Open AccessE6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases
Author(s) -
Hani M. Babiker,
Sara A. Byron,
William P.D. Hendricks,
William F. Elmquist,
Gautham Gampa,
Jessica Vondrak,
Jessica Aldrich,
Lori Cuyugan,
Jonathan Adkins,
Valerie De Luca,
Raoul Tibes,
Mitesh J. Borad,
Katie Marceau,
Thomas J. Myers,
Linda J. Paradiso,
Winnie S. Liang,
Ronald L. Korn,
Derek Cridebring,
Daniel D. Von Hoff,
John D. Carpten,
David W. Craig,
Jeffrey M. Trent,
Michael Gordon
Publication year - 2018
Publication title -
investigational new drugs
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 87
eISSN - 1573-0646
pISSN - 0167-6997
DOI - 10.1007/s10637-018-0668-8
Subject(s) - melanoma , cancer research , medicine , mek inhibitor , in vivo , mutation , mutant , v600e , metastatic melanoma , transcriptome , oncology , biology , mapk/erk pathway , signal transduction , gene , biochemistry , gene expression , microbiology and biotechnology
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.