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Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03 Page 7 of 16

the activation of an antineoplastic immune attack. KEYNOTE-016 is a phase II trial that showed with
pembrolizumab an ORR of 40% in MSI-H stage IV colon cancers treatment refractory vs. 0% in MMR-
proficient.

Programmed death-ligand 1 inhibition
BMS936559 (MDX 1105), an anti Programmed death-ligand 1 (PD-L1) monoclonal antibody has been evaluated
in a phase I/II trial with > 200 cases, including several non-haematological tumours. In this study, iv anti-
PD-L1 antibody was given to patients (escalating doses from 0.3 to 10 mg per kilogram of weight) every
2 weeks in 6-week cycles for up to 16 or until a complete response is confirmed or disease progression
whichever was documented first. Eighteen of these patients had colon cancer and the ORR reported was 17%
[34]
but none was seen in colon cancer patients .

Atezolizumab is an anti PD-L1 that blocks PD1 and B7.1 to stimulate T-cell priming and all suppressed
immune cells and its anticancer activity as monotherapy has been reported, although the RR in MSS colon
[35]
cancer is not encouraging .

Another study called COMMITT (NCT02997228) will assess atezolizumab in 439 untreated cases with
stage IV colon cancer MSI-H/dMMR. They will be randomized to FOLFOX/bevacizumab, atezolizumab
monotherapy or atezolizumab/FOLFOX/bevacizumab. The primary endpoint is PFS and other endpoints are
OS, ORR, duration of response, DCR and QOL. This study is recruiting patients.

A phase III study will test if the combination of atezolizumab with adjuvant FOLFOX can improve patient
disease-free survival vs. FOLFOX alone in stage III dMMR or MSI colon cancers (NCT02912559).

By inhibiting PD-1/PD-L1 connection, atezolizumab may activate T cells, thereby, repairing the capacity to
find and destroy malignant cells.

Limited results suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that may serve as
“immune priming”.

Patients with curatively resected stage III colon cancers dMMR will be randomized to modified FOLFOX6
for 6 months (12 cycles) alone or combined with atezolizumab (840 mg iv every two weeks) continued
as monotherapy for 6 months (total duration of 12 months). Patients will be stratified by T, N stage and
tumour sidedness and the local testing for MSI or MMR proteins is permitted. Atezolizumab should start
with cycle 2 or before. This study will be performed by the Alliance for Clinical Trials in Oncology and is
[36]
planning to recruit around 700 patients . A multicenter phase Ib trial was carried out to test atezolizumab
with bevacizumab in 14 refractory metastatic colon cancer and with bevacizumab and FOLFOX in 30 cases
[37]
oxaliplatin-naive metastatic colon cancer .
The dose of atezolizumab was 20 mg/kg every 3 weeks and bevacizumab 15 mg/kg every 3 weeks in the first
group and atezolizumab 14 mg/kg every 2 weeks, bevacizumab 10 mg/kg every 2 weeks and FOLFOX at
standard doses in the second group.

The study showed an ORR of 8% in combination with bevacizumab and 36% in combination with
chemotherapy in patients who had received previous therapies, whereas an ORR of 44% was documented in
treatment naïve cases.

Bevacizumab is an anti-VEGF-A antibody with reported clinical activity in metastatic colon cancer. In
preclinical studies, it has shown an enhanced T-cell infiltration in tumours. It has been suggested that by