Reference Detail

Ref Type

Journal Article

PMID

(30264293)

Authors

Babiker HM, Byron SA, Hendricks WPD, Elmquist WF, Gampa G, Vondrak J, Aldrich J, Cuyugan L, Adkins J, De Luca V, Tibes R, Borad MJ, Marceau K, Myers TJ, Paradiso LJ, Liang WS, Korn RL, Cridebring D, Von Hoff DD, Carpten JD, Craig DW, Trent JM, Gordon MS

Title

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	37	4	2019 08	636-645	Invest New Drugs

URL

Abstract Text

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
E6201	E6201	20	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
E6201			FLT3 Inhibitor 69 MEK1 Inhibitor 26	E6201 is a dual inhibitor of MEK1 and FLT3, which may lead to decreased tumor cell growth (Blood Nov 2013, 122 (21) 2683; PMID: 23039341, PMID: 29867224, PMID: 30264293).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	E6201	Case Reports/Case Series	Actionable	In a Phase I trial, a patient with metastatic melanoma and brain metastasis harboring BRAF V600E demonstrated an ongoing near complete response with an overall survival of more than 8 years, and preclinical analysis of melanoma cell lines harboring homozygous or heterozygous BRAF V600E in culture were sensitive to treatment with E6201 (PMID: 30264293).	30264293