1. E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.
- Author
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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, and Gordon MS
- Subjects
- Aged, 80 and over, Animals, Antineoplastic Agents blood, Antineoplastic Agents pharmacokinetics, Brain metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms secondary, Cell Line, Tumor, Female, Gene Expression Profiling, Humans, Lactones blood, Lactones pharmacokinetics, Male, Melanoma genetics, Melanoma metabolism, Melanoma pathology, Mice, Knockout, Mutation, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors pharmacokinetics, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Treatment Outcome, Exome Sequencing, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Lactones therapeutic use, Melanoma drug therapy, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms drug therapy
- Abstract
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.
- Published
- 2019
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