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Page 6 of 17                     Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31

               Table 1. Immunotherapy trials in metastatic colorectal cancer
                Population                     Drugs           Target     Patients        Response rate
                Refractory MSI-H CRC   Pembrolizumab (42)    PD-1          25       57%
                                                                                    Sporadic cases:100% (n = 6/6)
                                                                                    LS cases: 27% (n = 3/11)
                                 Nivolumab (43)              PD-1          74       31%
                                                                                    Sporadic cases: 36% (n = 10/36)
                                                                                    LS cases: 30% (n = 8/27)
                                 Nivolumab + ipilimumab (44)   PD-1 + CTLA-4   119   55%
                Refractory       Pembrolizumab (42)          PD-1          28       0%
                MSS CRC          Nivolumab + ipilimumab (44)   PD-1 + CTLA-4   20    5%
                Refractory CRC   Tremelimumab (41)           CTLA-4        49        2%
                                 Nivolumab (45)              PD-1          19        0%
                                 BMS-936559 (46)             PD-L1         18        0%
                                 Atezolizumab + bevacizumab (49)   PD-L1   14       7%
                                 Atezolizumab + FOLFOX/bevacizumab,   PD-L1   30    40% (total)
                                 70% first line (49)                                48% (first-line)
                                 Atezolizumab + cobimetinib (53)   PD-L1 MEK   23   17%
                                                                                    (3 MSS, 1 unknown)
               CRC: colorectal cancer; CTLA-4: cytotoxic T lymphocyte associated antigen 4; PD-L1: programmed cell death ligand-1; PD-1: programmed
               cell death protein 1; MSS: stable microsatellite; MSI-H: high microsatellite instability

               Table 2. Ongoing studies in colorectal cancer
                Trial                        Treatment              Patient population       Endpoints
                Keynote-177        Pembrolizumab monotherapy   MSI-H CRC,                 PFS
                NCT02563002        vs. standard care           1st line metastatic
                                   chemotherapy
                Keynote-164        Pembrolizumab monotherapy   MSI-H CRC,  metastatic refractory   ORR
                NCT02460198                                    (Cohort A) or ≥ 1 prior therapy
                                                               (Cohort B)
                NRG-GI004/S1610    Atezolizumab vs. atezolizumab +   MSI-H CRC,           PFS
                NCT02997228        FOLFOX + bevacizumab vs.    1st line metastatic
                                   FOLFOX + bevacizumab
                Alliance A021502   Atezolizumab + FOLFOX vs. FOLFOX   MSI-H CRC, stage III   DFS
                NCT02912559        alone
                NCT02870920        BSC + durvalumab + tremelimumab vs.  MSS, chemorefractory  mCRC   OS
                                   BSC
                NCT02788279        Atezolizumab vs. atezolizumab +   Chemorefractory  mCRC   OS
                                   cobimetinib vs. regorafenib
                NCT02873195        Atezolizumab + capecitabina +   Chemorefractory mCRC   PFS
                BACCI study        bevacizumab
                NCT02948348        Nivolumab + chemoradiotherapy   Locally advanced CRC   Pathological complete
                                                                                          response
                NCT02888743        Durvalumab + tremelimumab +/-   Chemorefractory mCRC   ORR
                                   radiation
               CRC: colorectal cancer; MSS: stable microsatellite ; MSI-H: high microsatellite instability; BSC: best supportive care; PFS: progression free
               survival; OS: overall survival; DFS: disease free survival; ORR: overall response rate

               CMS1 tumours are characterized by upregulation of PD-1, PDL-1, CTLA-4 and IDO as described above and
               so they are the best candidates for immunotherapy.

               A major challenge is to render pMMR mCRC (second and third group descripted above) sensitive to
                                                                                  [42]
               immune checkpoint inhibitors. In the pivotal pembrolizumab trial by Le et al. , no responses in the MSS
               CRC pretreated cohort were observed with median overall survival of 5 months. Furthermore in the “combo”
               experience Checkmate 142 with nivolumab and ipilimumab, only 1 response was observed among 20
                                     [44]
               patients with pMMR CRC .
               CMS4 tumours should be considered “hot tumours” with immunosuppressive signalling ongoing:
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