Immunotherapy for Gastrointestinal Cancer
Andrés CervantesProfessor of Medicine
Immunotherapy for gastrointestinal cancer
� Squamous esophageal cancer
� Esophageal, junctional and gastric adenocarcinoma
� Hepatocellular Carcinoma
� Colorectal Cancer
� Biliary tract cancer
� Pancreatic Cancer
� Anal cancer
Kudo T et al. Lancet Oncol 2017; 18:631-639
Kudo T et al. Lancet Oncol 2017; 18:631-639
Doi T, et al. J Clin Oncol 2018; 36:61-67
Doi T, et al. J Clin Oncol 2018; 36:61-67
Doi T, et al. J Clin Oncol 2018; 36:61-67
Classification of gastric adenocarcinoma: Pathology
� Intestinal versus diffuse subtypes
Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31–49
TCGA, Nature 2014
9%
20%
50%
22%
Molecular subtypes of gastric cancer
EBV, Epstein–Barr virus (red); MSI, microsatellite instability (blue), GS, genomically stable (green);
CIN, chromosomal instability (light purple)
1. Wu C, et al. Acta Histochem 2006;
2. Geng Y, et al. Int J Clin Oncol 2015;
3. Hou J, et al. Exp Mol Pathol 2014
PD-L1 expression (TC or IC)
42-65%1,2
Presence of tumour-infiltrating
lymphocytes (TILs)
Yes2
PD-L1 as negative
prognostic factorYes2,3
Rationale for PD1/PDL1 inhibition in gastric cancer
Screening: 65 of 162 (40%) patients assessed for PD-L1 expression had PD-L1-positive tumors
Patients: 19 patients from Asia and 20 patients from the rest of the world
Treatment: 10 mg/kg IV Q2W
Response assessment: Performed every 8 weeks per RECIST v1.1 by central radiology reviewaAssessed in archival tumor samples using a prototype IHC assay (22C3 antibody). Positivity defined as PD-L1 staining in stroma or
≥1% of tumor cells.
Patients
• Recurrent or metastatic adenocarcinoma of the stomach or GEJ
• ECOG PS 0-1• PD-L1–positive
tumora
• No active brain metastases
Pembrolizumab
10 mg/kg Q2W
Complete Response
Partial Response or
Stable Disease
Confirmed Progressive
Disease
Discontinuation Permitted
Treat for 24 months or
until progression
or intolerable toxicity
Discontinue
KEYNOTE-012: Gastric Cancer Cohort
Muro K, et al Lancet Oncol 2016; 17:717-726
Muro K, et al Lancet Oncol 2016; 17:717-726
Muro K, et al Lancet Oncol 2016; 17:717-726
.
Cohort 3
• No prior therapy
• PD-L1 positive
Treat for up to 35 cycles
(~2 years), or until
progression or intolerable
toxicity
Follow-up for survival by
telephone until death,
withdrawal, or study end
Cohort 2
• No prior therapy
• PD-L1 positive or
negative
Pembrolizumab 200 mg Q3W +
Cisplatin 80 mg/m2 Q3W +
5-FU 800 mg/m2 Q3W or
Capecitabine 1000 mg/m2 BID
Q3Wa
Cohort 1
• ≥2 prior lines of
chemotherapy
• PD-L1 positive or negative
Pembrolizumab
200 mg Q3W
Pembrolizumab
200 mg Q3W
KEYNOTE-059 (NCT02335411) Study Design
Fuchs CS, et al JAMA Oncol 2018; March 15 ahead of print
Fuchs CS, et al JAMA Oncol 2018; March 15 ahead of print
Fuchs CS, et al JAMA Oncol 2018; March 15 ahead of print
24 of 25 (96%) patients
experienced a reduction in
target lesion size
–100
–80
–60
–40
–20
0
20
Ch
an
ge
Fro
m B
as
elin
e, %
(n
= 2
4)
PD-L1 positive
PD-L1 expression unknown
PD-L1 negative 0 2 4 6 8 10 12 14 16 18 20 22 24–100
–75
–50
–25
0
25
50
Ch
an
ge
Fro
m B
as
elin
e, %
(n
= 2
5)
Time Since Treatment Initiation, months
Median (range) duration of
response:
4.6 (2.6-20.3+) months
Best Percentage Change in All Patients (n = 24)a Longitudinal Change in All Patients (n = 25)b
Wainberg Z et al. Proc ESMO 2017
Cohort 2: Pembrolizumab + CDDP/FP, 1st lineBest percentage change
24 of 31 (77%) patients experienced
a reduction in target lesion size
Ch
an
ge
Fro
m B
as
eli
ne
, %
(n
= 3
1)
30% decrease in tumor size
–100
–80
–60
–40
–20
0
20
40
6
0
80
10
0
Ch
an
ge
Fro
m B
as
eli
ne
, %
(n
= 3
0)
20% increase in tumor size
0 2 4 6 8 10 12 14 16 18 20 22 24
–100
–80
–60
–40
–20
0
20
40
60
80
100Median (range) duration of response: 9.6
(2.1-17.8+) months
Time Since Treatment Initiation, months
Best Percentage Change in All Patients (n = 31)a Longitudinal Change in All Patients (n = 30)b
Cohort 3: Pembrolizumab s/a, 1st line PDL1 +Best percentage change
Wainberg Z et al. Proc ESMO 2017
CHECKMATE 032 EG COHORT
Presented By Yelena Janjigian at 2017 ASCO Annual Meeting
Best Reduction in Target Lesions
Presented By Yelena Janjigian at 2017 ASCO Annual Meeting
Overall Survival
Presented By Yelena Janjigian at 2017 ASCO Annual Meeting
Study Design and Endpoints
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.
R
2:1
Nivolumab3 mg/kg IV Q2W
Placebo
Key eligibility criteria:
• Age ≥ 20 years
• Unresectable advanced or recurrent gastric or gastroesophageal junction cancer
• Histologically confirmed adenocarcinoma
• Prior treatment with ≥ 2 regimens and refractory to/intolerant of standard therapy
• ECOG PS of 0 or 1
Primary endpoint:
• OS
Secondary endpoints:
• Efficacy (PFS,
BOR, ORR, TTR,
DOR, DCR)
• Safety
Exploratory endpoint:
• Biomarkers
Stratification based on:
• Country (Japan vs Korea vs Taiwan)
• ECOG PS (0 vs 1)
• Number of organs with metastases (< 2 vs ≥ 2)
� 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
Overall Survival
Time (months)
Pro
bab
ilit
y o
f S
urv
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
Patien
ts, n
Event
s, 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]
Kang YK, et al Lancet Oncol 2017; 390:2461-2471
Line Study N Treatment Arms Primary EP
1st Line
KEYNOTE-062
NCT02494583
(TPS 4138)
750
Pembrolizumab 200mg Q3W
vs
Pembro + CDDP + 5-FU/CPC
vs
Placebo + CDDP + 5-FU/CPC
OS
PFS
(RECIST 1.1)
CG & CUGE
PS 0-1, PD-L1+/HER2-
Stratification:
Europe/North
America/Australia vs Asia vs
ROW
RECIST 1.1 & irRECIST
Maintenance
JAVELIN
Gastric 100
NCT02625610
(TPS 4134)
666
FOLFOX/XELOX x12 weeks,
thereafter:
Avelumab 10mg/kg Q2W
vs Continuation
FOLFOX/XELOX
OS
PFS (from
random)
CG & CUGE, PS 0-1, PD-L1+
Exclusion HER2+
RECIST 1.1
2nd Line
KEYNOTE-061
NCT02370498
(TPS 4137)
720
Pembrolizumab 200mg Q3W
vs
Paclitaxel
PFS
(RECIST 1.1)
OS in PD-L1+
(negative)
CG & CUGE, PS 0-1
No molecular selection
RECIST 1.1 & irRECIST
3rd Line
JAVELIN
Gastric 300
NCT02625623
(TPS4135)
330
Avelumab 10mg/kg Q2W +
BSC vs
Paclitaxel/Irinotecan/BSC
OS
(negative)
CG & CUGE, PS 0-1
No molecular selection
Stratification: Asia vs non
Asia
Exclusion of previous
immunotherapy
RECIST 1.1
Ongoing Phase III Clinical Studies
El-Khoueri AB, et al Lancet Oncol 2017; 389:2492-2502
El-Khoueri AB, et al Lancet Oncol 2017; 389:2492-2502
El-Khoueri AB, et al Lancet Oncol 2017; 389:2492-2502
CMS subtypes – clinical and molecular correlates
CMS1 - MSI – Immune 14%
CMS2 –
Canonical 37% CMS3 –
Metabolic 13%
CMS4–Mesenchymal 23%
Guinney J, Dienstmann R et al. Nat Med 2015
Becht E et al, Clin Cancer Res 2016
Immune vs Transcriptomic subtypes of CRC
Supervised immune infiltration analysis
Pembrolizumab (anti-PD1) in mismatch repair-deficient/-proficient CRC: phase II
Le DT et al. ASCO 2015, Le DT NEJM 2015
KEYNOTE-164 – 3rd line (refractory)
Patient
population
• Locally advanced or metastatic MSI CRC
• Patients must have received at least 2 prior treatments
• Stage IV disease
Pembrolizum
ab
200 q3w IV
Complete
response
Discontinuation
permitted
Confirmed
progressive
disease
Discontinue
Partial response
or stable disease
Treat for up to 2
years or until
progression or
unacceptable
toxicity
• ORR by RECIST 1.1
Primary Endpoint
Target enrollment: 60
Assessments: Radiological assessments using
RECIST 1.1 and irRC every 9 weeks
A Phase 2, Single-arm Study of Pembrolizumab in Pretreated Patients to Address Significant Patient
Unmet Needs
mFOLFOX6 +
bevacizumab:
• Bevacizumab 5 mg/kg +
• Oxaliplatin 85 mg/m2
IV +
• Leucovorin 400 mg/m2
IV +
• 5-FU 400 mg/m2 IV bolus on Day 1, then 1,200 mg/m2/day for 2 day continuous infusion; repeat every 2 weeks until progressive disease
KEYNOTE-177 – 1st line
Patient
population
• Locally advanced or unresectable or metastatic CRC
• MSI
Target enrollment: 270
Pembrolizumab
200 mg q3w
Up to 2 years
A Phase 3 Study of Pembrolizumab Monotherapy vs Standard Chemotherapy in 1L MSI CRC
Randomizatio
n
1:1
PD
PD
OffStudy
Crossover
Primary Endpoint
• PFS
• OS
Overman MJ et al. J Clin Oncol 2018; 36:773-779
Overman MJ et al. J Clin Oncol 2018; 36:773-779
Overman MJ et al. J Clin Oncol 2018; 36:773-779
Cobimetinib + Atezolizumab
PD-L1 and MEK inhibition: a rational combination
Bendell J et al. Proc ASCO 2016
KRAS
MT
CRC
All CRC
pts
N=20 N=23
ORR 20% 17%
CR 0 0
PR 20% 17%
SD 20% 22%
PD 50% 52%
NE 10% 9%
mPFS (m) 2.3
(1.8-9.5)
2.3
(1.8-9.5)
mOS (m) NE
(6.5-NE)
NE
(6.5-NE)
Cobimetinib + Atezolizumab
Bendell J et al. Proc ASCO 2016
ARM
A
Cobimetinib +atezolizumab
n=180
ARM
BAtezolizumab
n=90
ARM
CRegorafenib
n=90
Treatment to
continue
until loss of
clinical
benefit
� Stratified by tumor extended RAS status and time since diagnosis of first metastasis
� MSI-H capped at approximately 5%
� At least 180 patients with extended RAS-mutant tumors to be enrolled
n=360
2:1:1
� UnresectablemCRC patients
� Received at least 2 regimens in metastatic setting (not including maintenance)
COTEZO TRIAL
Cobimetinib + Atezolizumab
Other agents with specific development in CRC
TherapyTarget
1Construct Phase Trial Design Trial ID
Cytokine-
constructs
CEA-
IL2v
Anti-CEA
antibody
carrying
mod. IL-2
molecule
I Tumors expressing CEANCT02004
106
Ib
Tumors expressing CEA
in combination with
atezolizumab
NCT02004
106
Bi-Specific
Antibodies
CEA-
CD3
T-Cell bi-
specific
antibody
I Tumors expressing CEANCT02324
257
Ib
Tumors expressing CEA
in combination with
atezolizumab
NCT02650
713
CEA-
CD3BITE I/II Tumors expressing CEA
NCT01284
231
Clinicaltrials.gov
• Binds simultaneously with 1 arm to CD3 on T cells and with 2 arms to CEA on tumor cells
• Flexible 2-to-1 format enables high-avidity binding and selective killing of high CEA-expressing tumor cells
• Longer half-life compared with other TCB formats
• Silent Fc results in reduced risk of FcγR-related cytokine release/IRRs
• Killing of tumor cells independent of pre-existing immunity
• T-cell proliferation at site of activation
2-to-1 Format1Flexible range of motion
in Fabs1
Fab, fragment antigen-binding region; IRR, infusion-related reaction.
Tabernero J et al, Proc ASCO 2017
CEA-TCB T-cell bispecific antibody
CEA-TCB clinical activity in mCRC
Study 1: CEA-TCB
monotherapyn = 31, 60-600 mg
Study 2: CEA-TCB +
atezolizumabn = 25, 5-160 mg
-100
-50
0
50
100
Be
st
ch
an
ge
in
ta
rge
t le
sio
ns
fro
m
ba
se
lin
e, %
No clear correlation between
CEA-TCB dose and response
Correlation between
CEA-TCB dose and response
Be
st
ch
an
ge
in
ta
rge
t le
sio
ns
fro
m
ba
se
lin
e, %
-100
-50
0
50
100
^
^160 mg20 mg
40 mg
80 mg10 mg
5 mg
MSI ^
Data reported by investigators, cutoff: March 3, 2017. a Radiological signs of tumor inflammation seen at ≥ 60 mg (safety data cutoff is ≥ 40 mg).
Tabernero J et al, Proc ASCO 2017
Data reported by investigators, cutoff: March 3, 2017. a Radiological signs of tumor inflammation seen at ≥ 60 mg (safety data cutoff is ≥ 40 mg).
Study 2: CEA-TCB + atezolizumab
(n = 25, 5-160 mg of CEA-TCB)
Study 2: CEA-TCB + atezolizumab (n = 11, 80 and
160 mg of CEA-TCB)
p
*p
*
p*p
WithdrawalProgressionOngoingFirst new lesion
MSI^
-50
0
50
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
pp
ppp
^
p
p
p pp^
p
p
160 mg20 mg
40 mg80 mg10 mg
5 mg
p
*p
*
p
-50
0
50
100*p
WithdrawalProgressionOngoingFirst new lesion
a
160 mg80 mg
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24Be
st
ch
an
ge
in
ta
rge
t le
sio
ns
fr
om
ba
se
lin
e, %
Be
st
ch
an
ge
in
ta
rge
t le
sio
ns
fr
om
ba
se
lin
e, %
*p
WithdrawalProgressionOngoingFirst new lesion
160 mg80 mg
*p
WithdrawalProgressionOngoingFirst new lesion
MSI^
160 mg20 mg
40 mg80 mg10 mg
5 mg
Weeks after treatment start Weeks after treatment start
MSS mCRC
Tabernero J et al, Proc ASCO 2017
CEA-TCB + Atezolizumab clinical activity in
mCRC
Baseline Week 16BaselineWeek 4
Partial response in a patient with MSS mCRCMSS mCRC: CEA-TCB 160 mg IV qw + atezolizumab 1200 mg IV
q3w
Patient from MSKCC (Neil H. Segal).
PET, positron emission tomography.
18F-FDG PET CT scans
Tabernero J et al, Proc ASCO 2017
Examples of vaccines for immune-stimulation in CRC
Therapy Antigen Enhancer PhaseStudy
populationTrial ID
Anti-tumor
vaccines
Autologous
tumor cells
BCG
II Adjuvant CRCPMID:
8445413
III Adjuvant CRC PMID:
15755632
IIIAdjuvant Stage
II CRC
NCT0244817
3
Newcastle
Disease Virus II
CRC Liver M1
resected
PMID:
18488223
Dendritic cell
vaccines
CEADendritic
cellsI
Adjuvant Stage
III CRC
NCT0189021
3
MUC 1Dendritic
cellsII
CRC Liver or
lung M1
resected
NCT0010314
2
Pubmed -
Clinicaltrials.gov
Examples of adoptive cell therapy for immune-stimulation in CRC
Therapy Target Enhancer Phase Trial Design Trial ID
TILs
Autologou
s tumor
cells
IL-2
Pembrolizum
ab
II GI tumors NCT01174121
CAR T Cells
CEA ITumors
expressing CEANCT02349724
CEA Yttrium 90 ITumors
expressing CEANCT02416466
EGFR I/IITumors
expressing EGFRNCT01869166
Cytokine-
induced-
killer cells
Autologou
s tumor
cells
II
Adjuvant CRC in
combination
with XELOX
NCT01929499
Clinicaltrials.gov
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