Skip to main content
SpringerLink
Log in
Book cover

BRAF Targets in Melanoma pp 67–84Cite as

Clinical Utility of BRAF-Targeted Therapy in Melanoma

  • Chapter
  • First Online:

  • 945 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 82))

Abstract

The identification of BRAFV600 mutations in melanoma rapidly translated into a search for strategies to exploit this recurrent genetic alteration. The selective BRAF inhibitors, vemurafenib and dabrafenib have demonstrated impressive antitumor activity with objective response rates of approximately 50 % and improved progression-free and/or overall survival compared to cytotoxic chemotherapy. The MEK inhibitor trametinib also subsequently demonstrated improved survival compared to chemotherapy. Acquired resistance, however, has limited the long-term antitumor efficacy of these therapies. Combined BRAF and MEK inhibition represents one strategy to delay the onset of resistance and potentially extend survival. Additional BRAF and MEK inhibitors and combinations are being developed with a goal of improving outcomes further. In this chapter, we review the development of approved BRAF and MEK inhibitors, the experience with combination therapy, and special clinical situations for BRAF-targeted therapy.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  2. Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene. 2004;23:6292–8.

    Article  CAS  PubMed  Google Scholar 

  3. Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95:581–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. McDermott DF, Sosman JA, Gonzalez R, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 study group. J Clin Oncol. 2008;26:2178–85.

    Article  CAS  PubMed  Google Scholar 

  5. Flaherty KT, Lee SJ, Zhao F, et al. Phase III Trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013;31:373–9.

    Article  CAS  PubMed  Google Scholar 

  6. Sondergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–901.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  CAS  PubMed  Google Scholar 

  13. Dummer R, Robert C, Nyakas M, McArthur GA, Kudchadkar RR, et al. Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma. J Clin Oncol. 2013;31:9028.

    Google Scholar 

  14. 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;366:207–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med. 2012;367(24):2316–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chapman PB, Metz, D., Sepulveda, A. et al. Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res. 2012;25:847.

    Google Scholar 

  17. Klein O, Ribas A, Chmielowski B, et al. Facial palsy as a side effect of vemurafenib treatment in patients with metastatic melanoma. J Clin Oncol. 2013;31(12):e215–7.

    Article  PubMed  Google Scholar 

  18. Johnson DB, Wallender E, Cohen DN, et al.. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol Res. 2013;1(6):373–7. doi:10.1158/2326-6066.CIR-13-0092

    Google Scholar 

  19. Chapman PB, Hauschild, A., Robert, C. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol. 2012;30:8502.

    Google Scholar 

  20. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Robert C, Dummer R, Gutzmer R, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol. 2013;14:733–40.

    Article  CAS  PubMed  Google Scholar 

  23. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29:3085–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Shi H, Hugo W, Kong X, et al. Acquired Resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Haq R, Yokoyama S, Hawryluk EB, et al. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci U S A. 2013;110:4321–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4:94–109.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Shi H, Hong A, Kong X, et al. A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition. Cancer Discov. 2014;4:69–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  36. Sosman JA, Daud A, Weber, JS, et al. BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). J Clin Oncol. 2013;(9005).

    Google Scholar 

  37. www.clinicaltrials.gov. Accessed 27 Jan 27 2014.

  38. Mittapalli RK, Vaidhyanathan S, Dudek AZ, et al. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344:655–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Long GV, Trefzer U, Davies MA, et al. 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. 2012;13(11):1087–95.

    Article  CAS  PubMed  Google Scholar 

  40. Azer MW, Menzies AM, Haydu L, Kefford R, Long GV. Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma metastatic to the brain treated with dabrafenib (GSK2118436). J Clin Oncol. 2012;30:8558.

    Google Scholar 

  41. Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R metastatic melanoma. Eur J Cancer. 2012;49(5):1073–9.

    Article  PubMed  Google Scholar 

  42. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study. Eur J Cancer. 2013;50(3):611–21.

    Article  PubMed  Google Scholar 

  43. Long GV, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma. Am Soc Clin Oncol Educ Book. 2013;2013:393–8.

    Article  Google Scholar 

  44. Kolar GR, Miller-Thomas MM, Schmidt RE, et al. Neoadjuvant treatment of a solitary melanoma brain metastasis with vemurafenib. J Clin Oncol. 2013;31:e40–3.

    Article  PubMed  Google Scholar 

  45. Anker CJ, Ribas A, Grossmann AH, et al. Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol. 2013;31:e283–7.

    Article  PubMed  Google Scholar 

  46. Kim KB, Flaherty KT, Chapman PB, et al. Pattern and outcome of disease progression in phase I study of vemurafenib in patients with metastatic melanoma (MM). J Clin Oncol. 2011;29:8519.

    Article  Google Scholar 

  47. Seghers AC, Wilgenhof S, Lebbe C, et al. Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor. Melanoma Res. 2012;22:466–72.

    Article  PubMed  Google Scholar 

  48. Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One. 2012;7:e35309.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. 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;70:5518–27.

    Article  CAS  PubMed  Google Scholar 

  50. Ponti G, Tomasi A, Pellacani G. Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma. J Hematol Oncol. 2012;5:60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Dahlman KB, Xia J, Hutchinson K, et al. BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012;2(9):791–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Bahadoran P, Allegra M, Le Duff F, et al. Major clinical response to a BRAF inhibitor in a patient with a BRAF L597R-mutated melanoma. J Clin Oncol. 2013;31(19):e324–6.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, Nashville, TN 37232, USA

    Jeffrey A. Sosman & Douglas B. Johnson

Authors
  1. Jeffrey A. Sosman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas B. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey A. Sosman .

Editor information

Editors and Affiliations

  1. Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

    Ryan J. Sullivan

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Sosman, J., Johnson, D. (2015). Clinical Utility of BRAF-Targeted Therapy in Melanoma. In: Sullivan, R. (eds) BRAF Targets in Melanoma. Cancer Drug Discovery and Development, vol 82. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2143-0_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-2143-0_4

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-2142-3

  • Online ISBN: 978-1-4939-2143-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation