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01-08-2019 | PRECLINICAL STUDIES

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

Authors: 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 S. Gordon

Published in: Investigational New Drugs | Issue 4/2019

Summary

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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Title: E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases
Authors: 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 S. Gordon
Publication date: 01-08-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0668-8

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