inmunoterapiaentumoresdigesvos -...

Inmunoterapia en Tumores Diges1vos Santander, 14 y 15 Julio 2016

Maria Alsina, MD

Hospital Universitari Vall d’Hebron

Outline •  The Immune System •  Immunotherapy in GI Tumors

– Gastric Cancer – Colorectal Cancer

•  Challenges – PaKerns of response & AEs

•  Conclusions

Tumors are complex systems • Successful growth of tumors and metastasis is not determined solely by geneQc alteraQons in tumor cells, but also by the advantage that such mutaQons confer in the environment.

• Tumor formaQon involves the co-‐evoluQon of neoplasQc cells together with extracellular matrix, tumor vasculature and immune cells.

Tumor Antigen Transport

Lymphocyte trafficking

Junttila Nature 2013

Acquired capaciQes of cancer: phenotype

Avoiding immune destruction

Evading growth suppressors

Enabling replicative immortality

Tumor- promoting inflammation

Activating invasion & metastasis

Genome instability mutation

Resisting cell death

Deregulating cellular energetics

Sustaining proliferative signaling

Inducing angiogenesis

Hanahan & Weinberg Cell 2011

EGFR inhibitors

Aerobic glycolysis inhibitors

Proapopto1c BH3 mime1cs

PARP inhibitors

Inhibitors of HGF/c-‐Met

Selec1ve an1-‐inflammatory drugs

Telomerase inhibitors

Cyclin-‐dependent kinase inhibitors

Inhibitors of VEGF signaling

Immunotherapy

Key aspects of the Immune System

Hanahan & Weinberg Cell 2011; Dunn Nat Rev Immunol 2006 Swann & Smyth J Clin Invest 2007; Prendergast Oncogene 2008; Mapara & Sykes J Clin Oncol 2004

•  The immune system recognises and destroys tumor cells

•  Key features of the immune response: 1.  Memory 2.  Specificity 3.  Adaptability

Immunotherapy has reset survival expectations

0 12 24 36 48 60 72 84 96 108 120 0.0

0.2

0.4

0.6

0.8

1.0

4846 1786 612 392 200 170 120 26 15 5 0

Months

Pooled OS data for 1,861 paQents from 10 prospecQve and two retrospecQve studies Median OS, months: 9.5 months (95% CI 9.0–10.0)

3-‐year OS rate: 21% (95% CI 20–22)

Ipilimumab Censored

Ipilimumab No at risk:

Schadendorf J Clin Oncol 2015

Overall survival

Ipilimumab was the first immune checkpoint inhibitor to demonstrate clinical benefit in stage IV melanoma paQents

The immune cycle in cancer

7. Killing of cancer cells

An1-‐PD1 An1-‐PDL1 An1-‐CTLA-‐4

An1-‐CD137 (agonist) An1-‐OX40 (agonist) An1-‐CD27 (agonist)

IL-‐2 IL-‐12

Tumor

Lymph node

Blood vessel

1.   Release of cancer cell an1gens

2. Cancer an1gen presenta1on

3. Priming and ac1va1on

5. Infiltra1on of T cells into tumors

6. Recogni1on of cancer cells by T cells

4. Trafficking of T cells to tumors

Vaccines IFN-‐α GM-‐CSF

An1-‐CD40 (agonist) TLR agonist

Chemotherapy Radia1on therapy Targeted therapy

An1-‐VEGF/VEGFR

CARs

An1-‐PDL1 An1-‐PD1

IDO inhibitors

Chen & Mellman Immunity 2013

T cell acQvaQon requirements

1.  AnQgen presentaQon –  MHC complex

2.  Co-‐sQmulatory signal –  B7 – CD28

3.  Cytokines

Ø  Inhibitory signal –  B7 – CTLA4 –  PDL-‐1 – PD-‐1

Amorena Science 1978, Mueller J Immunol 1989, Walunas Immunity 1994, Krummel J Exp Med 1995, Dong Nat Med 2002; Keir Annu. Rev. Immunol. 2008

The immune checkpoint targetable receptors/ligands

Mellman Nature 2011

T cell targets for modulaQng acQvity

CD28 OX40

GITR CD137

CD27

HVEM

CTLA-4 PD-1 TIM-3 BTLA

VISTA

LAG-3

Activating Receptors

Inhibitory Receptors

T cell stimulation

T cell

Agonistic Antibodies

Blocking Antibodies

Frequency of geneQc somaQc mutaQons in cancer

Altered proteins contain new epitopes for immune recogniQon, providing a common denominator for cancer immunotherapy

Rhabdo

id tu

mou

r

Ewing sarcom

a

Thyroid

Acute myeloid

leukaemia

Med

ulloblastoma

Carcinoid

Neu

roblastoma

Prostatre

Chronic lymph

ocyQc

leukaemia

Low-‐grade

glioma

Breast

Pancreas

MulQp

le m

yeloma

Kidn

ey clear cell

Kidn

ey

papillary cell

Ovaria

n

Glioblastoma

mulQforme

Cervical

Diffu

se large B-‐cell

lymph

oma

Head and

neck

Colorectal

Esop

hageal

aden

ocarcino

ma

Stom

ach

Bladde

r

Lung ade

no-‐

carcinom

a Lung sq

uamou

s cell

carcinom

a

Melanom

a 0.01

0.1

1

10

100

1000

SomaQ

c mutaQ

on freq

uency (/Mb)

22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121

C→T C→A C→G T→C T→A T→G

Lawrence Nature 2013

No at Risk

50%

20%

22%

9%

TCGA Nature 2014

TILs are predicQve of overall survival in GC

Lee Br J Cancer 2008

Pooled OS data for 220 paQents with gastric cancer surgically resected

Guinney J, Dienstmann R et al. Nat Med 2015




•  Conclusions

•  Pembrolizumab •  Nivolumab +/-‐ Ipi •  Avelumab •  Ipilimumab

Pembrolizumab

•  KEYNOTE 0121 ü Ph 1b with a GC cohort (39 pts)

•  KEYNOTE 0592 ü Ph II 1st Line ü Preliminary safety data

1.  Muro Lancet Oncol 2016 2.  Fuchs ASCO 2016

Screening: 65 of 162 (40%) paQents assessed for PD-‐L1 expression had PD-‐L1-‐posiQve tumors Pa1ents: 19 paQents from Asia and 20 paQents 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 anQbody). PosiQvity 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

Bang YJ et al. Proc ESMO GI 2015

Best Overall Response, RECIST v1.1

Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting

Change From Baseline in Target Lesions

aOnly paQents with measurable disease per RECIST v1.1 by central review at baseline and at least 1 postbaseline tumor assessment were included (n = 32). Analysis cutoff date: March 23, 2015.

53.1% of pa1ents experienced a decrease from

baseline

–100

–80

–60

–40

–20

0

20

40

60

80

100

Chan

ge From Bassline, %

Maximum Change

Asia

Rest of world

Chan

ge From Baseline, %

0 8 16 24 32 40 48 56 64 –100

–75

–50

–25

0

25

50

75

100

125

150

Time, weeks

Change Over Time

Asia

Rest of world


Kaplan-‐Meier EsQmates of Survival

•  OS (ITT) –  6-‐months OS rate: 66% –  Median OS: 11m (95% CI, 5.7-‐NR)

•  Median response duraQon –  40w (20+ to 48+)

Analysis cutoff date: March 23, 2015.

OS

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 Time, months

Overall Survival, %

n at risk

17 15 12 11 10 8 1 0 0 Asia

19 16 13 11 8 7 6 5 0 ROW

Asia

Rest of world


AssociaQon between efficacy and PD-‐L1 expression

•  Preliminary evidence of a relaQonship between PD-‐L1 expression and efficacy in this preselected populaQon

•  Data suggest a relaQvely low cut-‐off is sufficient to detect most responders


Assessing PD-‐L1 Expression as a ConQnuous Variable

Analysis of Gene Expression Signatures NanoString Analysis of 19 biopsies (Discovery Set) and 62 biopsies (ValidaQon Set) from KEYNOTE-‐001

FFPE Tumor Tissue Collected at Baseline Before Receiving Pembrolizumab

NanoString Placorm

FFPET block or unstained slides (~27 patients)

RNA profiling (baseline assessment)•Affymetrix platforms•Already being performed with Covance

Depending on DNA yield (200 ng per slide?)• Affy SNP 6.0 CNV• Genotyping (Sequenom); should see Kras mutations etc.• To be initiated

MET IHC (baseline assessment)MET amplification status (baseline for only responders)• Already being performed with Ventana

(N=3)

(N=4)

(N=3)

Phase I

Gene Expression Data

680 Genes on Custom Plaqorm -‐ Immune Focused -‐

RNA

Discover Genes & Signatures Associated

With An1–PD-‐1 Response

• Most samples yield >20 ng of usable RNA per slide

• 50 ng of RNA required for 1 assay

Ribas A et al. Abstract 3001. Presented at the 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL.

IdenQfied Immune-‐Related Gene Expression Signatures

•  4 immune-‐related gene expression signatures were established in melanoma paQents treated with pembrolizumab in KEYNOTE-‐0011,2

•  Signatures were independently tested in gastric cancer paQents from KEYNOTE-‐0122

–  ORR in the 33 evaluable paQents was 30%

1. Ribas A et al. Abstract 3001. Presented at the 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. 2. Shankaran V et al. Abstract 3026. Presented at the 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL.

Biology of Evaluated Signatures1

AssociaQon 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

aFrom logistic (ORR) or Cox (PFS) regression, with signature scores as a continuous variable. bAssessed per RECIST v1.1 by investigator review. Shankaran V et al. Abstract 3026. Presented at the 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL.

•  PotenQal diagnosQc performance of IFN-‐γ signature

•  NegaQve predicQve value = 92% •  PosiQve predicQve value = 45% •  Prevalence = 61%

AssociaQon of IFN-‐γ Signature and PFSb

Patients with low values of the signature do not show delays in progression

PFS,

day

s Increasing Gene Expression Levels

IFN-γ Signature Score

Other Partial Response Stable Disease

1.5 2.0 2.5

100

200

300

KEYNOTE 059 •  Ph 2 Study in 1st Line GC/GEJ pts

•  Pembro 200 mg + 5-‐FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) + cisplaQn 80 mg/m2 Q3W for 6 cycles → Pembro + 5-‐FU (or capecitabine) for up to 2y

•  18 paQents treated, median follow-‐up 5.5 m ü  No treatment-‐related deaths ü  1 pt (6%) disconQnued treatment

•  StomaQQs unrelated to pembro or chemotherapy. ü  7 pts (39%) G1-‐2 AEs aKributed to pembro

•  Diarrhea, dysgeusia, hyperthyroidism, nausea (n = 2 each) ü  8 pts (44%) experienced G1-‐2 AEs of special interest, regardless of aKribuQon

by invesQgator •  Hyperthyroidism, hypothyroidism, infusion-‐related reacQon, pruritus, vasculiQs.

•  The combinaQon of pembro, cisplaQn, and 5-‐FU has a manageable safety profile as first-‐line therapy in paQents with advanced GC

Nivolumab +/-‐ Ipi (Checkmate 032) •  Phase I/II with a GC/GEJ/EC cohort (160 pts)

ü IrrespecQvely of PD-‐L1 status

•  3 different schemes of treatment

•  ORR (1st End Point)

Janjigian ASCO 2016

Nivo 3 mg/kg Q2W Nivo 1 mg/kg + ipi 3 mg/kg Nivo 3 mg/kg + ipi 1 mg/kg Q3W

x 4 cycles Nivo 3 mg/kg Q2W

Nivolumab +/-‐ Ipi (Checkmate 032)

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

Avelumab (JAVELIN) •  Ph 1b in GC/GEJ pts

ü  IrrespecQvely of PD-‐L1 status

•  Treatment-‐related adverse events

ü  Any grade: in 89 pts (58.9%) → Infusion-‐related reacQon (12.6%) and faQgue (10.6%)

ü  G3: in 15 pts (9.9%) → faQgue, asthenia, increased GGT, thrombocytopenia, and anemia

ü  1 treatment-‐related death (hepaQc failure/autoimmune hepaQQs)

Chung ASCO 2016

2L (n = 22) Mn (n = 52) PD-‐L1+ (n = 11) PD-‐L1− (n = 11) PD-‐L1+ (n = 20) PD-‐L1− (n = 32)

ORR % (95% CI) 18.2

(2.3, 51.8) 9.1

(0.2, 41.3) 10.0

(1.2, 31.7) 3.1

(0.1, 16.2)

mPFS w (95% CI) 6.3

(5.4, 18.0) 10.4

(4.1, 21.9) 17.6

(6.0, 24.1) 11.6

(5.7, 14.1)

•  1st Line Maintenance (89 pts) •  2nd Line (62 pts) Avelumab 10 mg/kg IV Q2W

Ipilimumab Mn (Ph II Trial)

•  1ary EP: irPFS •  The study was stopped post-‐interim analysis •  143 pts screened

•  Treatment-‐related adverse events occurred in 41/57 (72%) of ipi pts and 25/45 (56%) pts on acQve BSC ü Pruritus (32%), diarrhea (25%), faQgue (23%), and rash (18%)

Moehler ASCO 2016

1st Line Ttx •  Ipi 10 mg/kg Q3W x4 → Ipi 10 mg/kg Q12W x3y •  BSC (≈ 80% chemotherapy)

Ipilimumab Mn (Ph II Trial) •  irPFS similar between arms (HR=1.44, p=0.097) •  median OS for both arms ≈ 1 yr

Moehler ASCO 2016

Median irPFS (95% CI) ü  Ipi 2.92 (1.6 – 5.2) ü  BSC 4.9 (3.5-‐6.5)

Early progressors lost

When the immune system reacts, it reacts well, potenQally even in re-‐introducQon or 2nd L

Ongoing Phase III Clinical Trials Line Study N Treatment Arms 1ary EP

1st Line KEYNOTE-‐062 NCT02494583 (TPS 4138)

750

Pembrolizumab 200mg Q3W vs Pembro + CisplaQno + 5-‐FU/CPC vs Placebo + CisplaQno + 5-‐FU/CPC

OS PFS (RECIST 1.1)

CG & CUGE PS 0-‐1 PD-‐L1+/HER2-‐ StraQficaQon: Europe/North America/Australia vs Asia vs ROW RECIST 1.1 & irRECIST

Mn

JAVELIN Gastric 100 NCT02625610 (TPS 4134)

466

FOLFOX/XELOX x12 semanas, luego: Avelumab 10mg/kg Q2W vs ConQnuar FOLFOX/XELOX

OS PFS

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 en PD-‐L1+

CG & CUGE PS 0-‐1 No molecular selecQon RECIST 1.1 & irRECIST

3rd Line

JAVELIN Gastric 300 NCT02625623 (TPS4135)

330 Avelumab 10mg/kg Q2W + BSC vs Paclitaxel/Irinotencan/BSC

OS

CG & CUGE PS 0-‐1 No molecular selecQon StraQficaQon: Asia vs non Asia Exclusion of previous immunother RECIST 1.1

Ongoing Phase I/II Clinical Tria

ls ID Ph Strategy Indication Status

NCT02443324 I Pembrolizumab plus Ramucirumab Specific cohort, 2nd or 3rd Line Recruiting

NCT02335411 (KEYNOTE 059) II Pembrolizumab in monotherapy or in combination

with CT Different lines, HER2-neg Recruiting

NCT02563548 I Pembrolizumab plus PEGPH20 Specific cohort, at least 2nd Line Recruiting

NCT01848834 (KEYNOTE 012) I Pembrolizumab Specific cohort, refractory

setting Active, not recruiting

NCT02452424 I Pembrolizumab plus PLX3397 Specific cohort, refractory setting Recruiting

NCT02318901 I/II Pembrolizumab plus trastuzumab Specific cohort, HER2-positive Recruiting

NCT02268825 I/II Pembrolizumab plus FOLFOX Specific cohort Recruiting

NCT02340975 II Tremelimumab and/or durvalumab Refractory setting Recruiting

NCT01585987 II Ipilimumab vs FU/BSC Manteinance after 1st Line Completed

NCT01928394 I/II Nivolumab +/- ipilimumab Specific cohort, refractory setting Recruiting

NCT02267343 I Nivolumab Refractory setting Recruiting

NCT02488759 I/II Nivolumab EBV-positive Recruiting

NCT01772004 I Avelumab Specific cohort, 3rd Line Recruiting

NCT01943461 I Avelumab 2nd and 3rd Line, Japanesse and Asian Recruiting

NCT01633970 I Atezolizumab montherapy or in combination with bevacizumab or CT Basket Recruiting

NCT01375842 I Atezolizumab Basket Recruiting

NCT02471846 I Atezolizumab and GDC-0919 Specific cohort, refractory setting Recruiting




•  Conclusions

•  Pembrolizumab •  Nivolumab + Ipilimumab •  CobimeQnib + Atezolizumab

•  Immunoscore

Pembrolizumab (KEYNOTE 016)

Le DT et al. ASCO 2015, Le DT NEJM 2015

MMR-‐deficient CRC

MMR-‐proficient

CRC

MMR-‐deficient non-‐CRC

N 13 25 10

ORR 62% 0% 60%

DCR 92% 16% 70%

200 400 600

-100-90-80-70-60-50-40-30-20-10

0102030405060708090

100 MMR-proficient CRCMMR-deficient CRCMMR-deficient non-CRC

Days%C

han

ge f

rom

Baseli

ne S

LD

Pembrolizumab (KEYNOTE 016) Progression-‐Free Survival

CRC Cohorts

Mismatch-‐repair proficient

Mismatch-‐repair deficient

Mismatch-‐repair proficient

Mismatch-‐repair deficient

Overall Survival CRC Cohorts


MMR-deficient MMR-proficient

0

500

1000

1500

Den

sity

of

intr

atu

mo

ral

CD

8+ T

cel

ls


0

500

1000

1500

Den

sity

of

inva

sive

fro

nt

CD

8+ T

cel

ls


0

20

40

60

80

100

PD

-L1

+ T

ILS

(%

)


0

20

40

60

80

100

Inva

sive

fro

nt

PD

-L1

+ c

ells

(%

)


0

20

40

60

80

100

PD

-L1

+ T

um

or

Cel

ls (

%)

P = 0.07P = 0.04

P = 0.10 P = 0.04

P = 0.22


0

500

1000

1500

Den

sity

of

intr

atu

mo

ral

CD

8+ T

cel

ls


0

500

1000

1500

Den

sity

of

inva

sive

fro

nt

CD

8+ T

cel

ls


0

20

40

60

80

100

PD

-L1+

TIL

S (

%)


0

20

40

60

80

100

Inva

sive

fro

nt

PD

-L1

+ c

ells

(%

)


0

20

40

60

80

100

PD

-L1+

Tu

mo

r C

ells

(%

)

P = 0.07P = 0.04

P = 0.10 P = 0.04

P = 0.22


0

500

1000

1500

Den

sit

y o

f in

tratu

mo

ral

CD

8+ T

cell

s


0

500

1000

1500

Den

sit

y o

f in

vas

ive f

ron

t C

D8+

T c

ell

s


0

20

40

60

80

100

PD

-L1

+ T

ILS

(%

)


0

20

40

60

80

100

Invasiv

e f

ron

t P

D-L

1+ c

ell

s

(%)


0

20

40

60

80

100

PD

-L1

+ T

um

or

Cell

s (

%)

P = 0.07P = 0.04

P = 0.10 P = 0.04

P = 0.22

Invasive Front PD-‐L1 Expression and CD8 T Cell InfiltraQon

Invasive Front CD8+ T cells Invasive Front PD-‐L1 Expression Tumor Front PD-‐L1 Expression


MMR-deficient tumors MMR-proficient tumors

0

1000

2000

3000

4000

5000P=0.007

Som

atic

muta

tions p

er

tum

or

Objective Response Stable Disease Progressive Disease

0

1000

2000

3000

4000

5000P=0.02

Som

atic

muta

tions p

er tu

mor

MutaQon burden is associated with efficacy


Nivolumab +/-‐ Ipilimumab (Checkmate 142)

•  1ary end-‐point: InvesQgator-‐assessed ORR (RECIST 1.1) in MSI-‐H pts

Overman ASCO 2016

MSS Cohort

MSI Cohort

N = 70 (47 eval)

N = 30 (27 eval)

Nivolumab +/-‐ Ipilimumab (Checkmate 142) 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 (mo) 5.3 (1.5-‐NE)

NE (3.4-‐NE)

2.28 (0.6-‐4.4)

1.31 (0.9-‐1.7)

mOS (mo) 17.1 (8.6-‐NE)

NE (NE-‐NE)

11.5 (0.6-‐NE)

3.7 (1.2-‐5.6)

Overman ASCO 2016

Response in paQents with MSI-‐H

Overman ASCO 2016

CobimeQnib + Atezolizumab

•  PD-‐L1 and MEK inhibiQon: a raQonal combinaQon


Bendell 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 (mo) 2.3 (1.8-‐9,5)

2.3 (1.8-‐9,5)

mOS (mo) NE (6,5-‐NE)

NE (6,5-‐NE)

Bendell ASCO 2016

Target Therapy Phase Trial Design Trial ID

AnQ-‐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

AnQ-‐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 ablaQon) NCT02437071

II mCRC (+ chemotherapy) NCT02375672

II mCRC (+ azaciQdine) NCT02260440

II MSI-‐posiQve/-‐negaQve CRC NCT01876511

II MSI-‐posiQve CRC (to adress response) NTC02460198

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

Examples of anQ-‐PDL1/PD1 therapies currently under invesQgaQon in CRC

Clinicaltrials.gov

Slide Courtesy of Josep Tabernero Clinicaltrials.gov

IMMUNOSCORE •  ValidaQon of the Immunoscore as a prognosQc marker in stage I/II/III colon cancer – Worldwide consorQum –  Final analysis: 3855 paQents

Galon ASCO 2016

IMMUNOSCORE

Galon ASCO 2016

Galon ASCO 2016




•  Conclusions

IdenQfying paKerns of response

50

25

–125

–25

Change from

baseline SPD (%

)

–50

–75

–21 –63

RelaQve day from date of first dose 21 63 105 147 189 231 273 315 357

0

–100

2810 2482 2154 1826 1498 1171 843 515

–140 187

–468

SPD (mm

2)

50

25

–125

–25 Ch

ange from

baseline SPD (%

) –50

–75

–21 –63


0

–100

1272 1124 975 827 678 530 382 233

–64 85

–212

SPD (mm

2)

N

N N N N N

150 125

–125

75

Change from

baseline SPD (%

)

50 25

–21 –63


100

0

19373 17242 15111 12980 10849 8718 6587 4456

194 2325

–1937

50

25

–125

–25

Change from

baseline SPD (%

)

–50

–75

–21 –63

RelaQve day from first dose 21 63 105 147 189 231 273 315 357 399 441 483 525

0

–100

153 135 117 99 82 64 46 28

–8 10

–26

SPD (mm

2) SPD (m

m2)

–100 –75 –50 –25

N

Response in baseline lesions

Response ajer ini1al increase in total tumor volume

‘Stable disease’ with slow, steady decline in total tumor volume

Reduc1on in total tumor burden ajer appearance of new lesions

Wolchok Clin Cancer Res 2009

Managing immune-‐related AEs

Rash

Autoimmune hepaQQs Elevated transaminases

PneumoniQs

ColiQs -‐ duodeniQs

PancreaQQs

Type 1 diabetes mellitus

Hypothyroidism MyosiQs

Myasthenia Gravis

Melero Clin Cancer Res 2013




•  Conclusions

Conclusions 1 •  The immune system plays an important role in GC and CRC

tumorigenesis –  Specifically in some subtypes

•  Checkpoint inhibitors have shown encouraging efficacy, in monotherapy –  In GC → Pembro, nivo, nivo + ipi, avelumab –  In CRC → Pembro, nivo, nivo + ipi in MSI

•  And also with different combinaQons approaches –  Cobi + atezo in MSS CRC –  With RT (abscopal effect)1

•  Current prospecQve clinical trials will validate their real role

1. Seagal ASCO 216

Conclusions 2

•  In CRC, immune infiltrate may idenQfy risk pts –  The immunoscore predicts high risk stage II

•  Efforts to idenQfy predicQve biomarkers have already

begun

•  Future studies should idenQfy the immune-‐paKern of response and beKer understand how to manage the related adverse events

[email protected], [email protected]

Thank you!

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