Treatment of BRAF-Mutated Metastatic Melanoma: Immunotherapy or Target Therapy?
Abstract
Metastatic melanoma has been associated with a poor prognosis, with overall survival rates at 5 years of 10%. Until 2011, the only treatments available for metastatic melanoma were chemotherapy and immunotherapy with interleukin-2. The more in-depth knowledge about the molecular biology of melanoma and the identification of BRAF mutations, which are the most frequently found, allowed us to find new therapeutic targets that came to modify the prognosis of these patients. Currently, the treatments available for metastatic melanoma with BRAF mutation are immunotherapy with immunological checkpoint inhibitors (anti-PD-1 to anti-CTLA-4) and targeted therapy with BRAF inhibitors and MEK inhibitors. However, the first-line therapy to be instituted in these patients remains unknown.
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Kwong A, San lorenzo Lorenzo M, Rappersberger K, Vujic I. Update on advanced melanoma treatments : small molecule targeted therapy , immunotherapy , and future combination therapies. Springer-Verlag Wien Med Wochenschr; 2017. doi: 10.1007/s10354-016-0535-1
Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, Mccubrey JA, et al. Cutaneous melanoma: From pathogenesis to therapy. Int J Oncol. 2018;52:107180. doi: 10.3892/ijo.2018.4287
Moura C. Melanoma por Cecília Moura. Associação Portuguesa de Cancro Cutâneo. 2012. [Accessed 21-11-2020] Available from: http://www.apcancrocutaneo.pt/index.php/saiba-mais/artigos-de-opiniao/29-melanoma-por-cecilia-moura
Vanella V, Festino L, Trojaniello C, Vitale MG, Sorrentino A, Paone M, et al. The Role of BRAF-Targeted Therapy for Advanced Melanoma in the Immunotherapy Era. Curr Oncol Rep. 2019;21:76. doi: 10.1007/s11912-019-0827-x.
Arch V, Melis C, Rogiers A, Bechter O, Oord JJ Van Den. Molecular genetic and immunotherapeutic targets in metastatic melanoma. Virchows Arch. 2017;471:281-93. doi: 10.1007/s00428-017-2113-3.
Broman KK, Dossett LA, Sun J, Eroglu Z. Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant setting. Expert Opin Drug Saf. 2019;18:381-92. doi: 10.1080/14740338.2019.1607289.
Tétu P, Baroudjian B, Céleste L. Targeting BRAF and MEK inhibitors in melanoma in the metastatic, neoadjuvant and adjuvant setting. Curr Opin Oncol; 2020;1–6. doi: 10.1097/CCO.0000000000000614
Sun J, Carr MJ, Khushalani NI. Principles of Targeted Therapy for Melanoma. Surg Clin North Am. 2020;100:175-88. doi: 10.1016/j.suc.2019.09.013.
Sanches MM, Almeida LS De, Freitas JP. Genes e Melanoma. Rev Soc Port Dermatol Venereol. 2017;75:231–8.
Atkinson V. Recent advances in malignant melanoma. Intern Med J. 2017;47:1114–21. doi: 10.1111/imj.13574
Redman JM, Gibney GT, Atkins MB. Advances in immunotherapy for melanoma. BMC Med. 2016;1–11.doi: 10.1186/s12916-016-0571-0
Moreira RS, Bicker J, Musicco F, Pereira AMPT. Anti-PD-1 immunotherapy in advanced metastatic melanoma: State of art and future challenges. Life Sci. 2019;. doi:10.1016/j.lfs.2019.117093
Callahan MK, Flaherty CR, Postow MA. Checkpoint Blockade for the Treatment of Advanced Melanoma. Zurich: Springer; 2016.
Koppolu V, Rekha Vasigala VK. Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma. J Can Res Ther. 2018;14:1167-75. doi: 10.4103/jcrt.JCRT_1290_16
Marques Link RD, Garicochea B, de Paula Costa RL. Cancer immunology and melanoma immunotherapy. An Bras Dermatol. 2017; 92; 830–5.
Queirolo P, Boutros A, Tanda E, Spagnolo F, Quaglino P. Immune-checkpoint inhibitors for the treatment of metastatic melanoma: a model of cancer immunotherapy. Semin Cancer Biol. 2019;59:290-7. doi: 10.1016/j.semcancer.2019.08.001.
Glitza Oliva IC, Alqusairi R. Immunotherapy for Melanoma. Adv Exp Med Biol. 2018;995:43-63. doi: 10.1007/978-3-030-02505-2_2.
George DD, Armenio VA, Katz SC. Combinatorial immunotherapy for melanoma. Cancer Gene Ther. 2016;24:141–7. doi: 10.1038/cgt.2016.56
Herrscher H, Robert C. Immune checkpoint inhibitors in melanoma in the metastatic, neoadjuvant, and adjuvant setting. Curr Opin Oncol. 2020;32:106-13. doi: 10.1097/CCO.0000000000000610.
Davis LE, Shalin SC, Tackett AJ, Davis LE, Shalin SC, Tackett AJ. Current state of melanoma diagnosis and treatment. Cancer Biol Ther. 2019;20:1366-79. doi: 10.1080/15384047.2019.1640032.
Malissen N, Jacques J. Metastatic Melanoma: Recent Therapeutic Progress and Future Perspectives. Drugs. 2018;78:1197–209. doi: 10.1007/s40265-018-0945-z
Mitchell TC, Feld E. Immunotherapy in melanoma. Immunotherapy. 2018;10:987–98.
Onitilo AA, Wittig JA. Principles of Immunotherapy in Melanoma. Surg Clin N Am. 2019 doi:10.1016/j.suc.2019.09.009
Achkar T, Tarhini AA. The use of immunotherapy in the treatment of melanoma. J Hematol Oncol. 2017; 10:88; doi: 10.1186/s13045-017-0458-3
Food and Drug Adminstration. Highlights of prescribing information - ipilimumab. 2011;1–32. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125377s087lbl.pdf
Maio M, Grob J, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a Phase III Trial. J Clin Oncol. 2015 ;33:1191-6. doi: 10.1200/JCO.2014.56.6018
Ascierto PA, Vecchio M Del, Robert C, Mackiewicz A, Chiarion-sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;2045:1–12. doi: 10.1016/S1470-2045(17)30231-0
Franklin C, Livingstone E, Roesch A, Schilling B, Schadenforf D. Immunotherapy in melanoma: Recent advances and future directions. Eur J Surg Oncol. 2017;43:604–11. doi 10.1016/j.ejso.2016.07.145
Gomes F, Serra-bellver P, Lorigan P. The role of nivolumab in melanoma. Future Oncol. 2018;14:1241-52. doi: 10.2217/fon-2017-0484
Weber JS, Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, 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;2045:1–10. doi: 10.1016/S1470-2045(15)70076-8
Amaral T, Meraz-torres F, Garbe C. Immunotherapy in managing metastatic melanoma: Which treatment when? Exp Opin Biol Therap. 2017;2598. doi: 10.1080/14712598.2017.1378640
Food and Drug Adminstration. Highlights of prescribing information - nivolumab. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125554s070lbl.pdf
Robert C, Ribas A, Schachter J, Arance A, Grob J, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;4:1–13. doi: 10.1016/S1470-2045(19)30388-2
Food and Drug Adminstration. Highlights of prescribing information - pembrolizumab. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s040lbl.pdf
Larkin J, Chiarion-sileni V, Gonzalez R, Grob J, Rutkowski P, Lao CD, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;1–11. doi: 10.1056/NEJMoa1910836
Hodi FS, Chiarion-sileni V, Gonzalez R, Grob J, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480-92. doi: 10.1016/S1470-2045(18)30700-9.
Larkin J, Chiarion-sileni V, Gonzalez R, Grob J, Rutkowski P, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. 2015;373:1270-1. doi: 10.1056/NEJMc1509660.
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, Mcdermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet. 2016;1–11. doi: 10.1016/S1470-2045(16)30366-7
Long G V, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, Mcneil CM, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029 ): an open-label, phase 1b trial. Lancet Oncol. 2017;1:1–9. doi: 10.1016/S1470-2045(17)30428-X
Food and Drug Adminstration. Highlights of prescribing information - vemurafenib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf
Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, et al. Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the randomised BRIM-3 study. Ann Oncol. 2017;28:2581-7. doi: 10.1093/annonc/mdx339.
Hauschild A, Ascierto PA, Schadendorf D, Jacques J, Ribas A, Kiecker F, et al. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials. Eur J Cancer. 2020;125:114–20. doi: 10.1016/j.ejca.2019.10.033
Food and Drug Adminstration. Highlights of prescribing information - dabrafenib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf
Grimaldi AM, Simeone E, Festino L, Vanella V, Strudel M, Ascierto PA. MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors. Am J Clin Dermatol. 2017;18:745–54. doi: 10.1007/s40257-017-0292-y
Robert C, Flaherty K, Nathan P, Hersey P, Garbe C, Milhem M, et al. Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K - mutant advanced or metastatic melanoma. Eur J Cancer. 2019;109:61–9. doi:10.1016/j.ejca.2018.12.015
Food and Drug Adminstration. Highlights of prescribing information - trametinib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
Long G V, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, et al. Long-Term Outcomes in Patients With BRAF V600 – Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J Clin Oncol. 2018;36. doi: 10.1200/JCO.2017. 74.1025
Sileni VC, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;381:626- 36. doi: 10.1056/NEJMoa1904059
Dhillon S. Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF V600 Mutation. Target Oncol. 2016. doi: 10.1007/s11523-016-0443-8
Simeone E, Grimaldi AM, Festino L, Vanella V, Palla M, Ascierto PA. Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care. BioDrugs. 2017;31:51-61. doi: 10.1007/s40259-016-0208-z.
Spain L, Julve M, Larkin J. Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations. Exp Opin Pharmacother. 2016;17:1031–8. doi:10.1517/14656566.2016.1168805
Food and Drug Adminstration. Highlights of prescribing information - cobimetinib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
Keating GM. Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma. Drugs. 2016;76:605–15. doi: 10.1007/s40265-016-0562-7
Ascierto PA, Mcarthur GA, Dréno B, Atkinson V, Liszkay G, Maria A, et al. Cobimetinib combined with vemurafenib in advanced BRAF V600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;2045:1–13. doi: 10.1016/S1470-2045(16)30122-X
Boespflug A, Thomas L. Cobimetinib and vemurafenib for the treatment of melanoma. Exp Opin Pharmacother. 2016;17:1005–11. doi:
1517/14656566.2016.1168806
Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;2045:1– 13.doi:10.1016/S1470-2045(18)30142-6
Trojaniello C, Festino L, Vanella V, Ascierto PA. Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Expert Rev Clin Pharmacol. 2019;12:259-66. doi: 10.1080/17512433.2019.1570847.
Ascierto PA, Dummer R, Gogas HJ, Flaherty KT, Arance A, Mandala M, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant. Eur J Cancer. 2020;126:33–44. doi:10.1016/j.ejca.2019.11.016
Gogas HJ, Flaherty KT, Dummer R, Ascierto PA, Arance A, Mandala M, et al. Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. Eur J Cancer. 2019;119:97–106. doi: 10.1016/j.ejca.2019.07.016
Food and Drug Adminstration. Highlights of prescribing information - encorafenib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210496s006lbl.pdf
Food and Drug Adminstration. Highlights of prescribing information - binimetinib. [Accessed 21-11-2020] Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf
Swe T, Kim KB. Update on systemic therapy for advanced cutaneous melanoma and recent development of novel drugs. Clin Exp Metastasis. 2018;35:503-20. doi: 10.1007/s10585-018-9913-y.
Sullivan RJ, Atkins MB, Kirkwood JM, Agarwala SS, Clark JI, Ernstoff MS, et al. An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. J Immunother Cancer. 2018;1–23. doi: 10.1186/s40425-018-0362-6
U.S. National Library of Medicine. A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (COMBI-i). [Accessed 06-12-2020] Available from: https://clinicaltrials.gov/ct2/show/results/NCT02967692
Tyrell R, Antia C, Stanley S, Deutsch GB. Surgical resection of metastatic melanoma in the era of immunotherapy and targeted therapy. Futur Med. 2017;4: 61–8.
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