Table 2.
Ongoing clinical trials tackling RAS-mutant metastatic colorectal cancer
| Strategy | NCT/trial name | Drugs | Phase |
|---|---|---|---|
| Direct RAS targeting | |||
| KRASG12C inhibitors | NCT03600883/CodeBreaK100 | Sotorasib (AMG 510) | II |
| NCT03785249/KRYSTAL-1 | Adagrasib (MRTX849) | I/II | |
| NCT04006301 | JNJ-74699157 | I | |
| NCT04165031b | LY3499446 | I/II | |
| KRASG12C inhibitor-based combinations | NCT04185883/CodeBreaK101 | AMG 510 with anti-PD-1, MEKi, SHP2 allosteric inhibitor, pan-ErbB inhibitor, anti-PD-L1, anti-EGFR, ChT, mTORi, or CDK4/6i | I |
| NCT03785249/KRYSTAL-1 | MRTX849 with pembrolizumab, cetuximab or afatininb | I/II | |
| NCT04330664/KRYSTAL-2 | MRTX849 + TNO155 (SHP2 inhibitor) | I/II | |
| NCT04793958/KRYSTAL-10 | MRTX849 + cetuximab versus ChT | III | |
| KRAS-derived mRNA binder | NCT03101839 | AZD4785 | I |
| SOS1 inhibitor | NCT04111458 | BI 1701963 ± trametinib (MEKi) | I |
| SHP2 inhibitors | NCT03634982 | RMC-4630 | I |
| NCT03518554 | JAB-3068 | I | |
| NCT03565003 | JAB-3068 | I/II | |
| SHP2 inhibitor-based combinations | NCT03989115 | RMC-4630 with osimertinib (anti-EGFR) or cobimetinib (MEKi) | I/II |
| Targeting the MAPK pathway | |||
| RAF/MEKi ± mTORi | NCT02407509 | RO5126766 ± everolimus | I |
| ERK inhibitors | NCT02857270 | LY3214996 ± midazolam, abemaciclib (CDK4/6i), nab-paclitaxel (ChT), gemcitabine (ChT), encorafenib (MEKi), or cetuximab (anti-EGFR) | I |
| NCT02313012 | CC-90003 | I | |
| Pan-ErbB inhibitor-based combinations | NCT03065387 | Neratinib with everolimus (mTORi), palbociclib (CDK4/6i), or trametinib (MEKi) | I |
| cMET inhibitor + MEKi | NCT02510001 | Crizotinib with PD-0325901 or binimetinib | I |
| EGFR inhibitor + MEKi | NCT03087071 | Panitumumab ± trametinib | II |
| NCT01927341 | Panitumumab + binimetininb | I/II | |
| MEKi + CDK4/6i | NCT02065063 | Trametinib + palbociclib | I |
| NCT03981614 | Binimetinib + palbociclib | II | |
| FAK inhibitor + RAF/MEKi | NCT03875820/FRAME trial | VS-6063 + RO5126766 | I |
| PI3K + MEKi | NCT01337765 | BEZ235c + binimetinib | I |
| NCT01859351 | WX-037 ± WX-554 | I | |
| MEKi + ChT | NCT02613650 | Binimetinib + mFOLFIRI | I |
| NCT03317119 | Trametinib + TAS-102 | I | |
| MEKi + MDM2 inhibitor | NCT03714958 | Trametinib + HDM201 | I |
| Harnessing RAS through immunotherapy combinations | |||
| Anti PD-1 + MEKi ± anti-CTLA-4 | NCT03271047 | Nivolumab + binimetinib ± ipilimumab | I/II |
| Anti-PD-L1 + MEKi + PARPi | NCT03637491 | Avelumab + binimetinib + talazoparib | I/II |
| Anti-CTLA-4 + anti-PD-L1 + ChT | NCT03202758/MEDETREME | Tremelimumab + durvalumab + FOLFOX | I/II |
| Anti PD-1 + ChT + anti-VEGF | NCT04194359 | Sintilimab + XELOX + bevacizumab | III |
| CD137 agonist + ChT + anti-EGFR | NCT03290937 | Utomilumab + irinotecan + cetuximab | I |
| Adoptive cell transfer | NCT03745326 | Anti-KRASG12D/G12V mTCR PBL | I/II |
| Sequential ChT and anti-PD-1 | NCT03519412/ARETHUSA | Temozolomide followed by pembrolizumab | II |
| RAS targeting through metabolic pathways | |||
| Glutaminase inhibitor + CDK4/6i | NCT03965845 | Telaglenastat (CB-839) + palbociclib | I/II |
| Fatty acid synthase inhibitor | NCT02980029 | TVB-2640 | I |
| Metabolic damaging | NCT03146962 | High-dose i.v. vitamin C | II |
| NCT02969681 | High-dose i.v. vitamin C + FOLFOX ± bevacizumab | III | |
| Other miscellaneous approaches | |||
| Selective WEE1 inhibitor + ChT | NCT02906059 | Adavosertib (AZD1775) + irinotecan | I |
| TRAIL receptor agonist | NCT03082209 | Eftozanermin (ABBV-621) ± FOLFIRI and bevacizumab | I |
| Anti-EGFR + ChT | ACTRN12612000901808a/ICECREAM | Cetuximab ± irinotecan | II |
| Pan-ErbB inhibitor + anticonvulsant | NCT03919292 | Neratinib + valproate | I/II |
CDK, cyclin-dependent kinase; ChT, cytotoxic chemotherapy; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; FAK, focal adhesion kinase; I, inhibitor; i.v., intravenous; MEK; mTCR, murine T-cell receptor; mTOR, mammalian target of rapamycin; NCT, unique identification code given to each clinical study upon registration at ClinicalTrials.gov; PARP, poly (ADP-ribose) polymerase; PBL, peripheral blood lymphocyte; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; SHP2, Src homology region 2 domain-containing phosphatase-2; SOS1, sevenless homologue 1; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.
Referring to Australian New Zealand Clinical Trials Registry (ANZCTR).
Early termination due to unexpected toxicity.
BEZ235 is MEK/mTORi.