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Table 1 Summary of small molecule inhibitors approved and under clinical trials for treating Ras/RAF-mutated cancers

From: The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

Target Compound Development stages Description
KRas G12C AMG-510 Phase III, NCT04303780 Phase I results showed 54% ORR of non-small cell lung cancer (NSCLC) harboring KRas G12C.
MRTX849 Phase I/II, NCT03785249
Phase I/II, NCT04330664
Evaluation of clinical activity of MRTX849 alone and combined with TNO155 (SHP2 inhibitor) in KRas G12C mutated cancers.
JNJ-74699157 Phase I, NCT04006301 Safety and PK of JNJ-74699157.
Ras Rigosertib Phase I/II, NCT04263090 Evaluation of safety and clinical efficacy of Rigosertib plus Nivolumab (PD-1 Ab) in KRas mutated NSCLC.
BRAF Vemurafenib Approved Late-stage or unresectable melanoma expressing BRAF V600E in 2011.
Erdheim-Chester disease (ECD) with BRAF V600E mutation in 2017.
Dabrafenib Approved Late-stage or unresectable melanoma expressing BRAF V600E in 2013.
Combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E/K in 2014.
Combination with trametinib for the treatment of metastatic NSCLC with BRAF V600E in 2017.
Combination with trametinib for the adjuvant treatment of melanoma with BRAF V600E/K in 2018.
Combination with trametinib for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body with BRAF V600E in 2018.
Encorafenib Approved Combination with binimetinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E/K in 2018.
Combination with cetuximab (EGFR Ab) for the treatment of metastatic colorectal cancer with BRAF V600E in 2020.
PLX8394 Phase I/II, NCT02428712 PLX8394 with cobicistat (CYP3A inhibitor) was well tolerated and showed promising activity in BRAF-mutated refractory cancers.
BGB283 Phase I, NCT02610361
Phase I/II, NCT03905148
Evaluation of safety and PK of BGB-283 alone and combination with mirdametinib.
TAK-580 Phase I, NCT02327169
Phase I, NCT03429803
TAK-580 is the inhibitor of BRAF V600E and dimers.
Treatment in pediatric low-grade glioma.
CCT3833 Phase I, NCT02437227 CCT3833 is a pan-RAF inhibitor of mutant BRAF, CRAF and SRC kinases.
RAF/MEK RO5126766 Phase I, NCT00773526
Phase I, NCT03681483
Phase I, NCT03875820
Phase I, NCT02407509
RO5126766 is a dual inhibitor for both RAF and MEK.
Treatment of advanced KRas-mutant lung adenocarcinomas.
Evaluation of safety and PK of RO5126766 with VS-6063 (FAK inhibitor) or everolimus (mTOR inhibitor).
RO5126766 showed activity across Ras- and RAF-mutated malignancies, with significant response in lung and gynecological cancers.
MEK1/2 Trametinib Approved A single-agent oral treatment for unresectable or metastatic melanoma with BRAF V600E/K in 2013.
Combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E/K in 2014.
Combination with dabrafenib for the treatment of metastatic NSCLC with BRAF V600E in 2017.
Combination with dabrafenib for the adjuvant treatment of melanoma with BRAF V600E/K in 2018.
Combination with dabrafenib for the treatment of ATC that cannot be removed by surgery or has spread to other parts of the body with BRAF V600E in 2018.
Cobimetinib Approved
Phase I/II, NCT03989115
In combination with vemurafenib to treat advanced melanoma with BRAF V600E/K in 2015.
Dose-escalation of combination of RMC-4630 (SHP2 inhibitor) and cobimetinib.
Binimetinib Approved Combination with encorafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E/K in 2018.
Selumetinib Approved Selumetinib was approved for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas according to NCT01362803
Mirdametinib Phase II, NCT03962543
Phase II, NCT02022982
Phase I/II, NCT03905148
Evaluation of mirdametinib in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs).
Combination of mirdametinib with palbociclib in the treatment of KRas mutant non-small cell lung cancer (NSCLC).
Evaluation of safety and PK of BGB-283 alone and combination with mirdametinib.
SHR-7390 Phase I, NCT02968485 Evaluation of safety and PK of SHR-7390.
CS-3006 Phase I, NCT03516123
Phase I, NCT03736850
Evaluation of safety and PK of CS-3006.
ERK1/2 Ulixertinib Phase I/II, NCT01781429
Phase I, NCT04145297
Phase II, NCT03698994
Phase I, NCT03454035
Responses to ulixertinib in NRas, BRAF V600 and non-V600 BRAF mutant cancers.
Evaluation of ulixertinib alone or combined with hydroxychloroquine, palbociclib (CDK4/6 inhibitor) in MAPK mutated cancers.
MK-8353 Phase I, NCT01358331
Phase I, NCT03745989
Phase I, NCT02972034
MK-8353 was optimized from SCH772984 for better pharmacokinetics, and exhibited inhibition of BRAF V600 mutant cancers.
Evaluation of combination of MK-8353 with selumetinib or pembrolizumab (PD-1 Ab) in advanced malignancies.
LY3214996 Phase I, NCT04081259
Phase I, NCT04391595
Phase I, NCT02857270
Phase II, NCT04386057
Evaluation of treatment of MK-8353 alone or combined with abemaciclib (CDK4/6 inhibitor), Hydroxychloroquine in advanced malignancies.
ASTX029 Phase I/II, NCT03520075 Evaluation of safety and PK of ASTX029.
ATG-017 Phase I, NCT04305249 Evaluation of safety and PK of ATG-017.
KO-947 Phase I, NCT03051035 Evaluation of safety and PK of KO-947.