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

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. CarptenDavid W. Craig, Jeffrey M. Trent, Michael S. Gordon

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Pages (from-to)	636-645
Number of pages	10
Journal	Investigational New Drugs
Volume	37
Issue number	4
DOIs	https://doi.org/10.1007/s10637-018-0668-8
State	Published - Aug 15 2019

Bibliographical note

Funding Information:
The authors wish to thank Antoni Ribas, M.D., for providing BRAF V600E homozygous cell lines for this study (M-321, M-229, and M-262). The authors also thank Spirita Oncology, LLC for financial support, and the Helios Education Foundation and the Arizona State University School of Life Sciences Undergraduate Research Program for financial support (V.D.L.).

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

BRAF
Brain
Inhibitor
MEK
Melanoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Babiker, H. M., Byron, S. A., Hendricks, W. P. D., Elmquist, W. F., Gampa, G., Vondrak, J., Aldrich, J., Cuyugan, L., Adkins, J., De Luca, V., Tibes, R., Borad, M. J., Marceau, K., Myers, T. J., Paradiso, L. J., Liang, W. S., Korn, R. L., Cridebring, D., Von Hoff, D. D., ... Gordon, M. S. (2019). E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases. Investigational New Drugs, 37(4), 636-645. https://doi.org/10.1007/s10637-018-0668-8

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 2019, 'E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases', Investigational New Drugs, vol. 37, no. 4, pp. 636-645. https://doi.org/10.1007/s10637-018-0668-8

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

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.",

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note = "Funding Information: The authors wish to thank Antoni Ribas, M.D., for providing BRAF V600E homozygous cell lines for this study (M-321, M-229, and M-262). The authors also thank Spirita Oncology, LLC for financial support, and the Helios Education Foundation and the Arizona State University School of Life Sciences Undergraduate Research Program for financial support (V.D.L.). Publisher Copyright: {\textcopyright} 2018, Springer Science+Business Media, LLC, part of Springer Nature.",

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AU - Babiker, Hani M.

AU - Byron, Sara A.

AU - Hendricks, William P.D.

AU - Elmquist, William F.

AU - Gampa, Gautham

AU - Vondrak, Jessica

AU - Aldrich, Jessica

AU - Cuyugan, Lori

AU - Adkins, Jonathan

AU - De Luca, Valerie

AU - Tibes, Raoul

AU - Borad, Mitesh J.

AU - Marceau, Katie

AU - Myers, Thomas J.

AU - Paradiso, Linda J.

AU - Liang, Winnie S.

AU - Korn, Ronald L.

AU - Cridebring, Derek

AU - Von Hoff, Daniel D.

AU - Carpten, John D.

AU - Craig, David W.

AU - Trent, Jeffrey M.

AU - Gordon, Michael S.

N1 - Funding Information: The authors wish to thank Antoni Ribas, M.D., for providing BRAF V600E homozygous cell lines for this study (M-321, M-229, and M-262). The authors also thank Spirita Oncology, LLC for financial support, and the Helios Education Foundation and the Arizona State University School of Life Sciences Undergraduate Research Program for financial support (V.D.L.). Publisher Copyright: © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2019/8/15

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N2 - 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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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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