immunotherapy in gastro-intestinal tumours -...

Josep Tabernero MD PhDVall d’Hebron University Hospital

Vall d’Hebron Institute of Oncology (VHIO)Barcelona, Spain

Immunotherapy in Gastro -intestinal tumours

ESMO Preceptorship in Immuno-Oncology

February 2 - 3, 2017

• Consultant/Advisory role:

Amgen, Bayer, Boehringer Ingelheim, Celgene,

Chugai, Imclone, Lilly, MSD, Merck Serono, Novartis,

Roche, Sanofi, Symphogen and Taiho

Disclosure / COIs

Outline

• Molecular characterization in gastric/GEJ cancer• Immunotherapy in gastric/GEJ cancer• Molecular characterization in CRC• Immunotherapy in CRC

– MSI tumors– Other opportunities in CRC (including MSS tumors)

Frequency of genetic m

utations in cancer

Altered proteins contain new

epitopes for imm

une recognition,

providing a comm

on denominator for cancer im

munothe

rapy

Rhabdoid tumour

Ewing sarcoma

Thyroid

Acute myeloid leukaemia

Medulloblastoma

Carcinoid

Neuroblastoma

Prostatre

Chronic lymphocytic leukaemia

Low-grade glioma

Breast

Pancreas

Multiple myeloma

Kidney clear cell

Kidney papillary cell

Ovarian

Glioblastoma multiforme

Cervical

Diffuse large B-cell lymphoma

Head and neck

Colorectal

Esophageal adenocarcinoma

Stomach

Bladder

Lung adeno-carcinoma

Lung squamous cell carcinoma

Melanoma

0.01

0.1 1 10

100

1000

Somatic mutation frequency (/Mb)

2220

52134

2623

81227

9157

12113

63214

11394

21920

49181

23176

8835

335179

121

C→

TC

→A

C→

GT

→C

T→

AT

→G

Lawrence M

S, et al. N

ature 2013

No at

Risk

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)

TCGA, Nature 2014

Molecular characterization of GC

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-infiltratinglymphocytes (TILs)

Yes2

PD-L1 as negative prognostic factor

Yes2,3

Rationale for PD1/PDL1 inhibition in gastric cancer

Outline



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 review

aAssessed 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

tumor a

• 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

Best Overall Response (RECIST v1.1)


53.1% of patients experienced a decrease from

baseline

–100

–80

–60

–40

–20

0

20

40

60

80

100C

hang

e F

rom

Bas

slin

e, %

Maximum Change

Asia

Rest of world

Total population• 6-month OS rate: 66%• Median OS: 11.4 months (95% CI, 5.7-NR)

OS

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16

Time, months

Ove

rall

Sur

viva

l, %

n at risk

17 15 12 11 10 8 1 0 0Asia

19 16 13 11 8 7 6 5 0ROW

Asia

Rest of world

KEYNOTE-012: Gastric Cancer Cohort


Association of Immune-Related Gene Expression Signatures and ORR and PFS

Signature

Nominal 1-Sided

P Valuea

ORRb PFSb

IFN-γ (6 gene) 0.077 0.032

TCR signaling (13 gene)

0.034 0.024

Expanded immune(18 gene)

0.062 0.049

De novo (33 gene)

0.068 0.037

Similar results observed for other signatures

Potential diagnostic performance of IFN-γsignature• Negative predictive value = 92%• Positive predictive value = 45%• Prevalence = 61%

Association of IFN- γ Signature and PFS

Patients with lowvalues of the signaturedo not show delays inprogression

PF

S, d

ays

Increasing Gene Expression Levels

IFN-γ Signature Score

Other Partial Response Stable Disease

1.5 2.0 2.5

100

200

300

Bang YJ et al. Proc ESMO GI 2015

KEYNOTE-061 – 2nd line

Patient population

• Recurrent or metastatic adenocarcinoma of the stomach or GEJ

• Failure of chemotherapy combinations containing platinum and fluoropyrimidine doublet Pembrolizumab

200 mg q3w

Progressive disease orunacceptable toxicity

Randomized1:1

Paclitaxel 80 mg/m2 qw

Randomized Study of Pembrolizumab vs Paclitaxel in P atients With Metastatic Gastric Adenocarcinoma Who

Progressed After 1L Therapy With Platinum and Fluor opyrimidine

Survival follow-up

• If KEYNOTE-059 monotherapy arm is negative, will not include 1L monotherapy arm in this trial

• The treatment arm will be modified due to the result from KEYNOTE-059 safety run cohort

• Patients: 30% Asian cap (98 [13%] Japanese patients)• Response Assessment: Scans will be at 6 weeks (Scan 1) and 12 weeks

(Scan 2); Scan 2 used for futility analysis

Target enrollment: 720

• OS by RECIST 1.1 by central review

• PFS

• TTP

• BOR

• ORR by RECIST 1.1

• PD-L1 status

• Safety/tolerability

• QoL

• Immunogenicity

• PK profile

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

• PD profile

• Biomarkers and genomics

KEYNOTE-062 – 1st line

• If KEYNOTE-059 monotherapy arm is negative, will not include 1L monotherapy arm in this trial

• The treatment arm will be modified due to the result from KEYNOTE-059 safety run cohort

• 30% Asian cap (98 [13%] Japanese patients)

• PFS by RECIST 1.1 by central review

• OS

• PFS by RECIST 1.1

• PFS by irRECIST


• DOR by RECIST 1.1

• Safety/tolerability

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

• HRQoL

• EuroQoL

Patient population

• Metastatic gastric/ gastroesophagealadenocarcinoma

• HER2/neu negative

• PD-L1 positive


Pembrolizumabn=250

Progressive disease orunacceptable toxicity

PD-L1 positive

5-FU +cisplatinn=250

Randomized Study of Pembrolizumab With Fluoropyrimid ine and Cisplatin Combination Chemo in 1L Patients With Metastatic Ga stric/Gastroesphageal

Adenocarcinoma

Survival follow-up

Pembrolizumab +5-FU + cisplatinn=250

Dosing: Pembro 200 mg q3w; 5FU 800 mg/m2/day continuous IV infusion,days 1–5 q3w; cisplatin 80 mg/m2 q3w

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

Nivolumab

3 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

Kang YK et al. Proc ASCO GI 2017

Nivolumab in refractory GC/GEJCStudy design

Characteristic Nivolumab 3 mg/kg (n = 330) Placebo (n = 163)Median age (range), years

< 65 years, n (%)

62 (20–83)

189 (57.3)

61 (26–83)

95 (58.3)

Male, n (%) 229 (69.4) 119 (73.0)

Country, n (%)

Japan

Korea

Taiwan

152 (46.1)

146 (44.2)

32 ( 9.7)

74 (45.4)

74 (45.4)

15 ( 9.2)

ECOG PS, n (%)

0

1

95 ( 28.8)

235 ( 71.2)

48 ( 29.4)

115 ( 70.6)

Primary site of disease, n (%)

Gastric

Gastroesophageal junction

Unknown

272 (82.4)

30 ( 9.1)

28 ( 8.5)

135 (82.8)

12 ( 7.4)

16 ( 9.8)

Prior gastrectomy, n (%)

No

Yes

133 (40.3)

197 (59.7)

58 (35.6)

105 (64.4)

Organs with metastases (≥ 2), n (%) 246 (74.5) 119 (73.0)

Prior treatment regimens, n (%)

2

3

≥ 4

69 (20.9)

137 (41.5)

124 (37.6)

29 (17.8)

62 (38.0)

72 (44.2)

Any prior therapy, n (%)

Fluoropyrimidine

Platinum

Taxane

Irinotecan

Ramucirumab

330 (100)

329 (99.7)

311 (94.2)

284 (86.1)

247 (74.8)

35 (10.6)

163 (100)

163 (100)

157 (96.3)

140 (85.9)

123 (75.5)

22 (13.5)


Nivolumab in refractory GC/GEJC

Time (months)

Pro

ba

bil

ity

of

Su

rviv

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

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]


Nivolumab in refractory GC/GEJCOverall Survival

Subgroup Hazard Ratio [95%

CI]

Histological type (Lauren classification)

Intestinal type

Diffuse type

Mixed

Unknown

0.59 [0.41–0.85]

0.82 [0.57–1.17]

0.37 [0.13–1.04]

0.56 [0.37–0.84]

Number of organs with metastasis

< 2

≥ 2

0.70 [0.46–1.08]

0.61 [0.48–0.78]

Peritoneal metastasis

No

Yes

0.63 [0.50–0.81]

0.74 [0.48–1.15]

Liver metastasis

No

Yes

0.63 [0.50–0.80]

0.67 [0.42–1.07]

Measurable lesion

No

Yes

0.70 [0.43–1.14]

0.63 [0.50–0.80]

Number of previous regimens

2

3

≥ 4

0.82 [0.50–1.35]

0.87 [0.61–1.22]

0.44 [0.31–0.61]

Subgroup Hazard Ratio [95%

CI]

All 0.64 [0.52–0.80]

Country

Japan

Korea

Taiwan

0.63 [0.46–0.85]

0.70 [0.51–0.96]

0.46 [0.23–0.92]

Age, years

< 65

≥ 65

0.75 [0.57–0.98]

0.53 [0.38–0.74]

Sex

Male

Female

0.58 [0.45–0.75]

0.83 [0.56–1.23]

ECOG PS

0

1

0.59 [0.40–0.87]

0.67 [0.52–0.86]

Prior gastrectomy

No

Yes

0.69 [0.49–0.98]

0.60 [0.46–0.79]

Primary sites

Gastric (fundus, corpus, antrum, and pylorus)

Gastroesophageal junction

Unknown

0.69 [0.55–0.87]

0.44 [0.20–0.97]

0.52 [0.26–1.06]

0 1 2 3

Favors nivolumab Favors placebo

Hazard ratio [95% CI]

0 1 2 3

Favors nivolumab Favors placebo

Hazard ratio [95% CI]


Nivolumab in refractory GC/GEJCOverall Survival by Subgroups

Time (months)

Pro

ba

bil

ity

of

Pro

gre

ssio

n-F

ree

Su

rviv

al

(%)

20181614121086420

0

10

20

30

40

50

60

70

80

90

100

0024819314683131330

011224791741163

Nivolumab

Placebo

At risk:

Nivolumab

Placebo

Hazard ratio, 0.60 (95% CI, 0.49–0.75)

P < 0.0001

Median Progression-Free Survival

1.61 months

1.45 months

Patients,

n Events, n

Median PFS

[95% CI], months

12-Month PFS Rate

[95% CI], %

Nivolumab 330 253 1.61 [1.54–2.30] 7.6 [4.2–12.2]

Placebo 163 145 1.45 [1.45–1.54] 1.5 [0.3–4.8]


Nivolumab in refractory GC/GEJCProgression-free Survival

Nivolumab 3 mg/kg

(n = 268)

Placebo

(n = 131)

ORR, n (%)

[95% CI]

P value

30 (11.2)

[7.7–15.6]

< 0.0001

0

[0–2.8]

—

BOR, n (%)

Complete response

Partial response

Stable disease

Progressive disease

0

30 (11.2)

78 (29.1)

124 (46.3)

0

0

33 (25.2)

79 (60.3)

DCR, n (%)

[95% CI]

P value

108 (40.3)

[34.4–46.4]

0.0036

33 (25.2)

[18.0–33.5]

—

Median TTR (range), months 1.61 (1.4–7.0) —

Median DOR, months

[95% CI]

9.53

[6.14–9.82]—


Nivolumab in refractory GC/GEJCRECIST Response and Disease Control

Nivolumab Placebo

Ma

xim

um

Re

du

ctio

n F

rom

Ba

seli

ne

in T

arg

et

Lesi

on

s (%

)

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100

a

a Patients with a change in tumor burden that exceeds 100%.

a

Patients with Tumor reduction: 37.3% Patients with Tumor reduction: 12.4%


Nivolumab in refractory GC/GEJCMaximum Reduction in Tumor Burden From Baseline

Nivolumab +/- Ipilimumab (Checkmate 032)

• Phase I/II with a GC/GEJ/EC cohort (160 pts)

�Irrespectively of PD-L1 status

• 3 different schemes of treatment

• ORR (1st End Point)

Nivo 3 mg/kg Q2W

Nivo 1 mg/kg + Ipi 3 mg/kg Q3W

Nivo 3 mg/kg + Ipi 1 mg/kg Q3W

x 4 cyclesNivo 3 mg/kg Q2W

Janjigian YY et al. Proc ASCO 2016

N3 N1+I3 N3+I1

ORR 14% 26% 10%

mOS (m) (95% CI) 5.0 (3.4–12.4) 6.9 (3.6–NA) 4.8 (3.0–9.1)

• 12% of pts stopped therapy due to treatment toxicity

• Treatment-related serious AEs of any grade and Grade 3-4

occurred in 10% and 5% (N3), 43% and 35% (N1+I3), and 23%

and 15% (N3+I1) of pts

� 1 Grade 5 → tumor lysis syndrome (N3+I1)


Janjigian YY et al. Proc ASCO 2016

• Primary endpoint: irPFS

• The study was stopped post-interim analysis

• 143 pts screened

• irPFS similar between arms: mirPFS (95% CI) Ipi 2.92 (1.6 – 5.2)

vs BSC 4.9 (3.5-6.5) (HR=1.44, p=0.097)

• median OS for both arms ≈ 1 yr

• Treatment-related adverse events occurred in 41/57 (72%) on

Ipi pts and 25/45 (56%) pts on active BSC

�Pruritus (32%), diarrhea (25%), fatigue (23%), and rash (18%)

1st Line Tx• Ipi 10 mg/kg Q3W x4 → Ipi 10 mg/kg Q12W x3yr

• BSC (≈ 80% chemotherapy)

Ipilimumab Maintenance treatment – RP2 study

Moehler MH et al. Proc ASCO 2016

Line Study N Treatment Arms Primary EP

1st Line

KEYNOTE-062

NCT02494583

(TPS 4138)

750

Pembrolizumab 200mg Q3W

vs

Pembro + Cisplatin + 5-FU/CPC

vs

Placebo + Cisplatin + 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+

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

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

Outline



Genomic Landscape of CRC… 2012

Cancer Genome Atlas Network, Nature 2012

Facts:224 T/N pairsNext-Generation Sequencing – Whole Exome Seq >20X coverage32 somatic recurrent mutations per tumor

Hypermutated tumors16%

Non-hypermutated tumors84%

Molecular Classification of CRC… 2012

Right-sided, MSI-H, Hypermethylated, BRAF mut, Chromosomal stability

Left-sided, Rectal, MSS, KRAS mut, CIN +ve

Cancer Genome Atlas Network, Nature 2012

CRC subtyping consortium – 2015

Guinney J, Dienstmann R et al. Nat Med 2015

Summary – clinical and molecular correlates

CMS1 - MSI – Immune 14%

CMS2 – Canonical 37% CMS3 – Metabolic 13%

CMS4–Mesenchymal 23%

Immune checkpoint inhibitorsImmune regulatorsBRAF-driven strategies

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

Immune vs Transcriptomic subtypes of CRC

dMMR – MSIHypermutation

Immune-activated

Th1 cells

PDL1

MacrophagesNK cells

Cytotoxic T cells

Th1 cells IFNγIFNγ

CXCL9/10/13

Cancer cell

Cancer cell

Immune-ignorant

Inflammation

Cancer cell

TGFβ

Complement

Stromal cellsTh17 cells

MDSC

Stromal cells

MacrophagesNK cells

Cytotoxic T cells

CCL2

CCL2TGFβ IL-23

IL-17

Immune-tolerant

Inflamed

Monocytes

Outline



Pembrolizumab (anti-PD 1) 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

Pembrolizumab200 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


Primary Endpoint


Assessments: Radiological assessments using RECIST 1.1 and irRC

every 9 weeks

A Phase 2, Single-arm Study of Pembrolizumab in Pre treated 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


Pembrolizumab

200 mg q3w

Up to 2 years

A Phase 3 Study of Pembrolizumab Monotherapy vs Stan dard Chemotherapy in 1L MSI CRC

Randomization1:1

PD

PD

OffStudy

Crossover

Primary Endpoint

• PFS

• OS


• Primary end-point: Investigator-assessed ORR (RECIST 1.1) in MSI-H pts

MSS

Cohort

MSI

Cohort

N = 70 (47 evaluable)1

N = 30 (27 evaluable)1

Overman MJ et al. Proc ASCO 20161; Overman MJ et al. Proc ASCO GI 20172

MSI-H

Nivo

3mg/kg

MSI-H

Nivo 3 +

Ipi 1

MSS

Nivo 1 +

Ipi 3

MSS

Nivo 3 +

Ipi 1

≥12w follow-

up

N=47 N=27 N=10 N=10

ORR, N (%) 12 (25.5) 9 (33.3) 1 (10) 0

CR 0 0

PR 12 (25.5) 9 (33.3)

SD 14 (29.8) 14 (51.9)

PD 17 (36.2) 3 (11.1)

UNK 4 (8.5) 0

All pts N=70 N=30 N=10 N=10

mPFS (m) 5.3

(1.5-NE)

NE

(3.4-NE)

2.28

(0.6-4.4)

1.31

(0.9-1.7)

mOS (m) 17.1

(8.6-NE)

NE

(NE-NE)

11.5

(0.6-NE)

3.7

(1.2-5.6)


Overman MJ et al. Proc ASCO 2016



Response in patients with MSI-H tumors



Survival in patients with MSI-H tumors

Patients, n (%)

dMMR/MSI-H per

Local Laboratory

(N = 74)

dMMR/MSI-H per

Central Laboratory

(n = 53)

Investigator BICR Investigator BICR

ORR, n (%)

95% CI

23 (31.1)

20.8, 42.9

20 (27.0)

17.4, 38.6

19 (35.8)

23.1, 50.2

17 (32.1)

19.9, 46.3

Best overall response, n (%)

CR

PR

SD

PD

Unable to determine

0

23 (31.1)

29 (39.2)

18 (24.3)

4 (5.4)

2 (2.7)

18 (24.3)

28 (37.8)

20 (27.0)

6 (11.1)

0

19 (35.8)

21 (39.6)

10 (18.9)

3 (5.7)

1 (1.9)

16 (30.2)

21 (39.6)

12 (22.6)

3 (5.7)

Disease control for ≥ 12 weeks, n

(%)a51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8)

BICR, blinded independent central review.a Patients with CR, PR, or SD for ≥ 12 weeks.

Nivolumab (Checkmate 142 update)Response and disease control

Overman MJ et al. Proc ASCO GI 2017

PFS per Investigator

Median [95% CI], months

12-month rate [95% CI], %

9.6 [4.3, NE]

48.4 [33.6, 61.7]

PFS per BICR

12-month rate [95% CI], % 45.6 [32.2, 58.1]

BICR, blinded independent central review; NE, not estimable. a Investigator assessed dMMR/MSI-H by local laboratory.

0 3 6 9 12 15 18 21 24

Months

74 48 22 14 12 10 7 3 0No. at risk

0

10

20

30

40

50

60

70

80

90

100

Pro

babi

lity

of P

FS

(%

)a

Nivolumab (Checkmate 142 update)Progression-free survival


NR, not reached. a dMMR/MSI-H assessed by local laboratory.

3 6 9 12 15 18 21 2724

74 64 54 24 21 21 14 10 3 0

0

10

20

30

40

50

60

70

80

90

100

Pro

babi

lity

of S

urvi

val (

%)

a

Median OS [95% CI], months

12-month OS rate [95% CI], %

NR [17.1, NE]

73.8 [59.8, 83.5]

Months

No. at risk

0

Nivolumab (Checkmate 142 update)Overall survival


ORR, n/N (%) Investigator BICR

Tumor PD-L1 expression

≥ 1%

< 1%

6/21 (28.6)

13/45 (28.9)

7/20 (35.0)

11/45 (24.4)


Abundance of PD-L1 expressing

immune cells

Rare

Intermediate

Numerous

5/23 (21.7)

5/20 (25.0)

9/23 (39.1)

4/22 (18.2)

4/20 (20.0)

10/23 (43.5)n/N, responders/evaluable patients.

≥ 1%

< 1%

+ Confirmed CR/PR

Inv

est

iga

tor-

Ass

ess

ed

Be

st C

ha

ng

e in

Ta

rge

t Le

sio

n

Siz

e (

%)

Tumor PD-L1 Expression

100

-50

-100

50

0

Rare

Intermediate

Numerous

+ Confirmed CR/PR

Inv

est

iga

tor-

Ass

ess

ed

Be

st C

ha

ng

e in

Ta

rge

t Le

sio

n

Siz

e (

%)

Abundance of PD-L1 Expressing Tumor-

Associated Immune Cells

100

-50

-100

50

0

Nivolumab (Checkmate 142 update)Reduction in Target Lesions regardless of PD-L1 exp ression



BRAF mutation status

Mutant

Wild type

3/12 (25.0)

12/28 (42.9)

2/12 (16.7)

9/27 (33.3)

KRAS mutation status

Mutant

Wild type

7/26 (26.9)

12/28 (42.9)

6/26 (23.1)

9/27 (33.3)


Clinical history of Lynch

syndrome

Yes

No

8/23 (34.8)

8/26 (30.8)

8/23 (34.8)

6/26 (23.1)

n/N, responders/evaluable patients.

BRAF Mutation Status

100

-50

-100

50

0

Inv

est

iga

tor-

Ass

ess

ed

Be

st C

ha

ng

e in

Ta

rge

t Le

sio

n

Siz

e (

%)

Mutant

Wild type

+ Confirmed CR/PR

Clinical History of Lynch Syndrome

100

-50

-100

50

0

Inv

est

iga

tor-

Ass

ess

ed

Be

st C

ha

ng

e in

Ta

rge

t Le

sio

n

Siz

e (

%)

Yes

No

+ Confirmed CR/PR

Nivolumab (Checkmate 142 update)Reduction in Target Lesions Regardless of BRAF Mut S tatus and Lynch Syndrome


Examples of anti-PDL1/PD1 therapies currently under investigation in CRC*

*Recruiting studies Clinicaltrials.gov

Target Therapy Phase Trial Design Trial ID

Anti-PDL1

Atezolizumab (engineered

IgG1, no ADCC)

I Solid tumours NCT01375842

Ib Solid tumours (+ bevacizumab ± FOLFOX) NCT01633970

II mCRC (+ bevacizumab + fluoropyrimidine) NCT02291289

MEDI4736(modified IgG1,

no ADCC)II mCRC NCT02227667

Anti-PD1

Nivolumab(IgG4)

I/II mCRC (± ipilimumab) (CheckMate 142) NCT02060188

I/II Solid tumours (+INCB24360) NCT02327078

I/II Solid tumours (+ chemotherapy) NCT02423954

I/II Solid tumours (+ varlilumab) NCT02335918

Pembrolizumab(IgG4,

humanised)

I Solid tumours (+ aflibercept) NCT02298959

I/II GI cancers (+mFOLFOX6) NCT02268825

I/II WT mCRC (+ cetuximab) NCT02318901

II mCRC (+ radiotherapy or ablation) NCT02437071

II mCRC (+ chemotherapy) NCT02375672

II mCRC (+ azacitidine) NCT02260440

II MSI-positive/-negative CRC NCT01876511

II MSI-positive CRC (to address response) NTC02460198

III MSI-H and dMMR (Pembro vs 1st Line) NTC02563002

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)



ARMA

Cobimetinib +atezolizumab

n=180

ARMB

Atezolizumabn=90

ARMC

Regorafenibn=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

Therapy Target 1 Construct Phase Trial Design Trial ID

Cytokine-

constructsCEA-IL2v

Anti-CEA

antibody

carrying

mod. IL-2

molecule

I Tumors expressing CEA NCT02004106

Ib

Tumors expressing CEA in

combination with

atezolizumab

NCT02004106

Bi-Specific

Antibodies

CEA-CD3

T-Cell bi-

specific

antibody

I Tumors expressing CEA NCT02324257

Ib

Tumors expressing CEA in

combination with

atezolizumab

NCT02650713

CEA-CD3 BITE I/II Tumors expressing CEA NCT01284231

Clinicaltrials.gov

• Very high potency with EC50 values in the fM to pM range

• Serial killing of tumour cells, activity at low effector–to-target (E:T) ratio

• T cell engagement independent of specificity, activation and differentiation status

• Mode of action may overcome most escape mechanisms that cancer cells employ to evade T cell recognition

T cell bispecific antibodies (TCBs)Highly potent molecules leading to T cell-mediated killing of tumour cells

Bacac, et al. ITOC 2014

T cell

Tumour cell

Cytotoxic granules

Mode of action

CD3 T cell engagement

Silent Fc forhalf-life extension

High avidity binding to tumor antigen

Format

• Simultaneous binding to tumour and T cells results in– T cell engagement, activation and killing of

tumour cells by delivery of cytotoxic granules– T cell proliferation (expansion) at site of

activation

Examples of vaccines for immune-stimulation in CRC

Therapy Antigen Enhancer PhaseStudy

populationTrial ID

Anti-tumor

vaccines

Autologous

tumor cells

BCG

II Adjuvant CRC PMID: 8445413

III Adjuvant CRC PMID: 15755632

IIIAdjuvant Stage

II CRC NCT02448173

Newcastle

Disease Virus II

CRC Liver M1

resectedPMID: 18488223

Dendritic cell

vaccines

CEADendritic

cellsI

Adjuvant Stage

III CRC NCT01890213

MUC 1Dendritic

cellsII

CRC Liver or

lung M1

resected

NCT00103142

Pubmed - Clinicaltrials.gov

Examples of adoptive cell therapy for immune-stimulation in CRC

Therapy Target Enhancer Phase Trial Design Trial ID

TILsAutologous

tumor cells

IL-2

PembrolizumabII 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

Autologous

tumor cellsII

Adjuvant CRC in

combination

with XELOX

NCT01929499

Clinicaltrials.gov

Strategy:

PD1 blockade

Molecular-driven therapeutic hypothesis

Immune

CMS1

Immune

CMS1

MSI

PD1 blockade responsive

Giannakis M et al. Cell Reports 2016

?

Molecular-driven therapeutic hypothesis

MSS

Metabolic

CMS3

Epithelial

CMS2

Strategy: PD1 blockade +

epigenetic modulation

or MEK inhibitors or TCBs?

Strategy: combination of immune-

stimulatory drugs and inhibitors of

immune suppression

Mesenchymal

CMS4

Acknowledgements

All the patients and their familiesVall d’Hebron University Hospital

Oncology Dep.

Pathology Dep.• S. Landolfi• P. Nuciforo• J. Jiménez

• R. Dienstmann• E. Elez• G. Argiles• M. Alsina• E. Sanz• C. Hierro

Genomics Lab.• A. Vivancos• A. Prat

Translational Lab.• V. Serra• H. García-Palmer

• R. Dienstmann• J. Guinney• S. Friend

• R. Salazar• G. Capella• V. Moreno

• I. Simon• L. Dekker• R. Bernards

• S. Kopetz• E. Vilar

• E. Van Cutsem• S. Tejpar

• A. Bardelli• F. Di Nicolantonio

• F. Ciardiello• E. Martinelli

• S. Siena• A. Sartore-Bianchi

• A. Cervantes

• J. Schellens

• I. Melero• J.L. Pérez-García

Colorectal cancer subtyping consortium (CRCSC)

THANK YOU

immunotherapy in gastro-intestinal tumours -...

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