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Page 6 of 16 Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03

Another update in the monotherapy arm was discussed at ASCO Gastrointestinal Cancers Symposium
[29]
2017 as the combination arm was still recruiting and the results showed that 74 patients MSI-H who were
treated with single-agent nivolumab had ORR of 31.1% and DCR of 68.9%. PFS at one year was 48.9% with
OS rate of 73.8%. The OS median had not been reached yet.

Most patients (> 50%) had the treatment after 3 previous lines of chemotherapy and therate of BRAF and
KRAS mutations was 16% and 35%, respectively.

Around 30% had PD-L1 positive tumours and Lynch syndrome was present in around 30%.

ORR was documented without any relation to PD-L1 status or the BRAF/KRAS mutational status. Lynch
syndrome did not impact either.

This trial showed similar adverse events to those documented in previous immunotherapy trials without any
treatment-related deaths and grade 3-4 side-effects were documented in around 20% of the cases. Diarrhoea
and fatigue in the monotherapy arm (around 30% each in nivolumab alone) and diarrhea (around 45%) in
the combination arm were the most frequently reported side-effects.

These results led to NCCN guidelines (1.2017) to adopt pembrolizumab and nivolumab as potential options
for advanced MSI-H colon cancer after the Food and Drug Administration (FDA) approved both for the
treatment of metastatic colon cancer MSI-H that has progressed after previous treatment. Earlier, in 2015,
pembrolizumab had been granted breakthrough therapy designation for MSI-H colon cancer.

In July 2018 the FDA has approved the combination of nivolumab and ipilimumab for the treatment of
metastatic colon cancer MSI-H that has failed in previous treatments.

Confirmatory trials are still ongoing, such as the already mentioned KEYNOTE-164 (NCT02460198)
although it is not recruiting and it is expected to be complete in one year.

Nivolumab is another monoclonal antibody directed against PD-1 that was initially assessed in a phase I
[30]
study of non-haematological cancers . Thirty-nine patients were recruited, 14 of them with metastatic colon
cancer and one showed a durable complete response off-treatment. This patient had a dMMR tumour which
was considered a predictive factor of benefit, the same as positivity for PD-L1 on the cancer cell surface.

[31]
Topalian et al. carried out a phase II study of nivolumab in 296 patients with several solid neoplasias and
unfortunately no responses were reported on colon cancer patients. KEYNOTE-177 is a phase III study,
international, open-label, conceived to assess the efficacy and safety of pembrolizumab in comparison to
standard-of-care (SOC) treatment in first-line regardless MMR status in colon cancer(NCT02563002) .
[32]
Two hundred and seventy cases will be recruited and will receive chemotherapy at the investigator’s decision
(mFOLFOX6, FOLFIRI either alone or combined with bevacizumab or cetuximab) vs. pembrolizumab,
although crossover is allowed. The primary endpoint is PFS while OS and ORR will be secondary endpoints
and the treatment will be maintained until progressive disease (PD) is documented or significant toxicity,
patient/investigator’s choice, or 35 cycles are completed (pembrolizumab only).

The trial is active but not recruiting.

MSI-H colon cancers are significantly infiltrated by lymphocytes and show a significant expression of PD-1
[33]
and PD-L1 , and the pembrolizumab inhibits the connection PD-1-PD-L1 and PD-1-PD-L2, allowing