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
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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