ESMO Oesophageal cancer webinar.

1. OESOPHAGEAL CANCER WEBINAR
Management strategies of patients with oesophageal
cancer

2. INTRODUCTION
Faculty

3. INTRODUCTION
Programme
Welcome and Introduction
Andrès Cervantes
Optimal multimodality management of localized oesophageal cancer
Radka Obermannová
The role of immune checkpoint inhibitors in the continuum of care for patients with advanced oesophageal cancer
Ian Chau
Presentation of a clinical case and management focusing on the role of biomarkers for prognostication and
prediction of benefit from immunotherapeutic approaches
Sarah Derks
Q&A
All faculty

4. OESOPHAGEAL CANCER
Introduction
Prof. Andrés Cervantes MD PhD

5. DISCLOSURE OF INTERESTS
Consultant or Advisory Role: Merck Serono, Roche, Beigene, Takeda and Astellas.
Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas,
Fibrogen, Natera, Astra Zeneca, Medimmune, BMS, MSD.
Speaking: Merck Serono, Roche, Amgen, Foundation Medicine.

6. OESOPHAGEAL CANCER: GLOBAL INCIDENCE AND
MORTALITY
Sung H, et al. Global Cancer Statistics 2020. CA Cancer J Clin 2021; 71:209-249.

7. REGION-SPECIFIC INCIDENCE AGE-STANDARDIZED
RATES BY SEX FOR OESOPHAGEAL CANCER IN 2020
Sung H, et al. Global Cancer Statistics 2020. CA Cancer J Clin 2021; 71:209-249.

8. OESOPHAGEAL CANCER TUMOUR FEATURES
◆ Oesophageal cancer is the sixth most common cause of cancer-related deaths worldwide.
◆ Squamous cell carcinomas
◆ Upper and mid-oesophagus location
◆ Smoking and alcohol related in Western
countries
◆ More prevalent in developing countries
◆ Adenocarcinomas
◆ Lower third and junctional location
◆ Related to obesity, smoking, gastric reflux
and
◆ Barret’s oesophagus
◆ Increasing incidence in Western countries
(x4.6 US)

9. INTEGRATED GENOMIC CHARACTERISATION OF
OESOPHAGEAL CANCERS
Cancer Genome Atlas Research Network. Nature. 2017; 12:169-175.

10. THE TUMOUR IMMUNE MICROENVIRONMENT
COMPOSITION OF OESOPHAGEAL SQUAMOUS CELL CARCINOMA
Baba Y, et al. Cancer Sci. 2020; 111:3132-3141

11. OESOPHAGEAL CANCER
Learning objectives
• To understand the best standard approach for patients with localized oesophageal cancer
• To select the optimal sequence of Immune Checkpoint Inhibitors when treating advanced
oesophageal cancer
• To properly use different predictive biomarkers to get the maximum benefit of Immune
Checkpoint Inhibitors

12. esmo.org
Contacts ESMO
European Society for Medical Oncology
Via Ginevra 4, CH-6900 Lugano
T. +41 (0)91 973 19 00
esmo@esmo.org
Thank you

13. CURRENT AND FUTURE MANAGEMENT
STRATEGIES OF PATIENTS WITH
OESOPHAGEAL CANCER
The role of immune checkpoint inhibitors in the continuum
of care of patients with advanced oesophageal cancer
Professor Ian Chau
Consultant Medical Oncologist
The Royal Marsden Hospital
London & Surrey

14. THE CANCER GENOME ATLAS OESOPHAGO-GASTRIC
CANCER
The Cancer Genome Atlas Research Network; Nature 2017

15. RMH METASTATIC SCC VS. ADENOCARCINOMA
POOLED ANALYSIS FROM 3 RCTS (N=973)
2
3
5
6
11
26
79
315
841
Adeno
1
1
1
1
3
5
12
37
132
Squam
Number at risk
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Years since randomisation
%
Survival
Adeno
Squam
HR 0.85 (95% CI; 0.70-1.03, p=0.09)
n=841
n=132
Davidson et al World J Gastrointest Oncol 2017
Adeno SCC
N 841 132
mOS 9.4 months 7.6 months

16. PD-1 INHIBITORS IN PREVIOUSLY TREATED
OESOPHAGEAL CANCER
KEYNOTE-181
(KN-181)1
ATTRACTION-3
(ATT-3) 2 ESCORT3 RATIONALE 3024
Regions
32 countries
(Asian, 39%)
8 countries
(Asian, 96%)
China Global
Anti-PD-1
> Pembrolizumab
> 200 mg Q3W up to
35 cycles or
intolerance
> Nivolumab
> 240 mg Q2W until PD
or intolerance
> Camreli-zumab
> 200 mg Q2W
until PD or
intolerance
> Tislelizumab
> 200mg Q3 W until
PD or intolerance
Chemo
Control
> Paclitaxel/Docetaxel
/ Irinotecan
> Paclitaxel/ Docetaxel
> Docetaxel/
Irinotecan
> Paclitaxel/Doce-
taxel/irinotecan
Histology > SCC and ADC > SCC only > SCC only > SCC only
Tumor
Assessment
> Every 9 weeks
> Every 6 weeks for 1
year then every 12
weeks
> Every 8 weeks > Not reported
Primary
Endpoints
> OS (ITT),
> OS (SCC),
> OS (CPS≥ 10)
> OS > OS > OS
> EC Progressed on
1st-line
chemotherapy for
advanced disease
> Progression during
or within 6 months
CRT
> Measurable disease
by RECIST 1.1
R
A
N
D
O
M
I
Z
A
T
I
O
N
ANTI-PD-1 mAb
2ND LINE CHEMOTHERAPY
> 1:1 randomization, multicenter
> Stratified by:
– KENOTE-181: histology, region
– ATTRACTION-3: region, involved
organ sites, PD-L1
– ESCORT: disease (advanced or
metastatic), ECOG
– RATIONALE 302: region, ECOG,
chemo option
1Kojima et al J Clin Oncol 2020; 2Kato et al Lancet Oncol 2019; 3Huang et al Lancet Oncol 2020; 4Shen et al ASCO 2021

17. CONSISTENT SURVIVAL EFFICACY OF PD-1 INHIBITORS IN
PREVIOUSLY TREATED OESOPHAGEAL CANCER
OS in ITT OS in ITT
OS in SCC OS in ITT
1 2 3 4
1Kojima et al J Clin Oncol 2020; 2Kato et al Lancet Oncol 2019; 3Huang et al Lancet Oncol 2020; 4Shen et al ASCO 2021

18. KEYNOTE 590: CHEMO + IO IN FIRST LINE TREATMENT
OF ADVANCED SCC OESOPHAGUS
CF + placebo
n=274
R n=274 CF + pembrolizumab
KEYNOTE 590 (SCC)
SCC and PD-
L1 CPS ≥10
SCC all
Sun et al Lancet 2021
SCC all

19. CHEMO + IO IN FIRST LINE TREATMENT OF ADVANCED SCC
OESOPHAGUS
CHECKMATE 648
Doki et al N Engl J Med 2022

20. OS PFS
ESCORT-1st
Paclitaxel/cisplatin
+ placebo
n=298
R n=298 Paclitaxel/cisplatin +
camrelizumab
Luo et al JAMA 2021
CHEMO + IO IN FIRST LINE TREATMENT OF ADVANCED SCC
OESOPHAGUS

21. 1Shen et al ESMO 2021; 2Xu, Wang et al ESMO 2021
© 2021 European Society for Medical Oncology. Published by
Elsevier Ltd. All rights reserved.
CF/TP + placebo
n=332
R n=327 CF/TP + sintilimab
ORIENT 151
TP + placebo
n=257
R n=257 TP + toripalimab
JUPITER -062
TORI + chemo
(n = 257)
Chemo
(n = 257)
Median OS, mo 17.0 11.0
(95% CI) (14.0-NE) (10.4-12.6)
HR (95% CI) 0.58 (0.43–0.78)
P value 0.00036
CHEMO + IO IN FIRST LINE TREATMENT OF ADVANCED SCC
OESOPHAGUS

22. CONSISTENT SURVIVAL EFFICACY OF CHEMO PLUS PD-1
INHIBITORS IN 1L ESCC
1Sun et al Lancet 2021; 2Doki et al N Engl J Med 2022; 3Luo et al JAMA 2021; 4Chen et al ESMO 2021, 5Xu, Feng et al ESMO 2021
OS in SCC OS in ITT* OS in ITT OS in ITT OS in ITT

23. IO + IO IN 1ST LINE TREATMENT OF ADVANCED SCC
OESOPHAGUS
CHECKMATE 648
Doki et al N Engl J Med 2022

24. TREATMENT PARADIGM IN ADVANCED/ METASTATIC
SCC OESOPHAGUS 2021
Inoperable/ metastatic/
recurrent SCC
Nivolumab/ pembrolizumab/
camrelizumab/sintilimab/toripa-
limab plus Platinum +
Paclitaxel/FP- chemotherapy
Taxanes
irinotecan
Nivolumab
Pembrolizumab if
PD-L1 CPS 10
Nivolumab + ipilimumab
Platinum/fluoropyrimidine
if nivo/ipi used first line
PD-L1 IHC – which assay? Which cut-
off? Tumour cells ± immune cells
(CPS)? 1%, 5%, 10%?

25. CONTINUUM OF CARE IN ADVANCED GEJ/ OESOPHAGEAL
CANCER
Cisplatin
Oxaliplatin
HER2 +ve
Trastuzumab Capecitabine
Paclitaxel
Docetaxel
5-FU
+ Ramucirumab
6-8 cycles
OR
till disease
progression
+
EGFR antibody
cMET antibody
VEGFR2 antibody
MMP9 antibody
CLN18.2 antibody
PD-1 antibody
Trifluridine/tipiracil
Nivolumab/ pembrolizumab
Irinotecan

26. RANDOMISED FIRST LINE PHASE III NIVOLUMAB STUDY IN
OESOPHAGEAL/ GEJ/ GASTRIC ADENOCARCINOMA
(CHECKMATE-649)
Primary endpoint: OS and PFS (PD-L1 expression CPS 5; Dako 28-8 pharmDx assay)
Secondary endpoints: OS (PD-L1 CPS ≥1 or all randomised)
OS (PD-L1 CPS ≥10)
PFS (PD-L1 CPS ≥1, 10 or all randomised)
ORR
FOLFOX or CAPOX
n=792
Nivolumab + ipilimumab
R
Previously untreated
advanced gastric or GEJ
or oesophageal
adenocarcinoma HER2 –
ve or unknown
PD-L1 +ve or –ve
Nivolumab + FOLFOX or CAPOX
Janjigian et al Lancet 2021
n=789

27. CHECKMATE-649: OVERALL SURVIVAL (PD-L1 CPS ≥5)
Janjigian et al Lancet 2021

28. CHECKMATE-649 UPDATED ANALYSIS OVERALL SURVIVAL:
NIVO + CHEMO VS CHEMO
48%
19%
55%
28%
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months
NIVO + chemo
Chemo
789 733 624 508 422 349 287 246 212 156 115 84 57 33 25 9
792 701 591 475 364 273 215 170 144 103 72 46 28 20 12 6
2
0
0
0
Overall
survival
(%)
• Clinically meaningful improvement in OS with NIVO + chemo vs chemo was maintained with longer follow-up
― PD-L1 CPS ≥ 5: 30% reduction in the risk of death and 12% improvement in 24-month OS rate
― All randomized: 21% reduction in the risk of death and 9% improvement in 24-month OS rate
― Directionally improved HRs relative to the 12-month follow-up (PD-L1 CPS ≥ 5, 0.71 [98.4% CI, 0.59-0.86]; all randomized, 0.80 [99.3% CI, 0.68-0.94])1
◆
aMinimum follow-up, 24.0 months.
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months
473 440 380 315 263 223 187 161 141 107 81 61 43 26 19 6
482 424 353 275 215 154 125 97 83 62 46 31 18 11 6 1
2
0
0
0
Overall
survival
(%)
46%
19%
57%
31%
No. at risk
NIVO + chemo
NIVO + chemo
Chemo
Chemo
PD-L1 CPS ≥ 5 All randomized
NIVO + chemo
(n = 473)
Chemo
(n = 482)
Median OS,a mo 14.4 11.1
(95% CI) (13.1–16.2) (10.0–12.1)
HR (95% CI) 0.70 (0.61–0.81)
NIVO + chemo
(n = 789)
Chemo
(n = 792)
Median OS,a mo 13.8 11.6
(95% CI) (12.4–14.5) (10.9–12.5)
HR (95% CI) 0.79 (0.71–0.88)
Janjigian et al ESMO 2021
© 2021 European Society for Medical Oncology. Published by
Elsevier Ltd. All rights reserved.

29. CHEMO ± SINTILIMAB IN 1ST LINE TREATMENT OF ADVANCED
GASTRIC ADENOCARCINOMA
CAPOX × 6 cycles + placebo
followed by capecitabine + placebo
n=327
R n=323
1o endpoints:
- OS in pts with PDL-
1 CPS ≥5
- OS in all
randomised pts
CAPOX × 6 cycles + sintilimab
followed by capecitabine + sintilimab
Previously untreated
advanced gastric or GEJ
adenocarcinoma;Not known
to be HER2 +ve
PD-L1 +ve or –ve
PDL-1 CPS ≥5:
61% in all
randomised pts
Xu et al ESMO 2021
© 2021 European Society for Medical Oncology. Published by
Elsevier Ltd. All rights reserved.
ORIENT 16

30. CHEMO + PEMBROLIZUMAB DID NOT IMPROVE SURVIVAL IN
GASTRIC CANCER
Shitara et al JAMA Oncol 2020
PD-L1 CPS ≥1
Arm A
Placebo + Cisplatin/FP
n=250
Arm C
Pembrolizumab alone
R
Previously untreated
advanced PD-L1 +ve
gastric or GEJ
adenocarcinoma
Arm B
Pembrolizumab + Cisplatin/FP
n=257
n=256
Gastric: 69%
OGJ: 30%
KEYNOTE 062

31. KEYNOTE 590: EFFICACY IN OESOPHAGEAL AND OGJ
ADENOCARCINOMA
Sun et al Lancet 2021
Pembro + chemo Chemo
n 373 376
Asian, % 53 52
SCC, % 73 73
Adenocarcinoma tumour
location, %
OGJ type 1
Oesophageal
27
11
16
27
13
14
PD-L1 CPS ≥10, % 50 50

32. TRASTUZUMAB, CHEMO + PEMBROLIZUMAB IN HER2 +VE
GEJ/GASTRIC CANCER
Janjigian et al
Nature 2021;
Janjigian ASCO
2021

33. CONTINUUM OF CARE IN ADVANCED GEJ/OESPHAGEAL
ADENOCARCINOMA
Cisplatin
Oxaliplatin
HER2 +ve
Trastuzumab
±pembrolizumab
Capecitabine
Paclitaxel
Docetaxel
5-FU
+ Ramucirumab
6-8 cycles
OR
till disease
progression
+ + nivolumab
+?pembrolizumab
Trifluridine/tipiracil
Nivolumab/
pembrolizumab
Irinotecan

34. ACKNOWLEDGEMENT
National Health Service funding to the National Institute
for Health Research Biomedical Research Centre

35. OPTIMAL MULTIMODALITY
MANAGEMENT OF LOCALIZED
OESOPHAGEAL CANCER
Radka Obermannová, MD, PhD
Department of Comprehensive Cancer Care
and Faculty of Medicine, Masaryk Memorial Cancer Institute

36. CONFLICT OF INTEREST DISCLOSURE
Personal fees: BMS, Merck, MSD, Servier,
Research support (to institution):ROCHE
Employment and leadership: Masaryk Memorial Cancer Institute
( Department of Comprehensive Cancer Care), EORTC (Co-Chair of
Individualized Therapy Task Force), CZECRINonco (Chair of
CZECRINonco Board)

37. SQUAMOUS CELL CANCER AND ADENOCARCINOMA
Current evidence
MOLECULAR BIOLOGY TREATMENT GUIDELINES RANDOMIZED STUDIES
2012 CROSS
2021 Neo-
AEGIS
Ongoing
TOPGEAR
ESOPEC
1999 RTOG 85-01
2002 RTOG 9405
(INT 0123)
2021 ARTDECO
Ongoimg
SCOPUS-2
Neoadjuvant Definitive Perioperative
chemotherapy
The Cancer Genome Atlas Research Network. Nature. 2017;541:169-175 , Reproduced under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence; available at:
http://creativecommons.org/licenses/by/4.0/; accessed March 2022.
Lordick F, et al. Ann Oncol 2016;27(suppl 5):v50-v57. © 2016 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
2006 MAGIC
2011 FNCLCC
2019 FLOT4

38. ESMO GUIDELINES
OESOPHAGEAL CANCER
Lordick F, et al. Ann Oncol 2016;27(suppl 5):v50-v57. © 2016 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

39. OESOPHAGEAL CARCINOMA (SCC AND AC*)
CROSS study: Neoadjuvant CH/RT vs Surgery
R
A
N
D
O
M
Neoadjuvant CH/RT 41.4 Gy
Carbo AUC2 +
Paclitaxel 50mg/m² w
+SURGERY
SURGERY
Primary endpoint: OS
N=368
T1N1M0
or
T2–3N0–1M0
AC 75%
SCC 23%
Van Hagen et al. N Engl J Med 2012; 366: 2074-2084
Shapiro J et al., Lancet Oncol 2015; 16: 1090–98
*SCC: Squamous Cell Cancer; AC: Adenocarcinoma

40. OESOPHAGEAL ADENOCARCINOMA, HISTOLOGY MATTERS
CROSS study: Neoadjuvant CH/RT vs Surgery: LONG-TERM FOLLOW-UP
1. Reprinted from Lancet Oncol, 16(9), Shapiro J, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery
alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial, 1090–98.
Copyright 2015, with permission from Elsevier.
2. Eyck BM, et al. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The
Randomized Controlled CROSS Trial. J Clin Oncol. 2021;39(18):1995-
2004. Available at: https://ascopubs.org/doi/full/10.1200/JCO.20.03614; accessed March 2022. © 2021 by American
Society of Clinical Oncology.
Median F-U 84.1mo
mOS 48.6 vs 24.0 mo
SCC mOS 81.6 vs 21.1mo
AC mOS 43.2 vs 27.1mo
The absolute 10-year overall survival benefit 13%
(38% v 25%)

41. CASE REPORT
Neoadjuvant chemoradiotherapy
• Male, born 1952
• Overweight, no family history
• August 2017 diagnosed with oesophageal adenocarcinoma,
• Siewert I cT3N1M0, G3
• Neoadjuvant chemotherapy (CROSS regimen)
• with CR according to PET/MRI
• October 2017 SURGERY
• pT3pN0(0/14)M0, G2,PNP, R0

42. CASE REPORT
Disease Relapse
• March 2020 PET/MRI multiloculare relapse
- start of palliative systemic therapy
• March 2021 patient died 41months
after diagnosis
CROSS trial
Median F-U 84.1mo – mOS 48.6 vs 24mo,
SCC mOS 81.6 vs 21.1mo
AC mOS 43.2 vs 27.1mo
How to improve outcome after chemoradiotherapy?

43. HOW TO IMPROVE OUTCOME AFTER CHEMORADIOTHERAPY?
Adjuvant Immunotherapy after preoperative chemoradiation
CheckMate-577
Kelly RJ, et al. N Engl J Med 2021;384:1191-1203. ASCO 2021 Presentation No. LBA4003

44. HOW TO IMPROVE OUTCOME AFTER CHEMORADIATION?
CheckMate 577: Adjuvant Immunotherapy after preoperative chemoradiation
Kelly RJ, et al. N Engl J Med 2021;384:1191-1203
Nivolumab
(n = 532)
Placebo
(n = 262)
Median DFS, mo 22.4 11.0
(95% CI) (16.6–34.0) (8.3–14.3)
HR (96.4% CI) 0.69 (0.56–0.86)
P value 0.0003c

45. HOW TO IMPROVE OUTCOME AFTER CHEMORADIATION?
CheckMate 577: Adjuvant Immunotherapy after preoperative chemoradiation
Risk of distant recurrence or death
was 26% lower in nivolumab arm
Distant (29% vs 39%) and locoregional
(12% vs 17%) recurrences were
less frequent with Nivolumab
Grade 3 or 4 adverse events
13% vs 6%
Kelly RJ, et al. N Engl J Med 2021;384:1191-1203

46. NIVOLUMAB*
ESMO GUIDELINES
OESOPHAGEAL
CANCER
UPDATE
(DISCUSSION VERSION)
NIVOLUMAB*
*≥ypT1or ≥ ypN1N1
Lordick F, et al. Ann Oncol 2016;27(suppl 5):v50-v57. © 2016 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

47. ESMO
GUIDELINES
OESOPHAGEAL
CANCER
Lordick F, et al. Ann Oncol 2016;27(suppl 5):v50-v57. © 2016 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

48. ADENOCARCINOMA:
CHEMORADIOTHERAPY VS CHEMOTHERAPY
Neo-AEGIS study
Reynolds, J. BMC Cancer 17, 401, (2017)

49. OVERALL SURVIVAL
Reynolds JV, et al. ASCO 2021; abstract LBA4004
Median follow-up 24.5M
ADENOCARCINOMA:
CHEMORADIOTHERAPY VS CHEMOTHERAPY
Neo-AEGIS study

50. MSI-HIGH TUMOURS – PERIOPERATIVE IMMUNOTHERAPY
MSI- High 3-5%
The Cancer Genome Atlas Research Network. Nature. 2017;541:169-175 , Reproduced under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence; available at:
http://creativecommons.org/licenses/by/4.0/; accessed March 2022.

51. MSI-HIGH TUMOURS – PERIOPERATIVE IMMUNOTHERAPY
Andre T, et al. ASCO Gastrointestinal Cancers Symposium 2022. Abstract 244.

52. NEONIPIGA: Study design/metods
Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.

53. Results (1): Surgery and TNM and Tumor Regression Grading (TRG)<br />
Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.

54. THANK YOU FOR YOUR ATTENTION.
Masaryk Memorial Cancer Institute (MMCI), Brno, Czech Republic
obermannova@mou cz
www.mou.cz

55. esmo.org
Contacts ESMO
European Society for Medical Oncology
Via Ginevra 4, CH-6900 Lugano
T. +41 (0)91 973 19 00
esmo@esmo.org

56. THE ROLE OF BIOMARKER FOR PROGNOSTICATION
AND BENEFIT FROM IMMUNOTHERAPEUTIC
APPROACHES IN OESOPHAGEAL
ADENOCARCINOMAS
Dr. S. Derks
Medical Oncologist-Amsterdam UMC, The Netherlands
Oncode Institute-affiliated scientist

57. DISCLOSURE
Research support from Incyte
Honoraria from Servier, BMS.

58. CASE
• 72-year old patient with hematemesis in the emergency department based on a HER2 neg, MSS esophageal
adenocarcinoma.
• CT-scan: local and distant lymph node metastases (pathological confirmation).
• Start palliative chemotherapy: capecitabine and oxaliplatin.
• Progressive disease after 6 cycles (initial response after 3 cycles)
• Whole genome sequencing: (no PD-L1 testing at the time)

59. CASE
• Started with checkpoint inhibitor pembrolizumab within a trial.
• Mixed response after 3 cycles: good response lymph nodes, poor response liver metastasis
• After 6 cycles: response at all tumour locations
• After 9 cycles: progressive disease.

60. CASE
• Started with checkpoint inhibitor pembrolizumab within a trial.
• Mixed response after 3 cycles: good response lymph nodes, poor response liver metastasis
• After 6 cycles: response at all tumor locations
• After 9 cycles: progressive disease.
• Conclusion: benefit of checkpoint inhibition for this patient
• How can we select patients for checkpoint inhibitions?
• Which biomarkers should we use?

61. BIOMARKERS FOR RESPONSE TO CHECKPOINT INHIBITIONS
1. T cells infiltration/IFNy response?
2. PD-L1 expression?
3. High mutational load/ Microsatellite instability?

62. IMMUNOTHERAPY NEEDS T CELLS TO BE INFILTRATED IN THE
TUMOUR TO BE SUCCESFUL
researchcancerimmunotherapy.com

63. T CELL INFILTRATION LEADS TO PD-L1 EXPRESSION
Chen et al, JCI, 2015

64. PD-L1 EXPRESSION IN OESOPHAGEAL ADENOCARCINOMAS
T cell hot T cell cold T cell excluded
Different T cell infiltration pattern and heterogeneity
centrum
rand
PD-L1
Derks et al, CIR, 2015
Derks et al, Annals of Oncol, 2020

65. PD-L1 EXPRESSION IN OESOPHAGEAL ADENOCARCINOMAS
Heterogeneity in PD-L1 expression between primary tumor and metastases
Zhou et al, CCR 2020
Concordance 61% between primary and metastasis Concordance 63% pre- and post CT

66. OESOPHAGEAL ADENOCARCINOMAS ALSO EXPRESS PD-L2
Derks et al, CIR, 2015
PD-L2+ tumor cells
PD-L1
pro-inflammatory
PD-L2
immune suppressive

67. PD-L1 EXPRESSION AND RESPONSE TO PD-1 INHIBITION
Janjigian et al, Lancet 2021
CHECKMATE 649 study, 1L chemo+nivo vs chemo alone in EAC, GEJ and GC
PD-L1 CPS>5
PD-L1 CPS>1
MSI-H subgroup HR 0.33

68. PD-1 INHIBITION + CHEMOTHERAPY IN MSI CANCERS?
Keynote 062: RCT, 1L, pembro, vs chemo, vs pembro+chemo in PD-L1>CPS 1+ mGC or GEJ
Shitara et al, JAMA Oncology, 2020

69. PD-L1 EXPRESSION AND RESPONSE TO PD-1 INHIBITION
Sun et al, Lancet 2021
KEYNOTE-590 study, 1L chemo+nivo vs chemo alone in ESCC and EAC
PD-L1 CPS>10

70. PD-L1 EXPRESSION AND RESPONSE TO PD-1 INHIBITION
KEYNOTE-590 study, 1L chemo+nivo vs chemo alone in ESCC and EAC
Sun et al, Lancet 2021

71. TUMOUR MUTATIONAL BURDEN AS BIOMARKER?
Yarchoan et al., NEJM 2017
Only when TMB induces T cell infiltration……
TMB associates with response to immunotherapy
McGrail et al. Ann Oncol 2021

72. In Keynote 061 TMB predicts response to pembro as 2nd line treatment…
Shitara et al, Ann of Oncol, 2021

73. TUMOUR MUTATIONAL BURDEN AS BIOMARKER?
Shitara et al, Ann of Oncol, 2021

74. CONCLUSION
• PD-L1 expression seems to be the most promising biomarker for checkpoint inhibitors in
oesophageal cancer
• However, PD-L1 is heterogeneously expressed
• TMB is also a promising biomarker but expensive assay…
• More reliable biomarkers are needed

75. esmo.org
Contacts ESMO
European Society for Medical Oncology
Via Ginevra 4, CH-6900 Lugano
T. +41 (0)91 973 19 00
esmo@esmo.org