2018371

1:1

Avelumab vs. investigator

choice of chemotherapy1.10 ns

4.6 vs. 5.0

-0.4 months

Kang JK, et al.4

ATTRACTION-2


2017493

2:1Nivolumab vs. BSC 0.63 0.0001

5.26 vs. 4.14

1.12 months


Third or further line therapy randomised trials comparing with BSC or

active treatment

1. Jin Li, et al. J Clin Oncol 2016:34:1448-1454. 2. Shitara K, et al. Lancet Oncol 2018; 19:1437–48. 3. Bang YJ, et al. Ann Oncol 2018; 29:2052-60.

4. Kang JK, et al. Lancet 2017;390:2461-71.

TRIFLURIDINE/TIPIRACIL (TAS 102) PROLONGS

SURVIVAL IN THIRD LINE ADVANCED GASTRIC CANCER

Design: Multicentre, randomised, double-blind, placebo-controlled clinical trial

Endpoints: OS

Stratification

◆ Region (Japan vs. rest of the world)

◆ PS (0 vs. 1)

◆ Previous ramucirumab (yes vs. no)

Advanced gastric cancer previously

failed with the 2nd chemotherapy

(N=507)R

TAS-102 + BSC

35 mg po twice daily

Day 1-5 and 8-12 every 28 days

(N=337)

Placebo + BSC

35 mg po twice daily

Day 1-5 and 8-12 every 28 days

(N=170)

2:1

Shitara K, et al. Lancet Oncol. 2018;19(11):1437-1448

TRIFLURIDINE/TIPIRACIL (TAS 102) PROLONGS

SURVIVAL IN THIRD LINE ADVANCED GASTRIC CANCER

Reprinted from Lancet Oncol. 19(11), Shitara K, et al., Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial, 1437-1448,

Copyright 2018 with permission from Elsevier.

IMMUNOTHERAPY IN ADVANCEDGASTRO-OESOPHAGEAL ADENOCARCINOMAS

PEMBROLIZUMAB INDUCES RESPONSES IN

CHEMOREFRACTORY GASTRIC CANCER

Efficacy in evaluable patients in KEYNOTE-012

Central review

N = 36a

Investigator review

N = 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.

KEYNOTE-059

Phase 2 study of pembrolizumab for advanced gastric or GEJ adenocarcinoma

Primary end point: ORR per RECIST v1.1 by central review

COHORT 1

◆ PD-L1+ or PD-L1–

◆ ≥2 prior treatments

Pembrolizumab

200 mg Q3W

Pembrolizumab 200 mg +

Cisplatin + 5FU, all Q3W

N = 259

COHORT 2

◆ PD-L1+ or PD-L1–

◆ No prior therapy

N = 25

COHORT 3

◆ PD-L1+ only

◆ No prior therapy

N = 31

Pembrolizumab

200 mg Q3W

Modified from Muro K, et al. ASCO GI 2015; Abstract nr.03.

PEMBROLIZUMAB INDUCES RESPONSES IN

CHEMO REFRACTORY GASTRIC CANCER


Cohort 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.

ORR 60% (15/25)

PEMBROLIZUMAB INDUCES RESPONSES IN FIRST LINE

GASTRIC CANCER IN COMBINATION WITH CHEMOTHERAPY


Cohort 2

Bang YJ, et al. Gastric Cancer 2019; doi.org/10.1007/s10120-018-00909-5.This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/),.

ORR 25.8% (8/31)

Bang YJ, et al. Gastric Cancer 2019; doi.org/10.1007/s10120-018-00909-5 Distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), .

PEMBROLIZUMAB INDUCES RESPONSES IN FIRST

LINE GASTRIC CANCER AS SINGLE AGENT


Cohort 3

A PHASE III STUDY

Pembrolizumab vs. weekly paclitaxel in second line for advanced

gastro-oesophageal adenocarcinoma (KEYNOTE-061)

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

Objectives 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

R

1:1

Trial author Year Patients (n) TreatmentHR

OS

P

value

Gain in median

survival

Hironaka S, et al.1 2013 223Irinotecan

vs. paclitaxel1.13 0.38

0.9 months

for irinotecam

Wilke H, et al.2 2014 665Paclitaxel+/-

ramucirumab0.80 0.017

2.2 months

for ramucirumab

Shitara K, et al.3

KEYNOTE-061 2018592

1:1

Pembrolizumab vs.

wk paclitaxel0.82 0.084

0.8 months

for pembrolizumab

PEMBROLIZUMAB NOT SUPERIOR TO WEEKLY

PACLITAXEL

In second line for advanced gastro-oesophageal adenocarcinoma

1. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444. 2. Wilke H, et al. Lancet Oncol 2014;15:1224–1235. 3. Shitara K, et al. Lancet 2018;392:123–133.

PEMBROLIZUMAB NOT SUPERIOR TO WEEKLY

PACLITAXEL

In second line for advanced gastro-oesophageal 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.

CHECKMATE 032 EG COHORT

*Nivolumab + ipilimumab administered for 4 cycles followed by nivolumab 3 mg/kg IV Q2W.†Time from first dose to data cut-off; follow-up was shorter for patients who died prior to data cut-off.

Presented By Dr Yelena Janjigian at 2017 ASCO Annual Meeting.

Western patients with advanced/metastatic esophagogastric (including gastric/esophageal/gastro-oesophageal junction cancer)

cancer with progression on ≥1 prior chemotherapy N=160

Nivolumab 3 mg/kg IV Q2W

(NIVO 3)

Nivolumab 1 mg/kg +

ipilimumab 3 mg/kg IV Q3W*

(NIVO 1 + IPI 3)

Nivolumab 3 mg/kg +

ipilimumab 1 mg/kg IV Q3W*

(NIVO 3 + IPI 1)

Primary endpoint:

◆ ORR per RECIST v1.1

Secondary endpoints:

◆ OS, PFS, time to response,

duration of response

◆ Safety

Exploratory endpoint:

◆ PD-L1 tumour expression

(Dako 28-8 pharmDx assay)

Median (range) follow-up, mo†: 28 (17 to 35) 24 (21 to 33) 22 (19 to 25)

BEST REDUCTION IN TARGET LESIONS

*Investigator review. #Patients with confirmed response (complete or partial response). †Patients with 0% best reduction in target lesion, including 3 patients with PD-L1 ≥1% (NIVO 3, n=2;

NIVO 3 + IPI 1, n=1) and 1 patient with PD-L1 <1% (NIVO 1 + IPI 3). □Change truncated to 100%.Janjigian YY, et al. J Clin Oncol 2017;35(Suppl):Abstract 4014. With permission from Dr Janjigian; Janjigian YY, et al. J Clin Oncol 2018;36(28):2836–44. © 2018 by American Society of Clinical. Oncology. Creative Commons

Attribution Non-Commercial No Derivatives 4.0 License. https://creativecommons.org/licenses/bync-nd/4.0/; accessed June 2019

Responses were observed regardless of PD-L1 expression

NIVO 3 NIVO 1 + IPI 3 NIVO 3 + IPI 1

https://creativecommons.org/licenses/bync-nd/4.0/

OVERALL SURVIVAL

mOS, median OS.Janjigian YY, et al. J Clin Oncol 2017;35(Suppl):Abstract 4014. With permission from Dr Janjigian; Janjigian YY, et al. J Clin Oncol 2018;36(28):2836–44. © 2018 by American Society of Clinical. Oncology. Creative Commons

Attribution Non-Commercial No Derivatives 4.0 License. https://creativecommons.org/licenses/bync-nd/4.0/; accessed June 2019.

https://creativecommons.org/licenses/bync-nd/4.0/

A PHASE III STUDY

Nivolumab vs. BSC in second line advanced gastro-oesophageal

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

R

2:1

Trial author YearPatients random

(n)Treatment

HR

OS

P

value

mOS and

Gain in median survival

Li J, et al.1

Apatinib

Third line

2016273

2:1Apatinib vs. placebo 0,70 0,0149

6.5 vs. 4.7

1.8 months

Shitara K, et al.2

TAGS

Third line

2018507

2:1

Trifluridine/tipiracil vs.

BSC0.69 0.0003

5.7 vs. 3.6

2.1 months

Bang YJ, et al.3

JAVELIN 300


2018371

1:1

Avelumab vs.

investigator choice of

chemotherapy

1.10 ns4.6 vs. 5.0

-0.4 months

Kang JK, et al.4

ATTRACTION-2


2017493

2:1Nivolumab vs. BSC 0.63 0.0001

5.26 vs. 4.14

1.12 months


Third or further line therapy randomised trials comparing with BSC or

active treatment

1. Ji L, et al. J Clin Oncol 2016:34:1448-1454. 2. Shitara K, et al. Lancet Oncol 2018; 19:1437–48. 3. Bang YJ, et al. Ann Oncol 2018; 29:2052-60.

4. Kang JK, et al. Lancet 2017;390:2461-71.

OVERALL SURVIVAL NIVOLUMAB VS. BSC IN

ATTRACTION-2 TRIAL

Time (months)

Pro

bab

ility

of

surv

ival

(%

)

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

0351019395795142275330

0133410163253121163

Nivolumab

Placebo

At risk:

20

193

82

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 .

THE MOLECULAR CLASSIFICATION OF GASTRIC

CANCER ACCORDING TO THE CANCER GENOME ATLAS

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

PAN-TUMOUR GENOMIC BIOMARKERS FOR PD-1

CHECKPOINT BLOCKADE–BASED IMMUNOTHERAPY

From Cristescu R, et al. Science 2018;362(6411):eaar3593. Reprinted with permission from AAAS.

EPIGENOMIC PROMOTER ALTERATIONS PREDICT FOR

BENEFIT FROM IMMUNE CHECKPOINT INHIBITION

In metastatic gastric cancer

Sundar R, et al. Ann Oncol 2019; 30 (3): 424–430, doi:10.1093/annonc/mdy550, by permission of Oxford University Press on behalf of the European Society for Medical Oncology.

◆ 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


Conclusions I

◆ Immunotherapy (Pembrolizumab and 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


Conclusions II

THANK YOU!

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