Main ongoing trials with immune checkpoint inhibitors in colorectal cancer
| Target | Agent | Phase | Setting (treatment line) | Treatment | Main objectives | Biomarker | NCT identifier |
| PD-1 (±other agents) | Pembrolizumab | II | First line | Pembrolizumab+FOLFOX | ORR=55% | MMR | NCT02375672 |
| III | First line, MSI-H mCRC | Pembrolizumab vs FOLFOX or FOLFIRI (±cetuximab or bevacizumab) | Ongoing | MMR | NCT02563002 (KEYNOTE-177) | ||
| II | Refractory | Pembrolizumab | Ongoing | MRR | NCT01876511 (KEYNOTE-016) | ||
| II | Refractory | Pembrolizumab | ORR for MSI-H CRC=26.2% | MMR | NCT02460198 (KEYNOTE-164) | ||
| II | Refractory, advanced solid tumor including MSI-H mCRC | Pembrolizumab | ORR for MSI-H CRC=26.2% | MMR | NCT02628067 (KEYNOTE-158) | ||
| I/II | Refractory, RAS/BRAF wild-type | Pembrolizumab+Cetuximab | Ongoing | NA | NCT02318901 | ||
| I/II | Refractory, RAS wild-type | Pembrolizumab+Cetuximab | Ongoing | NA | NCT02713373 | ||
| II | Refractory pMMR | Pembrolizumab+Radiotherapy or ablation | Interim ORR=9% in the RT cohort | PD-L1 | NCT02437071 | ||
| Ib | Resectable liver mCRC | Pembrolizumab+Stereotactic body Radiotherapy | Ongoing | PD-L1 | NCT02837263 (KEYNOTE-290) | ||
| II | Refractory | Pembrolizumab+Azacitidine | ORR=3% | MMR | NCT02260440 | ||
| I | Refractory, advanced solid tumors including MSI-H mCRC | Pembrolizumab + Itacitinib (JAK1 inhibitor) | NA | MMR, TILs and the ratio of CD8 +lymphocytes to FOXP3 +cells infiltrating tumor post-treatment versus pretreatment by IHC | NCT02646748 | ||
| I/II | After first line, advanced solid tumors including MSI-H mCRC | Pembrolizumab + Epacadostat (IDO-inhibitor) | Ongoing | PD-L1 | NCT02178722 (KEYNOTE-037) | ||
| Nivolumab | II | Refractory, first line (cohort C3) | Nivolumab±other agents Cohort 1: Nivolumab Cohort 2: Nivolumab + Ipilimumab (anti-CTLA-4) (escalation dose) Cohort 3: Nivolumab + Ipilimumab Cohort 4: Nivolumab + Ipilimumab + Cobimetinib Cohort 5: Nivolumab + BMS-986016 (anti-LAG3) Cohort 6: Nivolumab + Daratumumab | ORR=31% | MMR | NCT02060188 (CHECKMATE 142) | |
| I/II | Refractory | Nivolumab+Irinotecan or XELIRI | NCT02423954 | ||||
| II | Refractory, MSS mCRC | Nivolumab +TAS-102 | ORR=0% | MRR, PD-L1, TILs | NCT02860546 | ||
| II | Refractory | Nivolumab + Ipilimumab + Radiotherapy | ORR=14% | MMR | NCT03104439 | ||
| I/II | Refractory | Nivolumab+Epacadostat (anti-IDO) | Ongoing | PD-L1 | NCT02327078 | ||
| I/II | Refractory | Nivolumab+Varlilumab (anti-CD27) | Ongoing | PD-L1 CD8+ | NCT02335918 | ||
| II | Stage I–III | Nivolumab+Ipilimumab±Celecoxib | Ongoing | NA | NCT03026140 | ||
| I/II | Neoadjuvant, Rectal cancer | Chemoradiotherapy followed by Nivolumab before surgery | Ongoing | NA | NCT02948348 | ||
| I/II | Refractory mCRC and GC | Nivolumab+Regorafenib (multi-TKI) | ORR= 29% in MSS CRC | PD-L1 | NCT03406871 | ||
| PD-L1 (±other agents) | Atezolizumab | III | First line, MSI-H mCRC | mFOLFOX6/bevacizumab ± Atezolizumab | Ongoing | PD-L1, T cell, cfDNA mutations | NCT02997228 |
| II | Refractory | Atezolizumab+Stereotactic Radiotherapy | NA | NA | NCT02992912 | ||
| II | Refractory | Atezolizumab+Bevacizumab | Ongoing | MRR | NCT02982694 | ||
| III | Stage III, MSI-H CRC | FOLFOX6± Atezolizumab | Ongoing | MMR | NCT02912559 | ||
| Avelumab | II | After first line, MSI-H mCRC or POLE mut | Avelumab | Ongoing | POLE mutations, MMR | NCT03150706 | |
| second line, MSI-H mCRC | Avelumab versus FOLFOX or FOLFIRI (±targeted treatment) | Ongoing | MSI-H | NCT03186326 | |||
| Durvalumab | II | Refractory, MSI-H mCRC | MEDI4736 (Durvalumab) | ORR=8% | MSI-H | NCT02227667 | |
| II | Refractory | MEDI4736 +Trametinib (anti-CTLA-4) versus BSC | NA | NA | NCT02870920 | ||
| II | Refractory, MSS mCRC | MEDI4736 +Trametinib ± Radiotherapy | Ongoing | PD-L1; T-cell infiltration | NCT02888743 | ||
| II | Refractory, advanced solid tumors including MSS mCRC | MEDI4736 +Azacitidine | Ongoing | MMR | NCT02811497 | ||
| Novel targets | PD-1/PD-L1 inhibitors+novel agents | I/II | Refractory | Pembrolizumab+BBI608 (Napabucasin, STAT3 and cancer cell stemness inhibitor) | ORR=5% in MSI-H | MMR, PD-L1, CD8 | NCT02851004 |
| I/II | Refractory | Pembrolizumab+Poly ICLC (TLR3 agonist) | Ongoing | NA | NCT02834052 | ||
| I/II | Refractory | Pembrolizumab+AMG820 (anti-CSF1R) | Ongoing | NA | NCT02713529 | ||
| I/II | Refractory, advanced solid tumors | BMS-986015 (KIR inhibitor)+Nivolumab ± Ipilimumab | Ongoing | NA | NCT01714739 | ||
| I | Refractory, advanced solid tumors including mCRC | Nivolumab+Enadenotucirev (oncolytic virus) | NA | NA | NCT02636036 | ||
| I | Refractory, advanced solid tumors including mCRC | TSR-022 (TIM3 inhibitor)±Nivolumab | NA | NA | NCT02817633 | ||
| I | Refractory, advanced solid tumors including mCRC | Atezolizumab+CPI-444 (adenosine-A2A receptor Iinhibitor) | NA | NA | NCT02655822 | ||
| I | Refractory, advanced solid tumors | Atezolizumab+MOXR0916 (OX-40 inhibitor) | NA | NA | NCT02410512 | ||
| I/II | Refractory, advanced solid tumors including MSS mCRC | Durvalumab+Olaparib and/or Cediranib | Ongoing | PD-L1 | NCT02484404 | ||
| I | Refractory | Durvalumab+PEXIDARTINIB (anti-CSF1R) | NA | NA | NCT02777710 | ||
| I | Refractory, advanced solid tumors | MEDI6469 (OX-40 inhibitor)+Durvalumab or Tremelimumab | NA | NA | NCT02705482 |
BSC, best supportive care; CRC, colorectal cancer; CSF1R, colony stimulating factor-1 receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FOLFOX, 5 fluorouracil, leucovorin, oxaliplatin; GC, gastric cancers; IDO, indoleamine-pyrrole 2,3-dioxygenase; IHC, Immunohistochemestry; LAG3, lymphocyte activation gene 3; mCRC, metastatic CRC; MMR, DNA mismatch repair; MSI-H, microsatellite instablility high; MSS, microsatellite stable; NA, not available/not applicable; NCT, national clinical trial; ORR, objective response rate; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; pMMR, MMR proficient; RT, Radiotherapy; SOC, standard of care; TILs, tumor-infiltrating lymphocytes; TKI, tyrosine kinase inhibitor ; TLR, toll-like receptor; XELIRI, capecitabine, irinotecan.