RAF and MEK Inhibitors in Non-Small Cell Lung Cancer
Abstract
:1. Introduction
2. The RTK/RAS/MAPK Pathway in Lung Cancer
2.1. RTK/RAS/MAPK Pathway
2.2. BRAF Inhibitors
2.3. Classification of BRAF Mutations
2.4. BRAF Alterations in NSCLC
2.5. MEK Inhibitors
2.6. Classification of MEK Mutations
2.7. MEK Alterations in NSCLC
3. BRAF and MEK Inhibitors in Lung Cancer
3.1. BRAF Inhibitors as Monotherapy in NSCLC
3.2. MEK Inhibitors as Monotherapy in NSCLC
3.3. BRAF and MEK Inhibitor Combinations in NSCLC
3.3.1. BRAF-Mutant NSCLC
3.3.2. KRAS-Mutant NSCLC
3.3.3. EGFR-Mutant NSCLC
4. BRAF and MEK Inhibitor-Mediated Resistance
5. BRAF and MEK Inhibitor Toxicities
6. Discussion
6.1. Future Directions—Next-Generation RAF Inhibitors
6.2. Biomarkers—Predictors of Response to RAF and MEK Inhibitors
7. Conclusions—Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Drug(s) | Target(s) | Second Drug(s) | Second Target(s) | Trial Phase | Clinical Trial Identifier |
---|---|---|---|---|---|
BGB-3245 | RAF | - | - | I | NCT04249843 |
BDTX-4933 | RAF | - | - | I | NCT05786924 |
Exarafenib | RAF | - | - | I | NCT04913285 |
FORE8394 | RAF | - | - | I/II | NCT02428712 |
ABM-1310 | RAF | +/− Cobimetinib | MEK | I | NCT04190628 |
Belvarafenib | RAF | Cobimetinib Cetuximab * | MEK EGFR | I | NCT03284502 |
BGB-3245 | RAF | Mirdametinib | MEK | I/II | NCT05580770 |
Dabrafenib | ΒRAFV600E | Trametinib | MEK | IV | NCT03340506 |
Encorafenib | ΒRAFV600E | Binimetinib | MEK | II | NCT03915951 |
Encorafenib | ΒRAFV600E | Binimetinib | MEK | II | NCT05195632 |
Encorafenib | ΒRAFV600E | Binimetinib | MEK | II | NCT04526782 |
Encorafenib | ΒRAFV600E | Binimetinib | MEK | II | NCT03839342 |
HLX208 | ΒRAFV600E | Trametinib | MEK | I | NCT04965220 |
Lifirafenib | RAF | Mirdametinib | MEK | I | NCT03905148 |
Naporafenib | RAF | Trametinib | MEK | I | NCT05907304 |
Naporafenib | RAF | Trametinib LTT462 Ribociclib | MEK ERK CDK4/6 | I | NCT02974725 |
PF-07799933 | RAF | Binimetinib Cetuximab * | MEK EGFR | I | NCT05355701 |
Tinlorafenib | RAF | Binimetinib | MEK | I | NCT04543188 |
Tovorafenib | RAF | +/− Pimasertib | MEK | I/II | NCT04985604 |
Vemurafenib | ΒRAFV600E | Cobimetinib | MEK | II/III | NCT05768178 |
XP-102 | RAF | +/− Trametinib | MEK | I/II | NCT05275374 |
ABM-168 | MEK | - | - | I | NCT05831995 |
IMM-6-415 | MEK | - | - | I/II | NCT06208124 |
IMM-1-104 | MEK | (Chemotherapy) | - | I/II | NCT05585320 |
Avutometinib | MEK/RAF | Sotorasib | KRASG12C | I/II | NCT05074810 |
Avutometinib | MEK/RAF | +/− Everolimus | mTOR | I | NCT02407509 |
Binimetinib | MEK | Palbociclib | CDK4/6 | I/II | NCT03170206 |
Binimetinib | MEK | Pembrolizumab | PD-1 | I | NCT03991819 |
Cobimetinib | MEK | Atezolizumab | PD-L1 | II | NCT03600701 |
Mirdametinib | MEK | Palbociclib | CDK4/6 | I/II | NCT02022982 |
PF-07799544 | MEK | Tinlorafenib PF-07799933 Encorafenib | RAF | I | NCT05538130 |
Selumetinib | MEK | Docetaxel † | Microtubule depolymerization | III | NCT01933932 |
Selumetinib | MEK | Osimertinib | EGFRL858R/T790M | II | NCT03392246 |
Trametinib | MEK | Anlotinib | VEGFR, FGFR, PDGFR, KIT | I | NCT04967079 |
Trametinib | MEK | EGF816 | EGFR | I | NCT03516214 |
Trametinib | MEK | Everolimus | mTOR | II | NCT04803318 |
Lenvatinib | VEGFR, FGFR, PDGFR, KIT, RET | ||||
Trametinib | MEK | Pembrolizumab | PD-1 | I | NCT03299088 |
Trametinib | MEK | Pembrolizumab | PD-1 | I/II | NCT03225664 |
Trametinib | MEK | Docetaxel † | Microtubule depolymerization | II | NCT02642042 |
Drug(s) | Target(s) | Second Drug(s) | Second Target(s) | Trial Phase | Clinical Trial Identifier |
---|---|---|---|---|---|
BI-1701963 | SOS1 | +/− Trametinib | MEK | I | NCT04111458 |
DCC-3116 | ULK1/2 | Trametinib Binimetinib Sotorasib | MEK MEK KRASG12C | I/II | NC04892017 |
Sasanlimab | PD-1 | Encorafenib/binimetinib Axitinib /SEA-TIGIT * | ΒRAFV600E MEK VEGFR1-3, PDGFRβ TIGIT | I/II | NCT04585815 |
PF-07284892 | SHP2 | Encorafenib Binimetinib Lorlatinib Cetuximab * | ΒRAFV600E MEK ROS1, ALK EGFR | I | NCT04800822 |
Opnurasib | KRASG12C | Trametinib Ribociclib Cetuximab * | MEK CDK4/6 EGFR | I/II | NCT05358249 |
Durvalumab * Tremelimumab * | PD-L1 CTLA-4 | Selumetinib | MEK | I/II | NCT03581487 |
Alectinib | ALK | Cobimetinib | MEK | I/II | NCT03202940 |
Caboplatin †/pemetrexed †/pembrolizumab * | PD-1 | Mirdametinib | MEK | I/II | NCT05937906 |
Vemurafenib Alectinib Atezolizumab * Trastuzumab emtansine # | BRAFV600E ALK PD-L1 HER2-microtubulin | - | - | II | NCT02314481 |
Atezolizumab * | PD-L1 | Cobimetinib /vemurafenib | MEK BRAFV600E VEGF-A | II/III | NCT03178552 |
Atezolizumab * | PD-L1 | Bevacizumab * /pemetrexed † /carboplatin † | |||
Atezolizumab * Alectinib Entrectinib | PD-L1 ALK ROS1 | ||||
Divarasib | KRASG12C | Docetaxel † | Microtubule depolymerization | ||
Vemurafenib | BRAFV600E | Cobimetinib | MEK | II | NCT04302025 |
Alectinib Entrectinib Pralsetinib Atezolizumab * Divarasib | ALK ROS1 RET PD-L1 KRASG12C | - | - | ||
Dabrafenib | BRAFV600E | Trametinib | MEK | II | NCT02465060 |
Binimetinib Trametinib Ulixertinib Adavosertib Afatinib Capivasertib Copanlisib Crizotinib Dasatinib Defactinib Erdafitinb Fexagratinib Ipatasertib Larotrectinib Osimertinib Palbociclib GSK2636771 Sapanisertib Sunitinib Taselisib Vismodegib | MEK MEK ERK WEE-1 EGFR, HER2 AKT PI3Kα,β,γ,δ ALK, MET, ROS1 SRC, BCR-ABL FAK FGFR1-4 FGFR1-4 AKT TRKA, B and C EGFRL858R/T790M CDK4/6 PI3Kβ mTOR VEGFR2, PDGFRβ PI3KCA, PI3Kα,β,γ,δ SMO, P-gp, ABCG2 | - | - | ||
Pertuzumab * | HER2 | Trastuzumab * | HER2 | ||
Nivulomab * | PD-1 | Relatlimab * | LAG-3 | ||
Selumetinib | MEK | Docetaxel † | Microtubule depolymerization | II | NCT02664935 |
Ceralasertib | ATR | Durvalumab * | PD-L1 | ||
Sitravatinib | Axl, MER, VEGFR1-3, KIT, FLT3, DDR1-2, TRKA and B | ||||
Capivasertib Fexagratinib Vistusertib Palbociclib Crizotinib Osimertinib | AKT FGFR1-4 mTOR CDK4/6 ALK, MET, ROS1 EGFRL858R/T790M |
Drug(s) | Target(s) | Number of Patients | ORR | TRAEs | Reference |
---|---|---|---|---|---|
Encorafenib + binimetinib | BRAFV600E MEK | 98 | 75% | Nausea, diarrhea, fatigue | [91] |
Dabrafenib + trametinib | BRAFV600E MEK | 93 | 68.4% | Pyrexia, nausea, vomiting | [87] |
Dabrafenib + trametinib | BRAFV600E MEK | 36 | 64% | Pyrexia, nausea, fatigue, peripheral oedema | [86] |
Dabrafenib | BRAFV600E | 84 | 33% | Pyrexia, hyperkeratosis, decreased appetite | [47] |
Vemurafenib | BRAFV600E | 101 | 44.9% | Nausea, hyperkeratosis, decreased appetite | [66] |
Cobimetinib + atezolizumab * | MEK PD-L1 | 28 | 18% | Diarrhea, rash, fatigue | [94] |
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Adamopoulos, C.; Papavassiliou, K.A.; Poulikakos, P.I.; Papavassiliou, A.G. RAF and MEK Inhibitors in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2024, 25, 4633. https://doi.org/10.3390/ijms25094633
Adamopoulos C, Papavassiliou KA, Poulikakos PI, Papavassiliou AG. RAF and MEK Inhibitors in Non-Small Cell Lung Cancer. International Journal of Molecular Sciences. 2024; 25(9):4633. https://doi.org/10.3390/ijms25094633
Chicago/Turabian StyleAdamopoulos, Christos, Kostas A. Papavassiliou, Poulikos I. Poulikakos, and Athanasios G. Papavassiliou. 2024. "RAF and MEK Inhibitors in Non-Small Cell Lung Cancer" International Journal of Molecular Sciences 25, no. 9: 4633. https://doi.org/10.3390/ijms25094633