Table 5.
Clinical trials targeting the mitogen-activated protein kinase (MAPK) pathway.
| Study | Phase | Treatment Arms | Setting | Results | References |
|---|---|---|---|---|---|
| NCT03600883 | I | AMG 510 (KRASG12C 1 inhibitor) | Locally-advanced/metastatic KRASG12C mutant solid tumors | -SD2 in 4/19 mCRC3 patients –Good tolerability with no dose limiting toxicities at studied doses Ongoing |
[88,89] |
| NCT03785249 | I/II | MRTX849 (KRASG12C inhibitor) | Advanced solid tumors with KRASG12C mutation | PR34 in 1 mCRC patient Ongoing |
[90] |
|
NCT02928224 BEACON CRC5 |
III | Encorafenib + binimetinib + cetuximab (triplet therapy group) vs.46 encorafenib + cetuximab (doublet therapy group) vs. investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI7 | BRAFV600E8 mutant mCRC with disease progression after one or two previous regimens | -mOS9: 9.0 months in the triplet arm vs. 5.4 months in the control arm (HR10 = 0.52; 95% CI11: 0.39–0.70; p < 0.001); 8.4 months in the doublet arm (HR vs. control, 0.60; 95% CI: 0.45 to 0.79; p < 0.001) -RR12: 26% in the triplet group and 2% in the control group (p < 0.001) - Grade ≥3 TRAEs13: 58% of patients in the triplet group, 50% of patients in the doublet therapy group and in 61% in the control group -Reduction of 44% in the risk of quality of life deterioration in patients treated in the experimental arms; no difference in quality of life between triplet and doublet arms |
[92,93] |
| NCT01072175 | I/II | Dabrafenib + trametinib | BRAFV600E or BRAFV600k 14 mutant mCRC; all lines | -CR15: 2%, with duration of response of 36 months -SD16: 56% |
[94] |
| NCT01750918 | I | Dabrafenib + panitumumab vs. dabrafenib + panitumumab + trametinib vs. trametinib + panitumumab | -BRAFV600E mutant mCRC and mCRC with secondary resistance to prior anti-EGFR17 therapy. | RR: 10% for dabrafenib + panitumumab, 21% for dabrafenib + panitumumab + trametinib, and 0% for trametinib+panitumumab | [95] |
| NCT03693170 ANCHOR –CRC18 Study | II | Encorafenib + binimetinib + cetuximab | First-line BRAF19 mutant mCRC | Ongoing | - |
| NCT04044430 | I/II | Encorafenib + binimetinib + nivolumab | MSS20 BRAFV600E mutant mCRC; prior treatment with at least one systemic chemotherapy regimen for mCRC, or recurrence or progression with development of unresectable or metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal cancer | Ongoing | - |
| NCT03727763 | II | FOLFIRI + vemurafenib (anti-BRAF) + cetuximab | Advanced BRAF mutant mCRC | Ongoing | - |
| NCT03981614 | II | Binimetinib + palbociclib vs. trifluridine/tipiracil | KRAS21 and NRAS22 mutant mCRC | Ongoing | - |
| NCT02906059 | I | Irinotecan + AZD1775 (adavosertib; selective WEE123-inhibitor) | Second-line RAS or BRAF mutant mCRC | Ongoing | - |
Note: 1KRASG12C = Kirsten RAS oncogene homolog G12C; 2SD = stable disease; 3mCRC = metastatic colorectal cancer; 4PR = partial response; 5BEACON CRC = Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer; 46vs. = versus; 7FOLFIRI = irinotecan, 5-fluorouracil, leucovorin; 8BRAFV600E = v-raf murine sarcoma viral oncogene homolog B1 V600E; 9mOS = median overall survival; 10HR = hazard ration; 11CI: = confidence interval; 12RR = response rate; 13TRAEs = treatment related adverse events; 14BRAFV600k = v-raf murine sarcoma viral oncogene homolog B1 V600k; 15CR = complete response; 16SD = stable disease; 17anti-EGFR: anti-epidermal growth factor receptor; 18ANCHOR CRC = Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer; 19BRAF = v-raf murine sarcoma viral oncogene homolog B1; 20MSS = microsatellite-stable; 21KRAS = Kirsten RAS oncogene homolog; 22NRAS = neuroblastoma RAS viral oncogene homolog; 23WEE1 = WEE1 G2 checkpoint kinase.