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

combining atezolizumab and bevacizumab, the anti-tumour immune responses would increase and so
would the clinical benefit.

A phase Ib study (NCT01633970) tested combinations with atezolizumab and several chemotherapeutic/
biologic regimens in advanced solid neoplasias (also metastatic colon cancer).

Atezolizumab was given at 1200 mg plus bevacizumab 15 mg/kg both every 3 weeks. Safety was the primary
endpoint and efficacy parameters were secondary endpoints.

Ten metastatic colon cancers MSI-H were recruited. The study showed an ORR of 30% (95% CI, 6.7%-65.3%),
OS was not reached after 11 months and 40% of patients had a G3/4 adverse event (proteinuria was the most
frequent side-effect documented). The disease control rate was 90% and the authors concluded that this
[38]
treatment did not have any unexpected side-effects and was given with good tolerance.
Active research is still needed for patients with MSI-L or MSS.

COMBINATION THERAPIES
MEK inhibitors
In preclinical studies, targeted blocking of MEK will upregulate MHC I on malignant cells, stimulate
intraneoplasticT-cell infiltration and stimulates anti-PDL1.

A phase Ib clinical trial of cobimetinib combined with atezolizumab in colon cancer was presented at the
[39]
2016 ASCO Annual Meeting .

Cobimetinib dose ranged from 20 to 60 mg daily (3 out of 4 weeks) and atezolizumab was given at 800 mg iv
every 2 weeks.

Twenty-three colon cancers were included and only one of them was wild type KRAS. The ORR was 17% (4
partial responses and 5 stable diseases), OS at 6 months was 72% and these results led to an extension of the
trial.

Three responses lasted long, and are still present at the time of the presentation of these results; one of those
was reported in MMR status unknown but three were seen in pMMR and these were not related to the
positivity of PD-L1.

A serial biopsy cohort demonstrated upregulation in PD-L1 activity, CD8 T-cell infiltration and expression
of MHC I.

The most frequent adverse events were diarrhea (in almost 70%), fatigue (around 50%), rash either acneiform
or maculopapular, pruritus and nausea. G3-4 side-effects were seen in 34.8%.

The authors concluded that MSS colon cancer can respond to the combination of cobimetininb and
[39]
atezolizumab .

Indoleamine 2,3-dioxygenase inhibitors
Different checkpoint inhibitors and immunomodulatory agents have been and continue to be tested in phase
I research. Drugs blocking repressing immune factors, for example the enzyme indoleamine 2,3-dioxygenase
(IDO) or LAG-3 are evaluated in phase I trials in combination with check point inhibitors. IDO is an
intracellular enzyme in charge of degradation of tryptophan whose expression increases by the stimulation