Study of pembrolizumab combined with ataluren in Patients with metastatic pMMR and dMMR colorectal cancer adenocarcinomas or metastatic dMMR endometrial carcinoma: the ATAPEMBRO study.

In the MK-3475-016 study2 8 out of 13 dMMR mCRC patients responded to immune
checkpoint inhibition treatment with pembrolizumab. This unexpectedly high
response rate identified dMMR CRC as a highly immunogenic tumour. Part of the
responses that were induced in the above mentioned trial may have been directed
against neo-antigens originating from neo-ORFs. Since out-of-frame translation
almost always encounters a premature termination codon (PTC), it leads to a
truncated gene product with a short out-of-frame C-terminal tail that usually
is no more than approximately 20 amino acids (aa) long. The short length of the
neo-ORF*s makes it unlikely to contain a stretch of approximately 10
consecutive aa*s that can bind MHC-1 or MHC-2. In dMMR mCRC and dMMR EC
patients the relatively large amount of frame-shifted coding microsatellites
(cMS) may yield sufficient neo-epitopes for tumor rejection. However, in pMMR
CRC frame shift mutations are scarce. This may partly explain the lack of
immunogenicity of pMMR CRC compared to dMMR CRC and dMMR EC. the same is the
case for dMMR SBC and dMMR SC
PTC Therapeutics nonsense mutation readthrough research has been focused on its
application of small molecules to identified nonsense mutations as they have
key roles in several congenital conditions. Recently, ataluren has shown
clinical activity in patients suffering from nonsense mutation Duchenne
Muscular Dysptrophy (nmDMD) by restoring expression of the mutant dystrophin
gene carrying a nonsense mutation resulting in truncation. Based on this
observation, we hypothesize that in CRC patients read through translation
induced by ataluren may result in an approximate doubling of the neo-epitopes
derived from neo-ORF*s. Thereby it might increase the immunogenicity of these
tumors (Fig1). Based on analyses on the TCGA dataset we have no reason to
believe that nonsense mediated decay (NMD) significantly impacts the expression
level of frameshifted neo-antigens in colorectal cancer tissue. In short, we
hypothesize a potential synergistic effect between immune checkpoint inhibition
and ataluren-enabled read-through translation.

This study has been transitioned to CTIS with ID 2023-509457-31-00 check the CTIS register for the current data.

To determine the immune-related progression free survival (irPFS) rate at 21
weeks and objective response rate (irORR) at 30 weeks in patients with pMMR
CRC, dMMR mCRC, dMMR EC , dMMR SBC, dMMR SC treated with pembrolizumab
combined with ataluren using immune related response criteria (irRC)

In the phase-1 part of the study 2-4 groups of 3 patients each are treated with
pembrolizumab 200mg i.v. q3w but with increasing ataluren doses (i.e. group1
25%, group2 50% and group3 100% of 10-10-20mg/kg). These can be either pMMR
mCRC, dMMR mCRC, dMMR EC patients , dMMR SBC, dMMR SC . The reported toxicity
in phase-1 will be used to define the maximum tolerated dose (MTD) of the
combination, that will determine the ataluren dose in phase-2.
In the phase-2 part of the study a dMMR group (cohort A, 20 patients either
CRC, EC, SC, SBC) and a pMMR group (cohort B, 15 CRC patients) will be treated
with pembrolizumab 200mg i.v. q3w combined with ataluren t.i.d. at the MTD
defined in phase-1.

Systemic treatment with Pembrolizumab anti-PD1 monoclonal antibodies by
3-weekly infusions, combined with oral ataluren taken three times daily every
day.

Patients will be at risk for the auto-immune side effects that may be the
result of anti-PD1 treatment. Additionally, patients will be at risk for the
side effects that may result from ataluren treatment. Both drugs have a
relatively mild toxicity profile compared to alternative systemic treatment
options, i.e. second line chemotherapy regimens. Moreover, in dMMR patients the
response rates that have been described with anti-PD1 monotherapy rival those
of chemotherapy regimens, but importantly the response duration after anti-PD1
treatement is longer on average. Moreover, anti-PD1 therapy is not available as
a standard treatment option.