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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 Investigational new drugs
Vol 37
Issue 4
Date 2019 08
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
E6201 FLT3 Inhibitor 61 MEK1 Inhibitor 22 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