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

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

doi:10.1007/s10637-018-0668-8

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

Invest New Drugs. 2019 Aug;37(4):636-645. doi: 10.1007/s10637-018-0668-8. Epub 2018 Sep 28.

Authors

Hani M Babiker^{1

2

3}, Sara A Byron⁴, William P D Hendricks⁴, William F Elmquist⁵, Gautham Gampa⁵, Jessica Vondrak⁶, Jessica Aldrich⁴, Lori Cuyugan⁴, Jonathan Adkins⁴, Valerie De Luca^{4

7}, Raoul Tibes⁸, Mitesh J Borad^{4

9}, Katie Marceau⁸, Thomas J Myers¹⁰, Linda J Paradiso¹⁰, Winnie S Liang⁴, Ronald L Korn^{4

8

11}, Derek Cridebring⁴, Daniel D Von Hoff^{4

8}, John D Carpten⁴, David W Craig⁴, Jeffrey M Trent⁴, Michael S Gordon⁸

Affiliations

¹ Early Phase Clinical Trials Program, University of Arizona Cancer Center, 1515 N. Campbell Ave, Tucson, AZ, 85724, USA. [email protected].
² Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, 85004, USA. [email protected].
³ Honor Health Research Institute, 10510 N. 92nd Street, #200, Scottsdale, AZ, 85258, USA. [email protected].
⁴ Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, 85004, USA.
⁵ Department of Pharmaceutics, University of Minnesota, 308 SE Harvard Street, Minneapolis, MN, 55455, USA.
⁶ Early Phase Clinical Trials Program, University of Arizona Cancer Center, 1515 N. Campbell Ave, Tucson, AZ, 85724, USA.
⁷ Arizona State University, 427 E. Tyler Mall #320, Tempe, AZ, 85281, USA.
⁸ Honor Health Research Institute, 10510 N. 92nd Street, #200, Scottsdale, AZ, 85258, USA.
⁹ Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA.
¹⁰ Spirita Oncology, LLC, 2450 Holcombe Blvd., Suite J, Houston, TX, 77021, USA.
¹¹ Imaging Endpoints, 9700 N. 91st St, STE B-200, Scottsdale, AZ, 85258, USA.

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.

Keywords: BRAF; Brain; Inhibitor; MEK; Melanoma.

Publication types

Case Reports
Clinical Trial, Phase I
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged, 80 and over
Animals
Antineoplastic Agents / blood
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Brain / metabolism
Brain Neoplasms / drug therapy*
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Brain Neoplasms / secondary
Cell Line, Tumor
Exome Sequencing
Female
Gene Expression Profiling
Humans
Lactones / blood
Lactones / pharmacokinetics
Lactones / therapeutic use*
Male
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / metabolism
Melanoma / pathology
Mice, Knockout
Mutation
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins B-raf / genetics*
Skin Neoplasms / drug therapy*
Skin Neoplasms / genetics
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
Treatment Outcome

Substances

14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione
Antineoplastic Agents
Lactones
Protein Kinase Inhibitors
BRAF protein, human
Proto-Oncogene Proteins B-raf

Grants and funding

P30 CA014089/CA/NCI NIH HHS/United States