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. |