1

Immunotherapy in metastatic colo-

rectal cancer (mCRC): the potential

of immune checkpoint inhibitors Th André

Service d’Oncologie Médicale

Et unité INSERM UMRS 938

‘Microsatellite Instability and Cancer’

Sorbonne université

Hôpital Saint Antoine

Et GERCOR

2

Consulting or Advisory Role and/or Honoraria:

Astra-Zeneca, Amgen, BMS, Chugai, MSD

Oncology, HalioDx, Roche/Ventana, Sanofi,

Sevier, Pierre Fabre, Yakult

Disclosures Information

3

Bevacizumab

Overall Survival

Tim

e (

month

s)

BSC5-FU

30

IrinotecanCapecitabine

Oxaliplatin

Cetuximab

1980s 1990s 2000s 2010 2020

PanitumumabAflibercept

Regorafenib/trifluridine-tipiracil

NGS

Molecular

targeting

strategy

20

10

0

Metastasis surgery

(Liver, Lung, carcinomatis)

Tournigand et al. JCO, 2004

25 - 30 months since 2015

Therapeutic progress, mCRC

4

Therapeutic progress, mCRC

Kras: mutation on exon 2, 3 and 4

Nras: mutation on exon 2, 3 and 4

Braf: V600E

OS

WT Kras and Nras 28- 30 months

Mut Kras and Nras 25 months

Mt Braf V600E 12 months

BRAF V600E

mt

~8%

MSI

5%

5%HER2

1%

NTRK

< 1%

EGFR

hyper-expression or amplification ALK/ROS/NTRK1,2,3 fusions

5

Emidemiology of MSI/dMMR GI Cancer

Primary Locally non M+ M+

Colo-Rectal/Small Intestine 10-20% 4-5%

Oeso-Gastric ADK 8-24% 3-6%

Chlangiocarcinoma 4-5% Unknown

Pancreas 1-2% ≤ 1%

Hepatocarcinoma 1-2% ≤ 1%

Anus Unknown but < 1% Unknown

Colle R et al; Bull du cancer 2018

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Anti-Tumour Immunity Across Different Stages of MSI CRC

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STAGE 2

▪Infiltration with activated cytotoxic T-cell L (CD8+/Th1) = effective anti-tumor immunity

▪Good prognosis for MSI

STAGE 3

▪Positive effect of cytotoxic T-cell L predominant

▪Expression of immune-checkpoints counterbalances the effects of cytotoxic T-cell in some patients who then progress to stage 4

▪Overall prognosis unclear

STAGE 4

▪Concomitant and specific overexpression of multiple immune checkpoints (e.g. CTLA-4, PD-1, LAG-3) and immune-inhibitory molecules (e.g. IDO) attenuate anti-tumoual immunity

▪Prognosis worse compare/MSS

▪ Most of dMMR/MSI tumours are highly infiltrated with cytotoxic T cells

Stage 2 Stage 3 Metastatic

Marisa L. et al. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. J

Natl Cancer Inst (2018) 110(1) Pages F, Lancet 2018; Yoon HH and Sinicrope F, Clin Cancer Research, 2019

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Potential of Immune Checkpoint

Inhibitors in MSI mCRC

Dendritic

cell

TCRMHC II

CTLA-4PD-L1

B7

TCR

PD-1

T cell

Tumor

cellT cell

MHC II

Investigation of checkpoint inhibitors as

novel agents in Cancer treatment

Tremelimumab

Ipilumumab

Pembrolizumab/

Nivolumab

TSR-042

Atezolizumab

Durvalumab

Avelumab

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• Primary Outcome Measures: PFS , Overal Response rate

• MSI and MSS CRC groups had received a median of 3 and 4 prior treatment regimens, respectively

n=28MSI CRC

MSS CRCn=25

n=30MSI non-CRC

Key Inclusion Criteria

Pembrolizumab

10 mg/kg Q2W

Phase II multicenter, open-label trial of pembrolizumab as monotherapy

in three different treatment-refractory patient populations

N=83

Le DT, et al. N Engl J Med 2015; 372: 2509–2520

Johns Hopkins

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ResponsedMMR CRC

n=28pMMR CRC

n=25

ORR, % (95% CI)

57(39–73)

0(0–13)

DCR, % (95% CI) 89(73–96)

16(6–35)

CR, % 11 0

PR, % 46 0

SD*, % 32 16

PD, % 4 44

NE, % 7 40

PFS, mo NR 2.3

OS, mo NR 5.98

Best Radiographic Response1,2

100

50

0

-50

-100

% C

han

ge F

rom

Bas

elin

e S

LD

pMMR CRC

dMMR CRC

20% increase (PD)

30% decrease (PR)

1. Le DT et al. Oral presentation at ASCO 2016. TPS3631. 2. Le DT et al. N Engl J Med. 2015;372(26):2509-2520.

Pembrolizumab: NCT01876511

Summary of Clinical Activity1-2

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Overall Response Rate with Pembrolizumab

for Metastatic Solid tumor MSI-H/dMMR

11 patients on CR and stopped pembrolizumab at 2 years

Without any progression after (median time after stopping: 8.3 months)Le DT, Science 2017

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Primary endpoint:

• Reponse rate

• (RECIST v1.1)

Other key endpoints:

• DCR

DOR, PFS, OS, and safety

• Histologically

confirmed metastatic

or recurrent CRC

• dMMR/MSI-H per

local laboratory

• ≥ 1 prior line of

therapy

Nivolumab 3 mg/kg +

ipilimumab 1 mg/kg Q3W

(4 doses and then

nivolumab 3 mg/kg Q2W)

Combination

Cohorta

Nivolumab 3 mg/kg Q2W

Monotherapy

Cohorta

Lancet Oncol 2017, M Overman

J Clin Oncol 2018, M Overman

Median follow-up in the combination therapy cohort (N = 119) : 13.4 months (range, 9–25)

Median follow-up in monotherapy cohort (N = 74) :21 months (range, 17–40)

Nivolumab ± Ipilumumab in Patients dMMR/MSI mCRC after

> 1 lines of chemotherapy ± targeted therapy

(Chekmate 142: phase 2 study non Randomized )

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Response Rate (Checkmate 142) mCRC after > 2

lines of chemotherapy ± targeted therapy (76%)

Disease Control Rate (Same Follow up):

80% with nivo + ipi and 69% with nivo monotherapy

1 Overman M, Lancet Oncol 2017; 2 Overman M, J Clin Oncol. 2018;3 André T, ASCO GI 2018

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Progression-Free and Overall Survival

(Checkmate 142)

1 Overman M, Lancet Oncol 2017; 2 Overman M, J Clin Oncol. 2018;3 André T, ASCO GI 2018

PFS OS

Median follow-up was 13.4 (range, 9–25) months

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Checkmate 142: ORR in first line in MSI mCRC

NIVO3 (Q2W) + IPI1 (Q6W)

N = 45

Overall Response Rate, n (%)

[95% CI]

27 (60)

[44.3–74.3]

Best response, n (%)*

CR

PR

SD

PD

Non done

3 (7)

24 (53)

11 (24)

6 (13)

1 (2)

Disease Control Rate , n (%)

[95% CI]

38 (84)

[70.5–93.5]

Lenz H.-J.J et al. Ann Oncol 2018;29:supplement 8; Late-Breaking Abstract 18.

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Pembrolizumab

Nivolumab± Ipilumumab

Is an option for MSI/dMMR mCRC

1 2019

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Challenge # 1:

Labelling in Europe and Asia of

pembrolizumab and/or nivolumab ±ipilumumab in MSI mCRC and other

metastaic GI cancer

• For treating patients MSI mCCR only possible in clinical trials

in Europe and other part of the world: : Unbelievable situation!

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Patients

• MSI-high or dMMR mCRC

• No prior therapy

• Measurable disease per

RECIST v1.1

• ECOG PS 0 or 1

Pembrolizumab

200 mg IV Q3W

Investigator-

Choice

Chemotherapy

• mFOLFOX6, or

• mFOLFOX6 + bevacizumab, or

• mFOLFOX6+ cetuximab, or

• FOLFIRI, or

• FOLFIRI + bevacizumab, or

• FOLFIRI + cetuximab

Pembrolizumab

200 mg IV Q3WCrossover

Eligible

R

1:1

• Open label, N = 307 included and inclusion closed. Curative resection

permitted on study

KEYNOTE 177

Inclusion closed Q1 2018Primary end point: PFS

per RECIST 1.1 by central imaging

vendor

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Phase 3b Randomized Clinical Trial of NIVO Alone,

NIVO + IPI, or an Investigator’s Choice Chemotherapy

For MSI-H/dMMR mCRC

Inclusion criteria

• Recurrent or metastatic CRC

• MSI-H/dMMR by local testing

• ECOG 0 and 1 Arm A:

Nivolumab monotherapy

Arm B:

Nivolumab plus ipilimumab

Randomization (N = 494*)

Arm C:

Investigator’s choice

chemotherapy

Follow-up

Participants in Arm C would be allowed to receive

nivolumab plus ipilimumab if they progress

Primary endpoint• PFS per BICR

Key Secondary endpoints• PFS, ORR, DCR per investigator assessment• ORR, DCR per BICR• OS, TTR, DOR

Treat until progression or toxicity

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Challenge # 2 :

MSI/dMMR diagnostic without

mis-diagnosed

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ESMO Recommendations on dMMR/MSI

testing

Luchini C, Annals Oncol 2019

• Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 first action to assess

MSI/dMMR

• In case of doubt of IHC, confirmatory molecular analysis is mandatory by PCR

• Next-generation sequencing, coupling MSI and TMB analysis, may represent a

decisive tool for selecting patients for immunotherapy, for common or rare cancers

not in the spectrum of Lynch syndrome.

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Challenge # 3:

To deal with the patient in clinical

practice

• What is the best regimen ?

• When we will treat: First line or if refractory to stantard therapy ?

• How long of treatment: one year, two year ? more?

• What is indication for surgery

In case of partial response (residual mass) ?

Necessary?

• In case of progressive disease: What will do ?

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February 2016

April 2018

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Challenge # 4: Try to understand Primary Resistance

• Misdiagnose MSI/dMMR (What is standard for agency ?)

• Pseudoprogression++++

• Deficiency of antigen presentation: Beta 2 microglobuline mutation;

Mutation of JAK1/2

• Evaluation of Immunoscore and Immunune Check Point expression

to use other IO (anti-Lag3, IDO inhibitors………)

• Exome sequencing if resistance to find genes fusion for targeted

therapy ?

• Microbiote ? Jass, Histopathology 2007; Llosa et al., Cancer Discov 2015; Kloor et al., Int J Cancer 2010

Llosa et al., Cancer Discov 2015; Clendenning, Fam Cancer 2018

Syn et al., Lancet Oncol 2017; Routy et al., Science 2018; Guinney et al., Nature Med 2015

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Challenge # 5:

Neo-adjuvant Treatment for non metastaaic

colo-rectal cancer

• Proof of concept

• Better that neo-adjuvant or adjuvant chemotherapy ?

• Rate of complete histologial response ?

• The dream: avoid surgery!

31Chalabi M et al. Ann Oncol 2018;29:supplement 8; Late-Breaking Abstract 37.

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Take Home Messages

• Immune checkpoint inhibitors (ICKs) in mCRC= New Paradigm

in the treatment of CRC dMMR/MSI but no Labelling in EU!

• dMMR/MSI (PCR or NGS) = strong predictive factor of

efficacy of ICKs in mCRC but also in all solid tumor

• Diagnostic of dMMR or MSI (PCR or NGS) is mandatory for all

stage CRC (Lynch syndrome, Indication of chemotherapy in

adjuvant situation, indication of ICKs in mCRC)

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Thanks for your attention