Table 2:
Novel non-direct KRAS inhibition treatment strategies for KRAS mutant colorectal cancer.
| Mechanism | Combination Drug | Phase | Cancer Type | Trial ID | Status |
|---|---|---|---|---|---|
| Immunotherapy | |||||
| Cancer Vaccines | |||||
| mRNA-5671/V941 vaccine | Alone or with Pembrolizumab (anti-PD-1) | 1 | Microsatellite Stable CRC; KRAS G12D, G12V, G13D or G12C; HLA-A11:01 or HLA C08:02 | NCT03948763 | Completed 2022 |
| Pooled Mutant KRAS-Targeted Long Peptide Vaccine | Nivolumab and ipilimumab | 1 | Microsatellite Stable CRC with KRAS mutation | NCT04117087 | Ongoing |
| Adoptive T cell therapies | |||||
| Peripheral blood lymphocytes transduced with HLA-A11:01-restricted anti-KRAS G12D murine T cell receptor | Preparative lymphodepletion (cyclophosphamide, fludarabine), post-infusion high dose aldesleukin (IL-2). | 1/2 | Advanced solid cancers including CRC; KRAS G12D; HLA-A11:01 | NCT03745326 | Ongoing |
| Peripheral blood lymphocytes transduced with HLA-A11:01-restricted anti-KRAS G12V murine T cell receptor | Preparative lymphodepletion (cyclophosphamide, fludarabine), post-infusion high dose aldesleukin (IL-2). | 1/2 | Advanced solid cancers including CRC; KRAS G12V; HLA-A11:01 | NCT03190941 | Ongoing |
| Stimulators of Innate Immunity | |||||
| SX-682 (inhibits chemokine receptors CXCR1/2, thereby decreasing myeloid- derived suppressor cells in tumor microenvironment) | Nivolumab | 1/2 | RAS mutated, MSS advanced CRC | NCT04599140 | Ongoing |
| Magrolimab (anti-CD47, promotes phagocytosis of cancer cells by macrophages) | Cetuximab | 1/2 | Advanced solid cancers, with KRAS mutant CRC cohorts | NCT02953782 | Completed 2020 |
| REOLYSIN® (Reovirus Type 3 Dearing replicates selectively in Ras-transformed cells causing cell lysis, and stimulates antigen presenting cells) | FOLFIRI and Bevacizumab | 1 | KRAS mutant metastatic CRC | NCT01274624 | Completed 2018 |
| Imprime PGG (soluble beta-1,3/1,6 glucan which binds to complement receptor 3 on innate immune cells) | Cetuximab | 2 | KRAS mutant metastatic CRC | NCT00912327 | Completed 2012 |
| Lenalidomide (activates natural killer cells) | Cetuximab | 2 | Advanced KRAS mutant CRC | NCT01032291 | Terminated due to lack of efficacy |
| Autophagy inhibitors | |||||
| DCC-3116 (ULK1/2 inhibitor) | Trametinib (MEK inhibitor) | 1/2 | Advanced solid cancers with RAS/MAPK pathway mutations (KRAS, NRAS, NF1, or BRAF), with a CRC cohort | NCT04892017 | Ongoing |
| Hydroxychloroquine | Ulixertinib (ERK inhibitor) | 2 | Advanced gastrointestinal cancers with MAPK mutations (KRAS, NRAS, HRAS, BRAF non-V600, MAP2K1/2 or ERK1/2), with a CRC cohort | NCT05221320 | Ongoing |
| Apoptosis inducers | |||||
| ABBV-621/Eftozanermin (TRAIL receptor agonist) | FOLFIRI ± bevacizumab (VEGF inhibitor) | 1 | Advanced cancers, with KRAS-mutant CRC cohort | NCT03082209 | Completed 2022 |
| HDM201 (MDM2 inhibitor) | Trametinib (MEK inhibitor) | 1 | RAS/RAF mutant and TP53 wild-type advanced colorectal cancer | NCT03714958 | Ongoing |
| RGX-202–01 (inhibits creatine transporter SLC6a8) | FOLFIRI ± bevacizumab (VEGF inhibitor) | 1 | RAS mutant advanced CRC | NCT03597581 | Ongoing |
| NBF-006 (inhibits Glutathione-S- Transferase P, GST-π, thereby causing oxidative stress) | - | 1 | CRC, NSCLC, Pancreatic Cancer | NCT03819387 | Ongoing |
| Conatumumab (Death Receptor 5 agonist) | FOLFIRI vs FOLFIRI alone | 2 | KRAS mutant metastatic CRC | NCT00813605 | Completed 2011 |
| Metabolism inhibitors | |||||
| Telaglenastat (Glutaminase Inhibitor) | Palbociclib (CDK4/6 inhibitor) | 1b/2 | Advanced solid cancers with expansion cohort in metastatic KRAS mutant CRC | NCT03965845 | Completed 2021 |
| Inhibition of Epithelial to Mesenchymal Transition | |||||
| TP-0903 (AXL kinase inhibitor, reverses mesenchymal phenotype) | - | 1 | BRAF, KRAS, or NRAS Mutant metastatic CRC | NCT02729298 | Ongoing |
Abbreviation: CRC: colorectal cancer.