SpringerLink
Log in

Therapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma

  • Review Article
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on develo** treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including develo** checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors.

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

Access this article

Log in via an institution

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ribas A, Wolchok JD. Combining cancer immunotherapy and targeted therapy. Curr Opin Immunol. 2013;25(2):291–6. https://doi.org/10.1016/j.coi.2013.02.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Allison JP, Krummel MF. The Yin and Yang of T cell costimulation. Science. 1995;270(5238):932–3. https://doi.org/10.1126/science.270.5238.932.

    Article  CAS  PubMed  Google Scholar 

  3. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8(5):765–72. https://doi.org/10.1093/intimm/8.5.765.

    Article  CAS  PubMed  Google Scholar 

  4. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34. https://doi.org/10.1084/jem.192.7.1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291(1):1–13. https://doi.org/10.1111/nyas.12180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hodi FS, O’Day SJ, McDermott DF, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64. https://doi.org/10.1016/s1470-2045(09)70334-1.

    Article  CAS  PubMed  Google Scholar 

  8. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. https://doi.org/10.1056/NEJMoa1305133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in Patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33(18):2004–12. https://doi.org/10.1200/jco.2014.58.3708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. https://doi.org/10.1056/NEJMoa1503093.

    Article  CAS  PubMed  Google Scholar 

  11. Larkin J, Minor D, D’Angelo S, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018;36(4):383–90. https://doi.org/10.1200/jco.2016.71.8023.

    Article  CAS  PubMed  Google Scholar 

  12. Larkin J, Chiarion-Sileni V, Gonzalez R, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56. https://doi.org/10.1056/NEJMoa1709684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24–34. https://doi.org/10.1056/NEJMoa2109970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54. https://doi.org/10.1038/nature00766.

    Article  CAS  PubMed  Google Scholar 

  16. Shain AH, Bastian BC. From melanocytes to melanomas. Nat Rev Cancer. 2016;16(6):345–58. https://doi.org/10.1038/nrc.2016.37.

    Article  CAS  PubMed  Google Scholar 

  17. Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239–71. https://doi.org/10.1146/annurev-pathol-012513-104658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014;14(7):455–67. https://doi.org/10.1038/nrc3760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Colombino M, Capone M, Lissia A, et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30(20):2522–9. https://doi.org/10.1200/jco.2011.41.2452.

    Article  PubMed  Google Scholar 

  20. Kiuru M, Busam KJ. The NF1 gene in tumor syndromes and melanoma. Lab Investig. 2017;97(2):146–57. https://doi.org/10.1038/labinvest.2016.142.

    Article  CAS  PubMed  Google Scholar 

  21. Rabbie R, Ferguson P, Molina-Aguilar C, Adams DJ, Robles-Espinoza CD. Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities. J Pathol. 2019;247(5):539–51. https://doi.org/10.1002/path.5213.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175–80. https://doi.org/10.1038/nature22071.

    Article  CAS  PubMed  Google Scholar 

  23. Newell F, Johansson PA, Wilmott JS, et al. Comparative genomics provides etiologic and biological insight into melanoma subtypes. Cancer Discov. 2022;12(12):2856–79. https://doi.org/10.1158/2159-8290.Cd-22-0603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yeh I, Jorgenson E, Shen L, et al. Targeted genomic profiling of acral melanoma. J Natl Cancer Inst. 2019;111(10):1068–77. https://doi.org/10.1093/jnci/djz005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pham DDM, Guhan S, Tsao H. KIT and melanoma: biological insights and clinical implications. Yonsei Med J. 2020;61(7):562–71. https://doi.org/10.3349/ymj.2020.61.7.562.

    Article  CAS  PubMed  Google Scholar 

  26. Yeh I, Bastian BC. Melanoma pathology: new approaches and classification. Br J Dermatol. 2021;185(2):282–93. https://doi.org/10.1111/bjd.20427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moran JMT, Le LP, Nardi V, et al. Identification of fusions with potential clinical significance in melanoma. Mod Pathol. 2022;35(12):1837–47. https://doi.org/10.1038/s41379-022-01138-z.

    Article  CAS  PubMed  Google Scholar 

  28. Yen I, Shanahan F, Lee J, et al. ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. Nature. 2021;594(7863):418–23. https://doi.org/10.1038/s41586-021-03515-1.

    Article  CAS  PubMed  Google Scholar 

  29. de Braud F, Dooms C, Heist RS, et al. Initial evidence for the efficacy of naporafenib in combination with trametinib in NRAS-mutant melanoma: results from the expansion arm of a phase Ib, open-label study. J Clin Oncol. 2023;41(14):2651–60. https://doi.org/10.1200/jco.22.02018.

    Article  PubMed  Google Scholar 

  30. Lebbe C. LBA40 Phase II study of multiple LXH254 drug combinations in patients (pts) with unresectable/metastatic, BRAF V600- or NRAS-mutant melanoma. Ann Oncol. 2022;33(7):S1407.

    Article  Google Scholar 

  31. Sullivan RJ, Infante JR, Janku F, 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.

    Article  CAS  PubMed  Google Scholar 

  32. Tarin M, Némati F, Decaudin D, et al. FAK inhibitor-based combinations with MEK or PKC inhibitors trigger synergistic antitumor effects in uveal melanoma. Cancers. 2023. https://doi.org/10.3390/cancers15082280.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 2016;45:129–38. https://doi.org/10.1016/j.ctrv.2016.03.002.

    Article  CAS  PubMed  Google Scholar 

  34. Steeb T, Wessely A, Petzold A, et al. c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis. Eur J Cancer. 2021;157:348–57. https://doi.org/10.1016/j.ejca.2021.08.015.

    Article  CAS  PubMed  Google Scholar 

  35. Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99(5):734–40. https://doi.org/10.1038/sj.bjc.6604482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arance A, de la Cruz-Merino L, Petrella TM, et al. Phase II LEAP-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination. J Clin Oncol. 2023;41(1):75–85. https://doi.org/10.1200/jco.22.00221.

    Article  CAS  PubMed  Google Scholar 

  37. Algazi AP, Esteve-Puig R, Nosrati A, et al. Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. Pigment Cell Melanoma Res. 2018;31(1):110–4. https://doi.org/10.1111/pcmr.12644.

    Article  CAS  PubMed  Google Scholar 

  38. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–50. https://doi.org/10.1038/s41591-018-0014-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Iijima N, Iwasaki A. Tissue instruction for migration and retention of TRM cells. Trends Immunol. 2015;36(9):556–64. https://doi.org/10.1016/j.it.2015.07.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Broz ML, Binnewies M, Boldajipour B, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26(5):638–52. https://doi.org/10.1016/j.ccell.2014.09.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65. https://doi.org/10.1084/jem.182.2.459.

    Article  CAS  PubMed  Google Scholar 

  42. Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26(36):5950–6. https://doi.org/10.1200/jco.2008.16.1927.

    Article  CAS  PubMed  Google Scholar 

  43. Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol. 2006;18(2):206–13. https://doi.org/10.1016/j.coi.2006.01.011.

    Article  CAS  PubMed  Google Scholar 

  44. Olson DJ, Eroglu Z, Brockstein B, et al. Pembrolizumab plus ipilimumab following anti-PD-1/L1 failure in melanoma. J Clin Oncol. 2021;39(24):2647–55. https://doi.org/10.1200/jco.21.00079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Graydon CG, Mohideen S, Fowke KR. LAG3’s enigmatic mechanism of action. Front Immunol. 2020;11: 615317. https://doi.org/10.3389/fimmu.2020.615317.

    Article  CAS  PubMed  Google Scholar 

  46. Ascierto PA, Lipson EJ, Dummer R, et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J Clin Oncol. 2023;41(15):2724–35. https://doi.org/10.1200/jco.22.02072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Melero I, Shuford WW, Newby SA, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3(6):682–5. https://doi.org/10.1038/nm0697-682.

    Article  CAS  PubMed  Google Scholar 

  48. Gauttier V, Judor JP, Le Guen V, Cany J, Ferry N, Conchon S. Agonistic anti-CD137 antibody treatment leads to antitumor response in mice with liver cancer. Int J Cancer. 2014;135(12):2857–67. https://doi.org/10.1002/ijc.28943.

    Article  CAS  PubMed  Google Scholar 

  49. Shuford WW, Klussman K, Tritchler DD, et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med. 1997;186(1):47–55. https://doi.org/10.1084/jem.186.1.47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Menk AV, Schar** NE, Rivadeneira DB, et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018;215(4):1091–100. https://doi.org/10.1084/jem.20171068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380–90. https://doi.org/10.1016/j.immuni.2016.01.021.

    Article  CAS  PubMed  Google Scholar 

  52. Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017;23(8):1929–36. https://doi.org/10.1158/1078-0432.Ccr-16-1272.

    Article  CAS  PubMed  Google Scholar 

  53. Segal NH, He AR, Doi T, et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res. 2018;24(8):1816–23. https://doi.org/10.1158/1078-0432.Ccr-17-1922.

    Article  CAS  PubMed  Google Scholar 

  54. Chen S, Lee LF, Fisher TS, et al. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol Res. 2015;3(2):149–60. https://doi.org/10.1158/2326-6066.Cir-14-0118.

    Article  CAS  PubMed  Google Scholar 

  55. Shindo Y, Yoshimura K, Kuramasu A, et al. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res. 2015;35(1):129–36.

    CAS  PubMed  Google Scholar 

  56. Vonderheide RH. CD40 agonist antibodies in cancer immunotherapy. Annu Rev Med. 2020;71:47–58. https://doi.org/10.1146/annurev-med-062518-045435.

    Article  CAS  PubMed  Google Scholar 

  57. Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173–85. https://doi.org/10.1038/s41577-019-0224-6.

    Article  CAS  PubMed  Google Scholar 

  58. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94. https://doi.org/10.1084/jem.20100643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417–21. https://doi.org/10.1038/nature19330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276(1):97–111. https://doi.org/10.1111/imr.12520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hamid O, Mehmi I, Dudzisz-Sledz M, Hoyle PE, Wei W, Powderly JD. A phase 1/2 study of retifanlimab (INCMGA00012, anti-PD-1), INCAGN02385 (anti-LAG-3), and INCAGN02390 (anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors. J Clin Oncol. 2023;41(16 suppl):2599–2599.

    Article  Google Scholar 

  62. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923–37. https://doi.org/10.1016/j.ccell.2014.10.018.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang Q, Bi J, Zheng X, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723–32. https://doi.org/10.1038/s41590-018-0132-0.

    Article  CAS  PubMed  Google Scholar 

  64. Wang Y, Du J, Gao Z, et al. Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. Br J Cancer. 2023;128(7):1196–207. https://doi.org/10.1038/s41416-022-02084-y.

    Article  CAS  PubMed  Google Scholar 

  65. Demerlé C, Gorvel L, Olive D. BTLA-HVEM couple in health and diseases: insights for immunotherapy in lung cancer. Front Oncol. 2021;11: 682007. https://doi.org/10.3389/fonc.2021.682007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dong P, **ong Y, Yue J, Hanley SJB, Watari H. B7H3 as a promoter of metastasis and promising therapeutic target. Front Oncol. 2018;8:264. https://doi.org/10.3389/fonc.2018.00264.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood. 2018;131(1):39–48. https://doi.org/10.1182/blood-2017-07-741025.

    Article  CAS  PubMed  Google Scholar 

  68. Amatore F, Gorvel L, Olive D. Role of inducible co-stimulator (ICOS) in cancer immunotherapy. Expert Opin Biol Ther. 2020;20(2):141–50. https://doi.org/10.1080/14712598.2020.1693540.

    Article  CAS  PubMed  Google Scholar 

  69. Zappasodi R, Sirard C, Li Y, et al. Rational design of anti-GITR-based combination immunotherapy. Nat Med. 2019;25(5):759–66. https://doi.org/10.1038/s41591-019-0420-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gu SS, Zhang W, Wang X, et al. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade. Cancer Discov. 2021;11(6):1524–41. https://doi.org/10.1158/2159-8290.Cd-20-0812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen X, Lu Q, Zhou H, et al. A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell. 2023;186(18):3903-3920.e21. https://doi.org/10.1016/j.cell.2023.07.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bentebibel SE, Diab A. Cytokines in the treatment of melanoma. Curr Oncol Rep. 2021;23(7):83. https://doi.org/10.1007/s11912-021-01064-4.

    Article  CAS  PubMed  Google Scholar 

  73. Diab A, Gogas H, Sandhu S, et al. Bempegaldesleukin plus nivolumab in untreated advanced melanoma: the open-label, phase III PIVOT IO 001 trial results. J Clin Oncol. 2023. https://doi.org/10.1200/jco.23.00172.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Greaney SK, Algazi AP, Tsai KK, et al. Intratumoral plasmid IL12 electroporation therapy in patients with advanced melanoma induces systemic and intratumoral T-cell responses. Cancer Immunol Res. 2020;8(2):246–54. https://doi.org/10.1158/2326-6066.Cir-19-0359.

    Article  CAS  PubMed  Google Scholar 

  75. Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2000;18(8):1614–21. https://doi.org/10.1200/jco.2000.18.8.1614.

    Article  CAS  PubMed  Google Scholar 

  76. Lawson DH, Lee S, Zhao F, et al. Randomized, placebo-controlled, phase III trial of yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) versus peptide vaccination versus GM-CSF plus peptide vaccination versus placebo in patients with no evidence of disease after complete surgical resection of locally advanced and/or stage IV melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). J Clin Oncol. 2015;33(34):4066–76. https://doi.org/10.1200/jco.2015.62.0500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Andtbacka RHI, Collichio F, Harrington KJ, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019;7(1):145. https://doi.org/10.1186/s40425-019-0623-z.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-1119.e10. https://doi.org/10.1016/j.cell.2017.08.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Andtbacka RHI, Curti B, Daniels GA, et al. Clinical responses of oncolytic coxsackievirus A21 (V937) in patients with unresectable melanoma. J Clin Oncol. 2021;39(34):3829–38. https://doi.org/10.1200/jco.20.03246.

    Article  CAS  PubMed  Google Scholar 

  80. Chmielowski B, Milhem MM, Sacco JJ, et al. Initial efficacy and safety of RP1 + nivolumab in patients with anti-PD-1-failed melanoma from the ongoing phase 1/2 IGNYTE study. J Clin Oncol. 2023;41(16 suppl):9509–9509. https://doi.org/10.1200/JCO.2023.41.16_suppl.9509.

    Article  Google Scholar 

  81. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7. https://doi.org/10.1158/1078-0432.Ccr-11-0116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med. 2012;10:169. https://doi.org/10.1186/1479-5876-10-169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656–66. https://doi.org/10.1200/jco.21.00612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2022-005755.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California San Francisco, 550 16th Street, 6809, San Francisco, CA, 94158, USA

    Alexandra Haugh & Adil I. Daud

  2. Department of Dermatology, University of California San Francisco, San Francisco, CA, USA

    Adil I. Daud

  3. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    Alexandra Haugh & Adil I. Daud

Authors
  1. Alexandra Haugh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adil I. Daud
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adil I. Daud.

Ethics declarations

Funding

Funding from the Cook/Juelsgaard and Amoroso Foundation (AD).

Conflict of Interest

AH declares no conflicts of interest. AD: stock and other ownership interests—Neuvogen, Trex bio. Honoraria—EMD Serono, Inovio Pharmaceuticals. Consulting or advisory role—Genoptix, GlaxoSmithKline, Oncosec, Caris, Eisai, GLG. Speakers' bureau—no relationships to disclose. Research Funding—Bristol-Myers Squibb, Checkmate Pharmaceuticals, Genentech/Roche (Inst), GlaxoSmithKline (Inst), Incyte, Merck/Schering Plough (Inst), Novartis, Oncosec (Inst), Pfizer (Inst).

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

No datasets were generated or analyzed during the current study.

Code Availability

No code was generated.

Author Contributions

Planning and conception AH, AD; writing AH, AD; final editing AH, AD.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haugh, A., Daud, A.I. Therapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma. Am J Clin Dermatol 25, 407–419 (2024). https://doi.org/10.1007/s40257-023-00841-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40257-023-00841-0

Search

Navigation