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Management of V600E and V600K BRAF-Mutant Melanoma

  • Alexandra M. Haugh
  • Douglas B. JohnsonEmail author
Skin Cancer (T Ito, Section Editor)
  • 202 Downloads
Part of the following topical collections:
  1. Topical Collection on Skin Cancer

Opinion statement

The optimal management of advanced stage BRAF-mutated melanoma is widely debated and complicated by the availability of several different regimens that significantly improve outcomes but have not been directly compared. While there are many unanswered questions relevant to this patient population, the major uncertainty in current practice is the choice between BRAF/MEK inhibitors or immunotherapy for those with previously untreated metastatic or high-risk disease. Decisions regarding first line therapy should include consideration of patient preference as well as the presence of symptomatic metastatic disease and degree of comorbidity, particularly secondary to any history of severe auto-immune disorder.

BRAF/MEK inhibitors have a high response rate and rapid onset and thus can be quickly introduced when patients are symptomatic. They have also produced long-term responses in a subset of patients with more favorable prognostic indicators. In addition, impressive survival benefits have also been observed in patients with resected stage 3 disease at high risk of recurrence. On the other hand, anti-PD-1 monotherapy is associated with high rates of clinical benefit (~45% response rate in the metastatic setting) and low rates of severe toxicity. In many patients with adverse prognostic features, we use combined anti-PD-1 and anti-CTLA-4 for metastatic disease. While associated with high rates of toxicity, adverse events are largely manageable with corticosteroids and treatment cessation, in which case patients may continue to benefit even after a limited duration of treatment.

Multiple treatment options exist for patients with BRAF V600 mutant melanoma. Herein, we review the clinical data for safety and efficacy of these options.

Keywords

Melanoma BRAF MEK PD-1 PDL-1 CTLA-4 Dabrafenib Encorafenib Binimetinib Cobimetinib Trametinib Vemurafenib Ipilimumab Nivolumab Pembrolizumab 

Notes

Compliance with Ethical Standards

Conflict of Interest

Alexandra M. Haugh declares that she has no conflict of interest.

Douglas B. Johnson has received research funding from Bristol-Myers Squibb and Incyte Corporation; has served on advisory boards for Array BioPharma, Bristol-Myers Squibb, Incyte Corporation, Merck, and Novartis; and has received travel support from Genentech.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Johnson DB, Smalley KS, Sosman JA. Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin Cancer Res. 2014;20(16):4186–92.  https://doi.org/10.1158/1078-0432.Ccr-13-3270.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.  https://doi.org/10.1038/nature00766.CrossRefPubMedGoogle Scholar
  3. 3.
    Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 2004;64(7):2338–42.CrossRefGoogle Scholar
  4. 4.
    Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.  https://doi.org/10.1056/NEJMoa1002011.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.  https://doi.org/10.1056/NEJMoa1103782.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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 randomized BRIM-3 study. Ann Oncol. 2017;28(10):2581–7.  https://doi.org/10.1093/annonc/mdx339.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, 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;15(3):323–32.  https://doi.org/10.1016/s1470-2045(14)70012-9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.  https://doi.org/10.1016/s0140-6736(12)60868-x.CrossRefPubMedGoogle Scholar
  9. 9.
    Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31(15_suppl):9013.  https://doi.org/10.1200/jco.2013.31.15_suppl.9013.CrossRefGoogle Scholar
  10. 10.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.  https://doi.org/10.1056/NEJMoa1203421.CrossRefPubMedGoogle Scholar
  11. 11.
    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.  https://doi.org/10.1016/j.ejca.2018.12.015.CrossRefPubMedGoogle Scholar
  12. 12.
    Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.  https://doi.org/10.1016/s0140-6736(15)60898-4.CrossRefPubMedGoogle Scholar
  13. 13.
    Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.  https://doi.org/10.1056/NEJMoa1412690.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019.  https://doi.org/10.1056/NEJMoa1904059 Five-year follow-up of the COMBI-v and COMBI-d trials showed a PFS of 19% and OS of 34% at 5 years, suggesting the possibility of long-term benefit or even cure with BRAF/MEK inhibitors in some patients. Outcomes were particularly promising in those with favorable disease at baseline as well as those who experienced complete response to treatment, which was associated with an OS of 71% at 5 years.CrossRefGoogle Scholar
  15. 15.
    Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.  https://doi.org/10.1056/NEJMoa1408868.CrossRefPubMedGoogle Scholar
  16. 16.
    Ascierto PA, McArthur GA, Dreno B, Atkinson V, Liszkay G, Di Giacomo AM, 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;17(9):1248–60.  https://doi.org/10.1016/s1470-2045(16)30122-x.CrossRefPubMedGoogle Scholar
  17. 17.
    •• 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;19(5):603–15.  https://doi.org/10.1016/s1470-2045(18)30142-6 Findings from the phase III COLUMBUS trial, which showed improved PFS with encorafenib/binimetinib compared with vemurafenib monotherapy. Although suggestive of benefit when compared with encorafenib monotherapy, the difference in PFS did not reach statistical significance, likely due to the robust responses seen with encorafenib in this trial.CrossRefPubMedGoogle Scholar
  18. 18.
    •• Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315–27.  https://doi.org/10.1016/s1470-2045(18)30497-2 Overall survival data from the COLUMBUS trial also showed improved OS with encorafenib/binimetinib compared with vemurafenib but failed to show a statistically significant difference when compared with encorafenib monotherapy.CrossRefPubMedGoogle Scholar
  19. 19.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.  https://doi.org/10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.  https://doi.org/10.1056/NEJMoa1412082.CrossRefPubMedGoogle Scholar
  21. 21.
    Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2019;5(2):187–94.  https://doi.org/10.1001/jamaoncol.2018.4514.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.  https://doi.org/10.1056/NEJMoa1503093.CrossRefPubMedGoogle Scholar
  23. 23.
    Robert C, Ribas A, Schachter J, Arance A, Grob JJ, 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.  https://doi.org/10.1016/s1470-2045(19)30388-2.CrossRefGoogle Scholar
  24. 24.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.  https://doi.org/10.1056/NEJMoa1504030.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, 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(11):1480–92.  https://doi.org/10.1016/s1470-2045(18)30700-9.CrossRefPubMedGoogle Scholar
  26. 26.
    Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J, et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF Wild-Type advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol. 2015;1(4):433–40.  https://doi.org/10.1001/jamaoncol.2015.1184.CrossRefPubMedGoogle Scholar
  27. 27.
    Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, et al. Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: association with overall survival? PLoS One. 2015;10(10):e0139438.  https://doi.org/10.1371/journal.pone.0139438.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018;30(2):125–33.  https://doi.org/10.1097/cco.0000000000000426.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, 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(2):555–67.  https://doi.org/10.1158/1078-0432.Ccr-11-1491.CrossRefPubMedGoogle Scholar
  30. 30.
    Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, et al. Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer. 2013;119(4):799–805.  https://doi.org/10.1002/cncr.27790.CrossRefPubMedGoogle Scholar
  31. 31.
    Rosen LS, LoRusso P, Ma WW, Goldman JW, Weise A, Colevas AD, et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Investig New Drugs. 2016;34(5):604–13.  https://doi.org/10.1007/s10637-016-0374-3.CrossRefGoogle Scholar
  32. 32.
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.  https://doi.org/10.1056/NEJMoa1210093.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, et al. Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014;32(33):3697–704.  https://doi.org/10.1200/jco.2014.57.3535.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15.  https://doi.org/10.1056/NEJMoa1105358.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162(6):1271–85.  https://doi.org/10.1016/j.cell.2015.07.061.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508(7494):118–22.  https://doi.org/10.1038/nature13121.CrossRefPubMedGoogle Scholar
  37. 37.
    Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013;494(7436):251–5.  https://doi.org/10.1038/nature11814.CrossRefPubMedGoogle Scholar
  38. 38.
    Moriceau G, Hugo W, Hong A, Shi H, Kong X, Yu CC, 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.  https://doi.org/10.1016/j.ccell.2014.11.018.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF(V600)-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017;18(4):464–72.  https://doi.org/10.1016/s1470-2045(17)30171-7.CrossRefPubMedGoogle Scholar
  40. 40.
    Valpione S, Carlino MS, Mangana J, Mooradian MJ, McArthur G, Schadendorf D, et al. Rechallenge with BRAF-directed treatment in metastatic melanoma: a multi-institutional retrospective study. Eur J Cancer. 2018;91:116–24.  https://doi.org/10.1016/j.ejca.2017.12.007.CrossRefPubMedGoogle Scholar
  41. 41.
    • Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, et al. First-in-class ERK1/2 inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discov. 2018;8(2):184–95.  https://doi.org/10.1158/2159-8290.Cd-17-1119 Findings from the first in-human dose escalation study of an ERK1/2 inhibitor in patients with advanced solid tumors.CrossRefPubMedGoogle Scholar
  42. 42.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.  https://doi.org/10.1038/nrc3239.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–8.  https://doi.org/10.4049/jimmunol.1490019.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. 2008;8(3):315–23.  https://doi.org/10.1517/14712598.8.3.315.CrossRefPubMedGoogle Scholar
  45. 45.
    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62.  https://doi.org/10.1016/s0140-6736(17)31601-x.CrossRefPubMedGoogle Scholar
  46. 46.
    • Pires da Silva I, Wang KYX, Wilmott JS, Holst J, Carlino MS, Park JJ, et al. Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma. Clin Cancer Res. 2019;25(4):1272–9.  https://doi.org/10.1158/1078-0432.Ccr-18-1680 A prospective study of patients enrolled in BRAF/MEK inhibitor trials, which found shorter PFS in patients with BRAF V600K-mutated melanoma compared with V600E. Analysis of a separate cohort found greater benefit from anti-PD1 (in terms of response rate, PFS, and OS) in V600K melanoma compared with V600E. Differences in response are possibly secondary to molecular features unique to each genotype and may inform treatment decisions.CrossRefPubMedGoogle Scholar
  47. 47.
    • Lebbe C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019;37(11):867–75.  https://doi.org/10.1200/jco.18.01998 Results from the CheckMate-511 trial, which found lower rates of grade 3-5 AEs in patients with melanoma treated with nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) compared with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg). Descriptive analysis also suggested no difference in efficacy.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Long GV, Robert C, Butler MO, Couture F, Carlino MS, O’Day S, et al. Standard-dose pembrolizumab (pembro) plus alternate-dose ipilimumab (ipi) in advanced melanoma: Initial analysis of KEYNOTE-029 cohort 1C. J Clin Oncol. 2019;37(15_suppl):9514.  https://doi.org/10.1200/JCO.2019.37.15_suppl.9514.CrossRefGoogle Scholar
  49. 49.
    Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120(11):1695–701.  https://doi.org/10.1002/cncr.28620.CrossRefPubMedGoogle Scholar
  50. 50.
    Ascierto PA, Simeone E, Giannarelli D, Grimaldi AM, Romano A, Mozzillo N. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med. 2012;10:107.  https://doi.org/10.1186/1479-5876-10-107.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Johnson DB, Pectasides E, Feld E, Ye F, Zhao S, Johnpulle R, et al. Sequencing treatment in BRAFV600 mutant melanoma: anti-PD-1 before and after BRAF inhibition. J Immunother. 2017;40(1):31–5.  https://doi.org/10.1097/cji.0000000000000148.CrossRefPubMedGoogle Scholar
  52. 52.
    •• Saab KR, Mooradian MJ, Wang DY, Chon J, Xia CY, Bialczak A, et al. Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy. Cancer. 2019;125(6):884–91.  https://doi.org/10.1002/cncr.31889 A retrospective analysis of a cohort of patients who received BRAF/MEK inhibitors after anti-PD1 found treatment-related AEs requiring dose modification in a majority of patients and hospitalization in a significant minority. These findings suggest that anti-PD1 exposure may impact the frequency of severity of toxicity from BRAF/MEK inhibitors, which may also be significant enough to affect outcomes with these agents.CrossRefPubMedGoogle Scholar
  53. 53.
    • Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2016;165(1):35–44.  https://doi.org/10.1016/j.cell.2016.02.065 Genomic and transcriptomic analyses of pre-treatment melanomas found a unique transcriptomic signature (termed IPRES) associated with a lack of response to anti-PD1. Further characterization of the associated biological processes may help guide understanding of the mechanisms involved with resistance to immunotherapy.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2017;168(3):542.  https://doi.org/10.1016/j.cell.2017.01.010.CrossRefPubMedGoogle Scholar
  55. 55.
    Yan Y, Wongchenko MJ, Robert C, Larkin J, Ascierto PA, Dreno B, et al. Genomic features of exceptional response in vemurafenib +/- cobimetinib-treated patients with BRAF (V600)-mutated metastatic melanoma. Clin Cancer Res. 2019;25(11):3239–46.  https://doi.org/10.1158/1078-0432.Ccr-18-0720.CrossRefPubMedGoogle Scholar
  56. 56.
    Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18(5):1386–94.  https://doi.org/10.1158/1078-0432.Ccr-11-2479.CrossRefPubMedGoogle Scholar
  57. 57.
    Schilling B, Paschen A. Immunological consequences of selective BRAF inhibitors in malignant melanoma: neutralization of myeloid-derived suppressor cells. Oncoimmunology. 2013;2(8):e25218.  https://doi.org/10.4161/onci.25218.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.  https://doi.org/10.1158/1078-0432.Ccr-12-1630.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44(3):609–21.  https://doi.org/10.1016/j.immuni.2016.01.024.CrossRefPubMedGoogle Scholar
  60. 60.
    Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015;7(279):279ra41.  https://doi.org/10.1126/scitranslmed.aaa4691.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Minor DR, Puzanov I, Callahan MK, Hug BA, Hoos A. Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res. 2015;28(5):611–2.  https://doi.org/10.1111/pcmr.12383.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.  https://doi.org/10.1056/NEJMc1302338.CrossRefPubMedGoogle Scholar
  63. 63.
    • Ribas A, Lawrence D, Atkinson V, Agarwal S, Miller WH Jr, Carlino MS, et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med. 2019;25(6):936–40.  https://doi.org/10.1038/s41591-019-0476-5 Findings from a recent phase I trial of patients with BRAF-mutated melanoma treated with a combination of BRAF/MEK inhibition (dabrafenib + trametinib) and anti-PD1 (pembrolizumab).CrossRefPubMedGoogle Scholar
  64. 64.
    • Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR, Hodi FS, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25(6):929–35.  https://doi.org/10.1038/s41591-019-0474-7 Findings from a recent phase I trial involving patients with BRAF-mutated melanoma treated with anti-PDL1 (atezolizumab) in combination with a BRAF inhibitor (vemurafenib) or with BRAF/MEK inhibition (vemurafenib + cobimetinib), the latter of which was extended into three expansion cohorts.CrossRefPubMedGoogle Scholar
  65. 65.
    • Ascierto PA, Ferrucci PF, Fisher R, Del Vecchio M, Atkinson V, Schmidt H, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019;25(6):941–6.  https://doi.org/10.1038/s41591-019-0448-9 Findings from a recent phase II trial in which patients with BRAF-mutated metastatic melanoma were randomized to dabrafenib + trametinib in combination with either pembrolizumab or placebo. While suggestive of a longer duration of response with all three agents, differences in PFS did not reach statistical significance.CrossRefPubMedGoogle Scholar
  66. 66.
    •• Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813–23.  https://doi.org/10.1056/NEJMoa1708539 Results from the phase III COMBI-AD trial, which found a statistically significant relapse-free survival benefit among patients with BRAF-mutated stage III melanoma treated with adjuvant dabrafenib + trametinib when compared with placebo.CrossRefPubMedGoogle Scholar
  67. 67.
    Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandala M et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018:Jco1801219.  https://doi.org/10.1200/jco.18.01219.CrossRefGoogle Scholar
  68. 68.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.  https://doi.org/10.1056/NEJMoa1611299.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–30.  https://doi.org/10.1016/s1470-2045(15)70122-1.CrossRefPubMedGoogle Scholar
  70. 70.
    Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.  https://doi.org/10.1056/NEJMoa1709030.CrossRefPubMedGoogle Scholar
  71. 71.
    Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801.  https://doi.org/10.1056/NEJMoa1802357.CrossRefPubMedGoogle Scholar
  72. 72.
    •• Long GV, RPM S, Lo S, Nieweg OE, Shannon KF, Gonzalez M, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019;20(7):961–71.  https://doi.org/10.1016/s1470-2045(19)30331-6 Findings from a single-arm phase 2 trial evaluating the use of BRAF/MEK inhibitors (dabrafenib + trametinib) in the neo-adjuvant setting among patients with BRAF-mutated stage III melanoma.CrossRefPubMedGoogle Scholar
  73. 73.
    Rozeman EA, Menzies AM, van Akkooi ACJ, Adhikari C, Bierman C, van de Wiel BA, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019;20(7):948–60.  https://doi.org/10.1016/s1470-2045(19)30151-2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineVanderbilt University Medical Center and Vanderbilt Ingram Cancer CenterNashvilleUSA
  2. 2.NashvilleUSA

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