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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
PRECLINICAL STUDIES

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.

Keywords

MEK BRAF Inhibitor Melanoma Brain 

Notes

Acknowledgments

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.).

Funding

This study was funded by Spirita Oncology, LLC.

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflicts of interest

Thomas J. Myers and Linda J. Paradiso are employees of Spirita Oncology, LLC. Daniel D. Von Hoff is a consultant for Spirita Oncology, LLC. Spirita Oncoloy, LLC provided funding for a portion of this study. The other authors declare no potential conflicts of interest.

Supplementary material

10637_2018_668_MOESM1_ESM.pdf (3.3 mb)
ESM 1 (PDF 3394 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30.  https://doi.org/10.3322/caac.21442 CrossRefPubMedGoogle Scholar
  2. 2.
    Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, Hwu P, Bedikian A (2011) Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117(8):1687–1696.  https://doi.org/10.1002/cncr.25634 CrossRefPubMedGoogle Scholar
  3. 3.
    Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N (2012) The role of BRAF V600 mutation in melanoma. J Transl Med 10:85.  https://doi.org/10.1186/1479-5876-10-85 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Niezgoda A, Niezgoda P, Czajkowski R (2015) Novel approaches to treatment of advanced melanoma: a review on targeted therapy and immunotherapy. Biomed Res Int 2015:851387–851316.  https://doi.org/10.1155/2015/851387 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D (2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13(11):1087–1095.  https://doi.org/10.1016/S1470-2045(12)70431-X CrossRefPubMedGoogle Scholar
  6. 6.
    Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, Veronese L, Hilfiker PR, Felderer L, Rinderknecht JD (2014) Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 50(3):611–621.  https://doi.org/10.1016/j.ejca.2013.11.002 CrossRefPubMedGoogle Scholar
  7. 7.
    McArthur GA, Maio M, Arance A, Nathan P, Blank C, Avril MF, Garbe C, Hauschild A, Schadendorf D, Hamid O, Fluck M, Thebeau M, Schachter J, Kefford R, Chamberlain M, Makrutzki M, Robson S, Gonzalez R, Margolin K (2017) Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 28(3):634–641.  https://doi.org/10.1093/annonc/mdw641 CrossRefPubMedGoogle Scholar
  8. 8.
    Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Marquez-Rodas I, Del Vecchio M, Lebbe C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV (2017) Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18(7):863–873.  https://doi.org/10.1016/S1470-2045(17)30429-1 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, Meyerson M, Garraway LA (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29(22):3085–3096.  https://doi.org/10.1200/JCO.2010.33.2312 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Samatar AA, Poulikakos PI (2014) Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 13(12):928–942.  https://doi.org/10.1038/nrd4281 CrossRefPubMedGoogle Scholar
  11. 11.
    Tawbi HA, PAJ F, Algazi AP, Hamid O, Hodi FS, Moschos SJ, Khushalani KI, Gonzalez R, Lao CD, Postow MA, Atkins MB, Ernstoff MS, Puzanov I, Kudchadkar RR, Thomas RP, Tarhini AA, Jiang J, Avila A, Demelo S, Margolin KA (2017) Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204. J Clin Oncol 35(15_suppl):9507.  https://doi.org/10.1200/JCO.2017.35.15_suppl.9507 CrossRefGoogle Scholar
  12. 12.
    Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, Wilmott JS, Edwards J, Gonzalez M, Scolyer RA, Menzies AM, McArthur GA (2018) Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19(5):672–681.  https://doi.org/10.1016/S1470-2045(18)30139-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465.  https://doi.org/10.1016/S1470-2045(12)70090-6 CrossRefPubMedGoogle Scholar
  14. 14.
    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM (2016) Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17(7):976–983.  https://doi.org/10.1016/S1470-2045(16)30053-5 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gampa G, Vaidhyanathan S, Sarkaria JN, Elmquist WF (2017) Drug delivery to melanoma brain metastases: can current challenges lead to new opportunities? Pharmacol Res 123:10–25.  https://doi.org/10.1016/j.phrs.2017.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Byron SA, Loch DC, Wellens CL, Wortmann A, Wu J, Wang J, Nomoto K, Pollock PM (2012) Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Mol Cancer 11:75.  https://doi.org/10.1186/1476-4598-11-75 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gampa G, Kim M, Cook-Rostie N, Laramy JK, Sarkaria JN, Paradiso L, DePalatis L, Elmquist WF (2018) Brain distribution of a novel MEK inhibitor E6201: implications in the treatment of melanoma brain metastases. Drug Metab Dispos 46(5):658–666.  https://doi.org/10.1124/dmd.117.079194 CrossRefPubMedGoogle Scholar
  18. 18.
    Tibes R, Borad MJ, Dutcus CE, Reyderman L, Feit K, Eisen A, Verbel DA, Von Hoff DD (2018) Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study. Br J Cancer 118:1580–1585.  https://doi.org/10.1038/s41416-018-0099-5 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liang WS, Hendricks W, Kiefer J, Schmidt J, Sekar S, Carpten J, Craig DW, Adkins J, Cuyugan L, Manojlovic Z, Halperin RF, Helland A, Nasser S, Legendre C, Hurley LH, Sivaprakasam K, Johnson DB, Crandall H, Busam KJ, Zismann V, Deluca V, Lee J, Sekulic A, Ariyan CE, Sosman J, Trent J (2017) Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma. Genome Res 27(4):524–532.  https://doi.org/10.1101/gr.213348.116 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF (2010) Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther 334(1):147–155.  https://doi.org/10.1124/jpet.110.167601 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, Gao J, Socci ND, Solit DB, Olshen AB, Schultz N, Taylor BS (2016) Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat Biotechnol 34(2):155–163.  https://doi.org/10.1038/nbt.3391 CrossRefPubMedGoogle Scholar
  22. 22.
    Helias-Rodzewicz Z, Funck-Brentano E, Baudoux L, Jung CK, Zimmermann U, Marin C, Clerici T, Le Gall C, Peschaud F, Taly V, Saiag P, Emile JF (2015) Variations of BRAF mutant allele percentage in melanomas. BMC Cancer 15:497.  https://doi.org/10.1186/s12885-015-1515-3 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lebbe C, How-Kit A, Battistella M, Sadoux A, Podgorniak MP, Sidina I, Pages C, Roux J, Porcher R, Tost J, Mourah S (2014) BRAF(V600) mutation levels predict response to vemurafenib in metastatic melanoma. Melanoma Res 24(4):415–418.  https://doi.org/10.1097/CMR.0000000000000088 CrossRefPubMedGoogle Scholar
  24. 24.
    Capaldo BJ, Roller D, Axelrod MJ, Koeppel AF, Petricoin EF, Slingluff CL Jr, Weber MJ, Mackey AJ, Gioeli D, Bekiranov S (2015) Systems analysis of adaptive responses to MAP kinase pathway blockade in BRAF mutant melanoma. PLoS One 10(9):e0138210.  https://doi.org/10.1371/journal.pone.0138210 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sondergaard JN, Nazarian R, Wang Q, Guo D, Hsueh T, Mok S, Sazegar H, MacConaill LE, Barretina JG, Kehoe SM, Attar N, von Euw E, Zuckerman JE, Chmielowski B, Comin-Anduix B, Koya RC, Mischel PS, Lo RS, Ribas A (2010) Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med 8:39.  https://doi.org/10.1186/1479-5876-8-39 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Narita Y, Okamoto K, Kawada MI, Takase K, Minoshima Y, Kodama K, Iwata M, Miyamoto N, Sawada K (2014) Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model. Mol Cancer Ther 13(4):823–832.  https://doi.org/10.1158/1535-7163.MCT-13-0667 CrossRefPubMedGoogle Scholar
  27. 27.
    Heffron TP (2016) Small molecule kinase inhibitors for the treatment of brain cancer. J Med Chem 59(22):10030–10066.  https://doi.org/10.1021/acs.jmedchem.6b00618 CrossRefPubMedGoogle Scholar
  28. 28.
    Choo EF, Ly J, Chan J, Shahidi-Latham SK, Messick K, Plise E, Quiason CM, Yang L (2014) Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm 11(11):4199–4207.  https://doi.org/10.1021/mp500435s CrossRefPubMedGoogle Scholar
  29. 29.
    Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF (2014) Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos 42(8):1292–1300.  https://doi.org/10.1124/dmd.114.058339 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Uitdehaag JC, de Roos JA, van Doornmalen AM, Prinsen MB, de Man J, Tanizawa Y, Kawase Y, Yoshino K, Buijsman RC, Zaman GJ (2014) Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS One 9(3):e92146.  https://doi.org/10.1371/journal.pone.0092146 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hani M. Babiker
    • 1
    • 2
    • 3
  • Sara A. Byron
    • 2
  • William P. D. Hendricks
    • 2
  • William F. Elmquist
    • 4
  • Gautham Gampa
    • 4
  • Jessica Vondrak
    • 1
  • Jessica Aldrich
    • 2
  • Lori Cuyugan
    • 2
  • Jonathan Adkins
    • 2
  • Valerie De Luca
    • 2
    • 5
  • Raoul Tibes
    • 3
  • Mitesh J. Borad
    • 2
    • 6
  • Katie Marceau
    • 3
  • Thomas J. Myers
    • 7
  • Linda J. Paradiso
    • 7
  • Winnie S. Liang
    • 2
  • Ronald L. Korn
    • 2
    • 3
    • 8
  • Derek Cridebring
    • 2
  • Daniel D. Von Hoff
    • 2
    • 3
  • John D. Carpten
    • 2
  • David W. Craig
    • 2
  • Jeffrey M. Trent
    • 2
  • Michael S. Gordon
    • 3
  1. 1.Early Phase Clinical Trials ProgramUniversity of Arizona Cancer CenterTucsonUSA
  2. 2.Translational Genomics Research InstitutePhoenixUSA
  3. 3.Honor Health Research InstituteScottsdaleUSA
  4. 4.Department of PharmaceuticsUniversity of MinnesotaMinneapolisUSA
  5. 5.Arizona State UniversityTempeUSA
  6. 6.Mayo ClinicScottsdaleUSA
  7. 7.Spirita Oncology, LLCHoustonUSA
  8. 8.Imaging EndpointsScottsdaleUSA

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