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Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

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Abstract

The MEK inhibitor cobimetinib (Cotellic®) is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf®). In the pivotal coBRIM trial, previously untreated patients with BRAF V600 mutation-positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival. Cobimetinib plus vemurafenib had a manageable tolerability profile. In conclusion, cobimetinib plus vemurafenib is a valuable option for use in BRAF V600 mutation-positive unresectable or metastatic melanoma.

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References

  1. Dossett LA, Kudchadkar RR, Zager JS. BRAF and MEK inhibition in melanoma. Expert Opin Drug Saf. 2015;14(4):559–70.

    Article  CAS  PubMed  Google Scholar 

  2. Spagnolo F, Ghiorzo P, Queirolo P. Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma. Oncotarget. 2014;5(21):10206–21.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Genentech USA Inc. Cotellic (cobimetinib) tablets, for oral use: US prescribing information. 2015. http://www.gene.com. Accessed 2 Feb 2016.

  4. European Medicines Agency. Cotellic (cobimetinib): EU summary of product characteristics. 2015. http://ec.europa.eu. Accessed 2 Feb 2016.

  5. Genentech USA Inc. Zelboraf® (vemurafenib) tablet for oral use: US prescribing information. 2015. http://www.gene.com. Accessed 2 Feb 2016.

  6. European Medicines Agency. Zelboraf (vemurafenib) film-coated tablets: EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 2 Feb 2016.

  7. Beck D, Niessner H, Smalley KSM, et al. Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. Sci Signal. 2013;6(260):ra7.

  8. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70(13):5518–27.

    Article  CAS  PubMed  Google Scholar 

  9. Søndergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAF V600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sala E, Mologni L, Truffa S, et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008;6(5):751–9.

    Article  CAS  PubMed  Google Scholar 

  11. Rice KD, Aay N, Anand NK, et al. Novel carboxamide-based allosteric MEK inhibitors: discovery and optimization efforts toward XL518 (GDC-0973). ACS Med Chem Lett. 2012;3(5):416–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hoeflich KP, Merchant M, Orr C, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012;72(1):210–9.

    Article  CAS  PubMed  Google Scholar 

  13. Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012;18(11):3090–9.

    Article  CAS  PubMed  Google Scholar 

  14. Musib L, Choo E, Deng Y, et al. Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects. Mol Pharm. 2013;10(11):4046–54.

    Article  CAS  PubMed  Google Scholar 

  15. Musib L, Eppler S, Choo E, et al. Clinical pharmacokinetics of GDC-0973, an oral MEK inhibitor, in cancer patients: data from a phase 1 study [abstract no. 1304]. Cancer Res. 2011;71(8 Suppl).

  16. Grippo JF, Zhang W, Heinzmann D, et al. A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAFV600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol. 2014;73(1):103–11.

    Article  CAS  PubMed  Google Scholar 

  17. Ribas A, Zhang W, Chang I, et al. The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics. J Clin Pharmacol. 2014;54(4):368–74.

    Article  PubMed  Google Scholar 

  18. Takahashi RH, Choo EF, Ma S, et al. Absorption, metabolism, excretion, and the contribution of intestinal metabolism to the oral disposition of [14C]cobimetinib, a MEK inhibitor, in humans. Drug Metab Dispos. 2016;44(1):28–39.

    Article  PubMed  Google Scholar 

  19. Han K, Jin J, Marchand M, et al. Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol. 2015;76(5):917–24.

    Article  CAS  PubMed  Google Scholar 

  20. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15(9):954–65.

    Article  CAS  PubMed  Google Scholar 

  21. Choo EF, Ly J, Chan J, et al. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm. 2014;11(11):4199–207.

    Article  CAS  PubMed  Google Scholar 

  22. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAFV600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;5(3):323–32.

    Article  Google Scholar 

  26. Pavlick AC, Ribas A, Gonzalez R, et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma [abstract no. 9020]. J Clin Oncol. 2015;33(Suppl).

  27. Lewis K, Ribas A, Gonzalez R, et al. Treatment beyond progression in advanced BRAF-mutated melanoma with vemurafenib and cobimetinib: results from the BRIM7 trial [abstract no. 3340 plus poster]. In: European Cancer Congress. 2015.

  28. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.

    Article  PubMed  Google Scholar 

  29. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. [abstract no. 9006]. J Clin Oncol. 2015;33(15 Suppl 1).

  30. Atkinson V, Larkin J, McArthur G, et al. Improved overall survival (OS) with cobimetinib (COBI) + vemurafenib (V) in advanced BRAF-mutated melanoma and biomarker correlates of efficacy [abstract]. In: Society for Melanoma Research 2015 Congress. 2015.

  31. McArthur G, Larkin J, Dréno B, et al. Impact of baseline genetic heterogeneities on progression-free survival (PFS) in patients (pts) with advanced BRAFV600-mutated melanoma treated with cobimetinib (COBI) + vemurafenib (VEM) in the phase 3 coBRIM study [abstract no. 25LBA]. In: European Cancer Congress. 2015.

  32. Wongchenko M, McArthur GA, Andries L, et al. Gene expression profiling reveals distinct subpopulations of BRAF-mutant melanoma patients each with different outcomes when treated with vemurafenib or combined vemurafenib and cobimetinib [abstract]. Pigment Cell Melanoma Res. 2015;28(6):823.

    Google Scholar 

  33. Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31(14):1767–74.

    Article  CAS  PubMed  Google Scholar 

  34. Atefi M, von Euw E, Attar N, et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS ONE. 2011;6(12):e28973.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20(7):1965–77.

    Article  CAS  PubMed  Google Scholar 

  36. Moriceau G, Hugo W, Hong A, et al. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell. 2015;27(2):240–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dréno B, Ribas A, Larkin J, et al. Incidence, course, and management of toxicities associated with vemurafenib and cobimetinib in the coBRIM study [abstract plus poster]. In: Society for Melanoma Research 2014 Congress. 2014.

  38. De La Cruz-Merino L, Di Guardo L, Grob J-J, et al. Clinical features of cobimetinib (COBI)-associated serous retinopathy (SR) in BRAF-mutated melanoma patients (pts) treated in the coBRIM study [abstract no. 9033 plus poster]. J Clin Oncol. 2015;33(15 Suppl 1).

  39. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF V600 mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15(4):436–44.

    Article  CAS  PubMed  Google Scholar 

  40. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.

    Article  PubMed  Google Scholar 

  41. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.

    Article  PubMed  Google Scholar 

  42. GlaxoSmithKline. Tafinlar (dabrafenib) capsules, for oral use: US prescribing information. 2015. http://www.pharma.us.novartis.com. Accessed 2 Feb 2016.

  43. GlaxoSmithKline. Mekinist (trametinib) tablets, for oral use: US prescribing information. 2015. http://www.pharma.us.novartis.com. Accessed 2 Feb 2016.

  44. European Medicines Agency. Tafinlar (dabrafenib): EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 2 Feb 2016.

  45. European Medicines Agency. Mekinist (trametinib): EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 2 Feb 2016.

  46. Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013;494(7436):251–5.

  47. Sullivan R, LoRusso P, Boerner S, et al. Achievements and challenges of molecular targeted therapy in melanoma. Am Soc Clin Oncol Educ Book. 2015:177–86.

  48. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF V600 mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50(3):611–21.

    Article  CAS  PubMed  Google Scholar 

  49. Yee MK, Lin Y, Gorantla VC, et al. Phase 2 study of cobimetinib in combination with vemurafenib in active melanoma brain metastases (coBRIM-B) [abstract no. TPS9088 plus poster]. J Clin Oncol. 2015;33(15 Suppl 1).

  50. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Anforth R, Carlos G, Clements A, et al. Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks. Br J Dermatol. 2015;172(1):239–43.

    Article  CAS  PubMed  Google Scholar 

  52. Goldwirt L, Chami I, Feugeas JP, et al. Low vemurafenib plasma exposure as a short-term predictive parameter of progression disease in metastatic BRAFV600 mut melanoma [abstract no. 9072 plus poster]. J Clin Oncol. 2015;33(15 Suppl 1).

  53. Kramkimel N, Thomas-Schoemann A, Sakji L, et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Target Oncol. 2015;11(1):59–69.

    Article  Google Scholar 

  54. Funck-Brentano E, Alvarez JC, Longvert C, et al. Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance. Ann Oncol. 2015;26(7):1470–5.

    CAS  PubMed  Google Scholar 

  55. Dummer R, Hauschild A, Lindenblatt N, et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v126–32.

    Article  PubMed  Google Scholar 

  56. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: melanoma (version 2.2016). 2015. http://www.nccn.org. Accessed 2 Feb 2016.

  57. Bristol-Myers Squibb Company. Nivolumab (Opdivo) injection, for intravenous use: US prescribing information. 2016. http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed 2 Feb 2016.

  58. European Medicines Agency. Opdivo (nivolumab): EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 2 Feb 2016.

  59. Merck & Co Inc. Keytruada® (pembrolizumab): US prescribing information. 2015. http://www.keytruda.com. Accessed 2 Feb 2016.

  60. European Medicines Agency. Keytruda (pembrolizumab): EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 2 Feb 2016.

  61. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17.

    Article  CAS  PubMed  Google Scholar 

  62. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

    Article  CAS  PubMed  Google Scholar 

  63. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.

    Article  CAS  PubMed  Google Scholar 

  64. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.

    Article  CAS  PubMed  Google Scholar 

  65. Olszanski AJ. Current and future roles of targeted therapy and immunotherapy in advanced melanoma. J Manag Care Pharm. 2014;20(4):346–56.

    Google Scholar 

  66. Hu-Lieskovan S, Robert L, Homet Moreno B, et al. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges. J Clin Oncol. 2014;32(21):2248–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.

    Article  CAS  PubMed  Google Scholar 

  68. Hamid O, Patel M, Hodi S, et al. Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600 metastatic melanoma [abstract]. Pigment Cell Melanoma Res. 2015;28(6):778.

    Google Scholar 

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Acknowledgments

During the peer review process, the manufacturer of cobimetinib and vemurafenib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Gillian M. Keating

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  1. Gillian M. Keating
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Correspondence to Gillian M. Keating.

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The preparation of this review was not supported by any external funding.

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Gillian Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: L. de la Cruz Merino, Clinical Oncology Department, Virgen Macarena University Hospital, Seville, Spain; I. Krajsová, Department of Dermato-oncology, University Hospital Prague, and Charles University First Medical Faculty, Prague, Czech Republic; M. Mandalà, Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; P. Queirolo, Medical Oncology 2, IRCCS San Martino - IST, Genova, Italy.

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Keating, G.M. Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma. Drugs 76, 605–615 (2016). https://doi.org/10.1007/s40265-016-0562-7

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  • DOI: https://doi.org/10.1007/s40265-016-0562-7

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