Immunotherapy in CRC

Myriam Chalabi

Medical Oncologist

Outline

• Immunogenicity of CRC

• Immune checkpoint blockade in CRC

– Monotherapy

– Combination therapy

• Future perspectives

FDA approval pembrolizumab

MSI tumors

Mismatch repair deficiency

• 15% of primary CRC

• 5% of mCRC

• High mutational burden, high levels of TILs,

high expression of PD-1, PD-L1, CTLA-4, LAG3,

IDO

MSI vs MSS

Diaz, ASCO 2016

CMS subtypes

Guinney et al, Nature 2015

“MSI-like”

Becht et al, Clin Canc Res 2016

Immunoscore

Mlecnik & Galon, 2016

Immunoscore

Galon et al, 2012

Immunoscore vs MSI

Mlecknik et al, Immunity 2016

Outline

• Immunogenicity of CRC

• Immune checkpoint blockade in CRC

– Monotherapy

– Combination therapy

• Future perspectives

• Anti-PD1 in solid tumors. RR 0% for CRC (0/19)

Anti-PD1 in CRC

Le et al, NEJM 2015

MSI vs MSS

Le et al, ASCO 2016

MSS (n=25) vs MSI (n=28)

ORR: 0% vs 57%

OS: 6mo vs NR

Checkmate-142

Overman et al, ASCO 2016

Nivolumab monotherapy

MSI

Duration of response and median OS: NR

N=74

ORR 31 %

Disease control 69 %

OS 73.8% (12 months)

Overman, ASCO GI 2017

Predictive biomarkers?ORR

Tumor PD-L1 expression

<1% 11/45; 24%

>1% 7/21; 33%

BRAF/KRAS mutations

BRAF mutant 2/12; 17%

KRAS mutant 6/26; 23%

BRAF/KRAS wild type 9/28; 32%

Lynch syndrome Yes 8/23; 35%

No 6/26; 23%

Responses irrespective of PD-L1 expression on tumor cells, KRAS or BRAF

mutation and MSI cause

Outline

• Immunogenicity of CRC

• Immune checkpoint blockade in CRC

– Monotherapy

– Combination therapy

• Future perspectives

Nivolumab + Ipilimumab

MSI

N3 (n=70) N3 + I1 (n=30)

ORR, n (%)b 12 (25.5) 9 (33.3)

CR 0 0

SD 14 (29.8%) 14 (51.9%)

PD 17 (36.2%) 3 (11.1%)

ND/NR 4 (8.5%) 1 (3.7%)

Overman, ASCO + ESMO 2016

MSS tumors

• 57-year old patient

• Metastatic mucosal melanoma

– PET-CT: colon tumor

• Start ipilimumab + nivolumab due to fast

progressive melanoma

What about the MSS?

Overman et al, ASCO 2016

MEK-i + anti-PD-L1

• Open-label, multicentre study including microsatellite stable (MSS) CRC tumours

mCRC*

(n=3)

Cobimetinib

20–60mg

daily

+

atezolizumab

800mg iv q2w

Dose escalation phase

KRAS MT

mCRC

(n=20)

Cobimetinib

60mg daily

+ atezolizumab

800mg iv q2w

Expansion phase

Bendell et al. ASCO 2016

Desai et al. ESMO 2016

Cobimetinib + Atezolizumab in MSS mCRC (phase Ib)

• MEKi: intratumoral T cell accumulation + MHC Class I upregulation

• MEK inhibition and anti-PDL1 are synergistic in xenograft models

Bendell et al, ASCO 2016;

Ebert et al. Immunity 2016

Tumour volume (mm3)

Day

Control

Anti-PDL1

MEKi (38963)

MEKi + anti-PDL1

ND MEKi

Class I MHCp=0.002

4

CD8+ T cell per tumour

cell

ND MEKi

T CELL

activation

Antigen presenta

tion

Increased potential for anti-PD(L)1

Effect of MEK-I on T-cells and TME

Bendell et al. ASCO 2016

Desai et al. ESMO 2016

Cobimetinib + Atezolizumab efficacy:

confirmed objective response

PR

SD

PD

Maxim

um

SLD

reduction f

rom

baselin

e, %

–60

–40

–20

20

40

0

50

–80

MS

I-lo

w

MS

S

MS

S

Unknow

n

Outline

• Immunogenicity of CRC

• Immune checkpoint blockade in CRC

– Monotherapy

– Combination therapy

• Future perspectives

Enhancing response to IT?

• Combinations with immunomodulatory agents

• Combinations with cytotoxic therapies

• Targeted therapy (VEGi/EGFRi)

• Radiotherapy/ablation

• Tumor-specific immune response: bispecific antibodies, vaccines, CAR-T-cell therapy

Melero & Haanen, Nat Rev 2015

Bever et al, JNCCN 2017

COX-inhibition

• COX-i associated with primary and secondary prevention in CRC

• PGE2 synthesis: cancer cell survival, invasion, angiogenesis and immunosuppression

• recruitment and induction of MDSCs

• inhibition of DCs

• COX2-I: reversion of CD8+ T-cell suppression

• when combined with anti-PD1, leads to improved responses

Li et al, Gut 2015; Zelenay et al, Cell 2015.

NICHE trial

• Pre-operative IT in non-metastatic colon

cancers

• Anti-PD1 + anti-CTLA4

• MSS: +/- celecoxib

NCT03026140

Important ongoing trials

• Keynote-177: randomized, first line treatment in MSI CRC: pembro vs SOC

• Keynote-164: single arm study with pembro in previously treated patients

• Checkmate-142: nivo +/- ipi in MSS + MSI CRCs

• Phase III trial of atezo + cobi vs regorafenib

Take home messages

• Response rates of checkpoint inhibitors in unselected CRC populations low

• Immunotherapy effective in pretreated MSI CRC

• Immunoscore: prognostic test. Predictive value in response to IT?

• MSS CRCs: promising results MEK-I + anti-PDL-1

Questions?