immunotherapy for gastrointestinal cancer · 2018. 10. 31. · (~2 years), or until progression or...

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

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

.

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

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


Overall Survival


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

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

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)


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


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).


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


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


160 mg80 mg

*p


MSI^

160 mg20 mg

40 mg80 mg10 mg

5 mg

Weeks after treatment start Weeks after treatment start

MSS mCRC


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


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

THANK YOU

immunotherapy for gastrointestinal cancer · 2018. 10. 31. · (~2 years), or until progression or...

Documents