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Bittoni et al. J Cancer Metastasis Treat 2018;4:55 I http://dx.doi.org/10.20517/2394-4722.2018.37 Page 7 of 14

Table 1. Clinical trials of immunotherapy in colorectal cancer
Trial Phase Drugs n (%) Setting PFS months OS months ORR Number of
identifier
PD-1 Blockade in Tumors with
Mismatch-Repair Deficiency
dMMR CRC II Pembrolizumab 10 mg/kg each 21 NR 40
14 days
pMMR CRC II Pembrolizumab 10 mg/kg each 11 2.2 (95% CI, 1.4 5.0 (95% CI, 0
14 days to 2.8) 3.0 to not
estimable)
Other dMMR non-CRC II Pembrolizumab 10 mg/kg each 9 5.4 (95% CI, 3 to NR 71
14 days not estimable)
CheckMate 142 II Nivolumab 3mg/Kg with Pre- NE* 55%*° NCT02060188
Ongoing (recruiting) Ipilimumab 1 mg/Kg every 3 treated 9-mo rate
Estimated primary completion weeks for 4 doses followed by 87%*
date December 3, 2018 Nivolumab 3mg/Kg every 2wk
until progression
A Phase 2 Study of II Pembrolizumab 200 mg on day 1 31 Pre- 2.1 m (1.8 to 2.8) 6.2 m (3.5 to 3% CI NCT02260440
Pembrolizumab (MK- of every 21 day cycle treated 8.7) (1-17)
3475) in Combination With PLUS
Azacitidine in Subjects With Azacitidine 100 mg daily on days
Chemo-refractory Metastatic 1-5 every 21 days.every 21 days
Colorectal Cancer AAM 2017 Treatment continued for 9 cycles
n 3054 or until evidence of progression of
Ongoing (not recruiting) disease or unacceptable toxicity
Actual primary completion Subjects with chemo-rfractorym
date March 2016 CRC without any further standard
Estimated study completation treatment option
date November 2020
*Preliminary data BRAF mutation and wild type; MSI: microsatellite instable; PFS: progression-free survival; OS: overall survival; ORR:
objective response rate; PD-1: programmed cell death-1; MMR: mismatch repair; CRC: colorectal cancer; NR: not reached; AAM:
American Society of Clinical Oncology Annual Meeting

cohort, one hundred ninety-nine previously treated patients with metastatic or recurrent dMMR CRC
were treated with 4 doses of combination immunotherapy with nivolumab and ipilimumab followed by
nivolumab. At median follow-up of 13.4 months, primary endpoint ORR was 55% (95% CI, 45.2-63.8) and
DCR for 12 weeks or more was 80%. PFS rates were 76% at 9 months and 71% at 12 months while OS rates
were 87% and 85%, respectively. Responses were observed irrespective of PDL-1 expression, BRAF or KRAS
mutational status or history of Lynch syndrome. Regarding toxicity, no new safety signals were reported
and no treatment related deaths were reported. Incidence of treatment related adverse events (73%) was
comparable to monotherapy while grade 3-4 adverse events were 32% compared to 20% for monotherapy
cohort. Common adverse events included fatigue, diarrhea, pruritus, fever, increase of aspartate
aminotransferase and hypothyroidism.

Although the comparison is only indirect, these results suggest that a double-blockade might improve
[37]
clinical outcomes, thus becoming a promising treatment option for MSI CRC . Nevertheless, data from
melanoma clinical trials have shown that combination of anti-PD-1 and anti-CTLA4 treatment may result
[38]
in significant toxicity with 55% grade 3-4 adverse events . In particular, diarrhea and colitis represented
adverse events leading to discontinuation of treatment in a significant proportion of patients. On this
basis, more studies about safety of this combination in treatment of CRC patients are warranted. Future
investigations may further clarify the role of immunotherapy in pMMR CRC, in particular regarding the
role of combination therapy compared to single agent anti-PD-1 treatment and the predictive value of PDL-1
expression [Table 2].

Immunotherapy in other CRCs subtypes
Albeit dMMR tumors proved to be responsive to immune-checkpoint inhibition, the majority of patients
with CRC have pMMR tumors and this status was related to lower response to PDL-1/PD-1 or CTLA4
blockade. Hence, other molecular subtypes require different strategies. Theoretically, immunotherapy