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Page 4 of 16 Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03

Finally, CMS2 and 3 show low inflammatory and immune signatures making them “cold” tumours and as
such will need an immune stimulus (i.e., radiotherapy, etc.) as part of the treatment.

IMMUNOTHERAPY IN COLON CANCER
PD-1
Recently, cancer immunotherapy has emerged as a relevant treatment in oncology as significant clinical
benefits have been obtained by inhibiting the programmed death 1 (PD-1) receptors or its ligands (PD-L1 or
PD-L2) in several types of cancer [20-22] .

In fact, the expression of PD-1 on the tumour or T, B and natural killer cells constitutes a predictive marker
of benefit to PD-1 inhibitors.

PD-1 exerts an inhibitory activity by joining to PD-L1 and PD-L2 and as such, it blocks apoptosis of the
tumour cell and promotes peripheral T-effector cell consumption and transformation to regulatory T (Treg)
[23]
cells .
Following the success in the treatment of other neoplasias, different trials have been carried out in cancers
such as colon.

Immune check-point inhibitors
As already mentioned, those metastatic colon cancers showing MSI-H, are associated with a high mutational
burden and immune cell invasion, making them ideal for immune checkpoint inhibitors [Table 1].

Two clinical trials have suggested the activity of these drugs for these tumours, leading to the National
Comprehensive Cancer Center Network (NCCN) to recommend nivolumab and pembrolizumab in second
[24]
and third lines .

A phase II clinical trial, KEYNOTE-164 tested pembrolizumab (MK-3475) in second or third line metastatic colon
[25]
cancers with or without MMR deficiency . Pembrolizumab was given intravenously (iv) at 10 mg/kg every two
weeks and patients were divided into 3 groups: colon MMR-deficient (n = 11), colon MMR-proficient (n = 21),
MMR-deficient non-colon (n = 9). The primary end-points were the immune-related objective response rate
(ORR) and immune-related progression-free survival (PFS) at twenty weeks.

This trial showed ORR of 40% and PFS of 78% for colon MMR-deficient while 0% and 11% for proficient
while the OS was not reached for colon MMR-deficient. PFS and OS were reported as 2.2 and 5.0 months
for colon MMR-proficient and a post hoc comparison of colon groups MMR-deficient and proficient
documented a hazard ratio (HR) for progression or death of 0.10 (P < 0.001), with a HR for death of 0.22
(P = 0.05).

Non-colon cancers MMR-deficient showed similar results to colon MMR-deficient with ORR of 71% and
PFS of 67%. This trial documented a longer PFS linked with high somatic mutation (P = 0.02) and longer OS
(P = 0.02) and interestingly, the sequencing of the whole-exome reported 1782 somatic mutations in MMR-
deficient cases and only 73 in MMR-proficient (P = 0.007).

Authors concluded that this study confirmed that MMR-deficient profile predicts benefit from
pembrolizumab.

Most frequent side-effects were manageable with fatigue (32%), rash or pruritus (24%), diarrhea (24%),
abdominal pain (24%), constipation (20%), anemia/lymphopenia (20%), headache (17%), arthralgia (17%),