Advertisement

Cobimetinib (GDC-0973, XL518)

  • Hana Andrlová
  • Robert Zeiser
  • Frank Meiss
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 211)

Abstract

The mitogen-activated protein kinase cascade (MAPK/ERK pathway) is a signaling pathway activated as a cellular response to various stimuli and for regulating the proliferation and survival of several types of eukaryotic cells, among others a wide variety of tumor cells. Mutations of the proteins involved in this pathway have been discovered in several tumor entities, indicating their inhibition as a potential therapeutic target. BRAF inhibitors have been in the clinical use since 2011. Several MEK inhibitors have been studied for metastatic cancer treatment in the recent past. After trametinib, cobimetinib is another potent, selective oral MEK1/2 inhibitor that was approved by European Medicine Agency (EMA) and Food and Drug Administration (FDA) in 2015 for treatment of malignant melanoma in a combination with the BRAF inhibitor vemurafenib.

Keywords

Cobimetinib MAPK/ERK pathway MEK inhibitors BRAF/MEK inhibition Combination therapy 

References

  1. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J (2016) Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248–1260.  https://doi.org/10.1016/S1470-2045(16)30122-XCrossRefPubMedGoogle Scholar
  2. Boulton TG, Yancopoulos GD, Gregory JS, Slaughter C, Moomaw C, Hsu J, Cobb MH (1990) An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249:64–67CrossRefPubMedGoogle Scholar
  3. Budha NR, Ji T, Musib L, Eppler S, Dresser M, Chen Y, Jin JY (2016) Evaluation of cytochrome P450 3A4-mediated drug-drug interaction potential for cobimetinib using physiologically based pharmacokinetic modeling and simulation. Clin Pharmacokinet 55:1435–1445.  https://doi.org/10.1007/s40262-016-0412-5CrossRefPubMedGoogle Scholar
  4. Cobb MH, Boulton TG, Robbins DJ (1991) Extracellular signal-regulated kinases: ERKs in progress. Cell Regul 2:965–978CrossRefPubMedPubMedCentralGoogle Scholar
  5. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954.  https://doi.org/10.1038/nature00766CrossRefPubMedGoogle Scholar
  6. Dréno B, Ribas A, Larkin J, Ascierto PA, Hauschild A, Thomas L, Grob J-J, Koralek DO, Rooney I, Hsu JJ, McKenna EF, McArthur GA (2017) Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol 28:1137–1144.  https://doi.org/10.1093/annonc/mdx040CrossRefPubMedGoogle Scholar
  7. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 39:D945–D950.  https://doi.org/10.1093/nar/gkq929CrossRefPubMedGoogle Scholar
  8. Han K, Jin JY, Marchand M, Eppler S, Choong N, Hack SP, Tikoo N, Bruno R, Dresser M, Musib L, Budha NR (2015) Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol 76:917–924.  https://doi.org/10.1007/s00280-015-2862-0CrossRefPubMedGoogle Scholar
  9. Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JFM, Zak M, Peck A, Orr C, Merchant M, Hoeflich KP, Chan J, Luoh S-M, Anderson DJ, Ludlam MJC, Wiesmann C, Ultsch M, Friedman LS, Malek S, Belvin M (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 501:232–236.  https://doi.org/10.1038/nature12441CrossRefPubMedGoogle Scholar
  10. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin A-M, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365.  https://doi.org/10.1016/S0140-6736(12)60868-XCrossRefPubMedGoogle Scholar
  11. Hoeflich KP, Merchant M, Orr C, Chan J, Den Otter D, Berry L, Kasman I, Koeppen H, Rice K, Yang N-Y, Engst S, Johnston S, Friedman LS, Belvin M (2012) Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res 72:210–219.  https://doi.org/10.1158/0008-5472.CAN-11-1515CrossRefPubMedGoogle Scholar
  12. Junttila MR, Devasthali V, Cheng JH, Castillo J, Metcalfe C, Clermont AC, Otter DD, Chan E, Bou-Reslan H, Cao T, Forrest W, Nannini MA, French D, Carano R, Merchant M, Hoeflich KP, Singh M (2015) Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer. Mol Cancer Ther 14:40–47.  https://doi.org/10.1158/1535-7163.MCT-14-0030CrossRefPubMedGoogle Scholar
  13. Kirkpatrick DS, Bustos DJ, Dogan T, Chan J, Phu L, Young A, Friedman LS, Belvin M, Song Q, Bakalarski CE, Hoeflich KP (2013) Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition. Proc Natl Acad Sci 110:19426–19431.  https://doi.org/10.1073/pnas.1309473110CrossRefPubMedGoogle Scholar
  14. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867–1876.  https://doi.org/10.1056/NEJMoa1408868CrossRefPubMedGoogle Scholar
  15. Lieu CH, Hidalgo M, Berlin JD, Ko AH, Cervantes A, LoRusso P, Gerber DE, Eder JP, Eckhardt SG, Kapp AV, Tsuhako A, McCall B, Pirzkall A, Uyei A, Tabernero J (2017) A phase Ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced or metastatic cancers with mutant KRAS. Oncologist 22:1024–e89.  https://doi.org/10.1634/theoncologist.2017-0175CrossRefPubMedPubMedCentralGoogle Scholar
  16. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob J-J, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444–451.  https://doi.org/10.1016/S0140-6736(15)60898-4CrossRefGoogle Scholar
  17. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O’Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A (2014) Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15:323–332.  https://doi.org/10.1016/S1470-2045(14)70012-9CrossRefPubMedPubMedCentralGoogle Scholar
  18. Moodie SA, Willumsen BM, Weber MJ, Wolfman A (1993) Complexes of Ras. GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260:1658–1661CrossRefPubMedGoogle Scholar
  19. Musib L, Choo E, Deng Y, Eppler S, Rooney I, Chan IT, Dresser MJ (2013) Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects. Mol Pharm 10:4046–4054.  https://doi.org/10.1021/mp400383xCrossRefPubMedGoogle Scholar
  20. Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA (2014) Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol 15:954–965.  https://doi.org/10.1016/S1470-2045(14)70301-8CrossRefPubMedGoogle Scholar
  21. Robbins DJ, Cheng M, Zhen E, Vanderbilt CA, Feig LA, Cobb MH (1992) Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade. Proc Natl Acad Sci USA 89:6924–6928CrossRefPubMedGoogle Scholar
  22. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin A-M, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39.  https://doi.org/10.1056/NEJMoa1412690CrossRefPubMedGoogle Scholar
  23. Roskoski R (2017) Allosteric MEK1/2 inhibitors including cobimetinib and trametinib in the treatment of cutaneous melanomas. Pharmacol Res 117:20–31.  https://doi.org/10.1016/j.phrs.2016.12.009CrossRefPubMedGoogle Scholar
  24. Takahashi RH, Choo EF, Ma S, Wong S, Halladay J, Deng Y, Rooney I, Gates M, Hop CECA, Khojasteh SC, Dresser MJ, Musib L (2015) Absorption, metabolism, excretion, and the contribution of intestinal metabolism to the oral disposition of [14C]Cobimetinib, a MEK inhibitor, in humans. Drug Metab Dispos 44:28–39.  https://doi.org/10.1124/dmd.115.066282CrossRefPubMedGoogle Scholar
  25. Wong H, Vernillet L, Peterson A, Ware JA, Lee L, Martini J-F, Yu P, Li C, Rosario GD, Choo EF, Hoeflich KP, Shi Y, Aftab BT, Aoyama R, Lam ST, Belvin M, Prescott J (2012) Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res 18:3090–3099.  https://doi.org/10.1158/1078-0432.CCR-12-0445CrossRefPubMedGoogle Scholar
  26. Yan Y, McArthur G, Hamid O, Puzanov I, Gonzalez R, Gajewski T, Wang Y, Wongchenko M, Choong N, Ribas A (2014) Biomarker analysis of on-treatment and at progression biopsies from BRIM7—a phase 1B trial of combined vemurafenib and cobimetinib treatment in BRAF V600 mutated melanoma. J Transl Med 12:O12.  https://doi.org/10.1186/1479-5876-12-S1-O12CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  2. 2.Department of Dermatology and Venereology, Medical Center - University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany

Personalised recommendations