Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations
Abstract
1. Introduction
2. Historical Approaches to Melanoma Treatment
2.1. Chemotherapeutic Agents
2.2. Treatments Involving the Use of IL-2 or IFN
3. Current Advances in Melanoma Therapy
3.1. Molecular Classification of Melanoma (The Cancer Genome Atlas Project)
3.2. Molecularly Targeted Therapies
3.2.1. BRAF V600 Mutation
3.2.2. KIT Mutation
3.2.3. NRAS Mutations
3.2.4. ROS1 Fusions and Mutations
3.2.5. NTRK Fusions and Mutations
3.3. Immunotherapy
3.4. Talimogene Laherparepvec (T-VEC)
4. Specific Considerations for Melanoma Treatment in Asian Populations
4.1. Immune Checkpoint Inhibitor Therapy in Asian Populations
4.2. Monotherapy vs. Combination Therapy for Asian Melanoma Patients
4.3. Therapeutic Approaches for BRAF-Positive Cases in Asian Populations
5. Future Perspectives on Melanoma Management
Phase | Trial Name | Intervention vs. Control | Patient Population | Reference |
---|---|---|---|---|
II/III | RELATIVITY-047 | Nivolumab + Relatlimab vs. Nivolumab | Treatment-naive advanced melanoma | [105,145] |
II | RadVax | Nivolumab + Ipilimumab + HFRT vs. Nivolumab + Ipilimumab alone | Unresectable stage IV melanoma | [146] |
I | NCT02858869 | Pembrolizumab + SRS (single arm) | Melanoma or NSCLC with untreated brain metastases | [147] |
I | NCT02716948 | Nivolumab + SRS (single arm) | Melanoma or NSCLC with untreated brain and/or spine metastases | [148] |
II | NIRVANA | Nivolumab + multisite HFRT (single arm) | Metastatic melanoma; no prior systemic therapy | [150] |
II | CHEERS | Standard-of-care ICI therapy combined with SBRT vs. standard-of-care ICI therapy | Advanced or metastatic melanoma | [152,153] |
II | NCT02617849 | Pembrolizumab in combination with carboplatin/paclitaxel (single arm) | Metastatic malignant melanoma | [153] |
I/II | IGNYTE-3 | Nivolumab + RP1 oncolytic HSV-1 or Rp1 alone | Advanced solid tumor (including melanoma) refractory to anti-PD-1 therapy | [156] |
II | KEYNOTE-D36 | Pembrolizumab + EVX-01 vs. historical control (no concurrent control arm) | Treatment-naive advanced melanoma | [158] |
III | TILVANCE-301 | Pembrolizumab + Lifileucel TIL vs. Pembrolizumab alone | Treatment-naive advanced melanoma | [159] |
II | ABC-X | Nivolumab + Ipilimumab + SRS vs. Nivolumab + Ipilimumab alone | Melanoma brain metastases; treatment-naïve | [160] |
III | MASTERKEY-265 | Pembrolizumab + T-VEC vs. Pembrolizumab + placebo | Unresectable stage IIIB–IVM1c melanoma, anti-PD-1 naïve, injectable lesions required | [161] |
II | KEYNOTE-942 | mRNA-4157 (V940) + Pembrolizumab vs. Pembrolizumab alone | Resected high-risk cutaneous melanoma | [162] |
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
DTIC | Dacarbazine |
DAV | Dacarbazine, ACNU, Vincristine |
TMZ | Temozolomide |
IFN-α | Interferon-alpha |
IFN-β | Interferon-beta |
nab-PTX | nab-Paclitaxel |
CBDCA | Carboplatin |
PTX | Paclitaxel |
V + C | Vemurafenib + Cobimetinib |
BRAF + MEK | BRAF inhibitor + MEK inhibitor |
E + B | Encorafenib + Binimetinib |
D + T | Dabrafenib + Trametinib |
N + I | Nivolumab + Ipilimumab |
RAS | Rat sarcoma |
NRAS | Neuroblastmoa RAS |
HRAS | Harvey RAS |
KRAS | Kristen RAS |
NF1 | Neurofibromin 1 |
ERK | Extracellular signal-regulated kinase |
RAF | Rapidly accelerated fibrosarcoma |
MAPK | Mitogen activated protein kinase |
MAPKK | Mitogen activated protein kinase kinase (MEK) |
FAK | Focal adhesion kinase |
PI3K | Phosphatidyl inositol 3 kinase |
CDK | Cyclin dependent kinase |
References
- Kushnir, I.; Merimsky, O. The evolution in melanoma treatment as a reflection of precision-oriented medicine. Oncol. Lett. 2013, 5, 424–426. [Google Scholar] [CrossRef] [PubMed]
- Baron, J.M.; Heise, R.; Merk, H.F.; Abuzahra, F. Current and future directions in the treatment of metastatic malignant melanoma. Curr. Med. Chem. Anti-Cancer Agents 2003, 3, 393–398. [Google Scholar] [CrossRef] [PubMed]
- Chapman, P.B.; Hauschild, A.; Robert, C.; Haanen, J.B.; Ascierto, P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011, 364, 2507–2516. [Google Scholar] [CrossRef] [PubMed]
- Flaherty, K.T.; Infante, J.R.; Daud, A.; Gonzalez, R.; Kefford, R.F.; Sosman, J.; Hamid, O.; Schuchter, L.; Cebon, J.; Ibrahim, N.; et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 2012, 367, 1694–1703. [Google Scholar] [CrossRef]
- Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef]
- Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr.; Lao, C.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, 375–384. [Google Scholar] [CrossRef]
- Hamid, O.; Robert, C.; Daud, A.; Hodi, F.S.; Hwu, W.J.; Kefford, R.; Wolchok, J.D.; Hersey, P.; Joseph, R.; Weber, J.S.; et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2019, 30, 582–588. [Google Scholar] [CrossRef]
- Garbe, C.; Eigentler, T.K.; Keilholz, U.; Hauschild, A.; Kirkwood, J.M. Systematic review of medical treatment in melanoma: Current status and future prospects. Oncologist 2011, 16, 5–24. [Google Scholar] [CrossRef]
- Avril, M.; Aamdal, S.; Grob, J.; Hauschild, A.; Mohr, P.; Bonerandi, J.; Weichenthal, M.; Neuber, K.; Bieber, T.; Gilde, K.; et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: A phase III study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004, 22, 1118–1125. [Google Scholar] [CrossRef]
- Bedikian, A.Y.; Millward, M.; Pehamberger, H.; Conry, R.; Gore, M.; Trefzer, U.; Pavlick, A.C.; DeConti, R.; Hersh, E.M.; Hersey, P.; et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study Group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2006, 24, 4738–4745. [Google Scholar] [CrossRef]
- Schadendorf, D.; Ugurel, S.; Schuler-Thurner, B.; Nestle, F.O.; Enk, A.; Bröcker, E.-B.; Grabbe, S.; Rittgen, W.; Edler, L.; Sucker, A.; et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: A randomized phase III trial of the DC study group of the DeCOG. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2006, 17, 563–570. [Google Scholar] [CrossRef] [PubMed]
- Falkson, C.I.; Ibrahim, J.; Kirkwood, J.M.; Coates, A.S.; Atkins, M.B.; Blum, R.H. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1998, 16, 1743–1751. [Google Scholar]
- Kim, C.; Lee, C.W.; Kovacic, L.; Shah, A.; Klasa, R.; Savage, K.J. Long-term survival in patients with metastatic melanoma treated with DTIC or temozolomide. Oncologist 2010, 15, 765–771. [Google Scholar] [CrossRef] [PubMed]
- Kaufmann, R.; Spieth, K.; Leiter, U.; Mauch, C.; von den Driesch, P.; Vogt, T.; Linse, R.; Tilgen, W.; Schadendorf, D.; Becker, J.C.; et al. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: A randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005, 23, 9001–9007. [Google Scholar] [CrossRef]
- Gradishar, W.J. Albumin-bound paclitaxel: A next-generation taxane. Expert Opin. Pharmacother. 2006, 7, 1041–1053. [Google Scholar] [CrossRef]
- Desai, N.; Trieu, V.; Yao, Z.; Louie, L.; Ci, S.; Yang, A.; Tao, C.; De, T.; Beals, B.; Dykes, D.; et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2006, 12, 1317–1324. [Google Scholar] [CrossRef]
- Hersh, E.M.; Del Vecchio, M.; Brown, M.P.; Kefford, R.; Loquai, C.; Testori, A.; Bhatia, S.; Gutzmer, R.; Conry, R.; Haydon, A.; et al. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann. Oncol. 2015, 26, 2267–2274. [Google Scholar] [CrossRef]
- Flaherty, K.T.; Lee, S.J.; Zhao, F.; Schuchter, L.M.; Flaherty, L.; Kefford, R.; Atkins, M.B.; Leming, P.; Kirkwood, J.M. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2013, 31, 373–379. [Google Scholar] [CrossRef]
- Bajetta, E.; Del Vecchio, M.; Nova, P.; Fusi, A.; Daponte, A.; Sertoli, M.R.; Queirolo, P.; Taveggia, P.; Bernengo, M.G.; Legha, S.S.; et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2006, 17, 571–577. [Google Scholar] [CrossRef]
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous, Version 3.2024. Published 23 September 2024. Available online: https://www.nccn.org (accessed on 18 December 2024).
- Fujimura, T.; Kambayashi, Y.; Ohuchi, K.; Muto, Y.; Aiba, S. Treatment of Advanced Melanoma: Past, Present and Future. Life Basel Switz. 2020, 10, 208. [Google Scholar] [CrossRef]
- Du Bois, J.S.; Trehu, E.G.; Mier, J.W.; Shapiro, L.; Epstein, M.; Klempner, M.; Dinarello, C.; Kappler, K.; Ronayne, L.; Rand, W.; et al. Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1997, 15, 1052–1062. [Google Scholar] [CrossRef] [PubMed]
- Smith, F.O.; Downey, S.G.; Klapper, J.A.; Yang, J.C.; Sherry, R.M.; Royal, R.E.; Kammula, U.S.; Hughes, M.S.; Restifo, N.P.; Levy, C.L.; et al. Treatment of Metastatic Melanoma Using Interleukin-2 Alone or in Conjunction with Vaccines. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2008, 14, 5610–5618. [Google Scholar] [CrossRef] [PubMed]
- Curti, B.; Crittenden, M.; Seung, S.K.; Fountain, C.B.; Payne, R.; Chang, S.; Fleser, J.; Phillips, K.; Malkasian, I.; Dobrunick, L.B.; et al. Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma. J. Immunother. Cancer 2020, 8, e000773. [Google Scholar] [CrossRef] [PubMed]
- Hauschild, A.; Garbe, C.; Stolz, W.; Ellwanger, U.; Seiter, S.; Dummer, R.; Ugurel, S.; Sebastian, G.; Nashan, D.; Linse, R.; et al. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: A randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br. J. Cancer 2001, 84, 1036–1042. [Google Scholar] [CrossRef]
- Young, A.M.; Marsden, J.; Goodman, A.; Burton, A.; Dunn, J.A. Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma. Clin. Oncol. R. Coll. Radiol. 2001, 13, 458–465. [Google Scholar]
- Egberts, F.; Gutzmer, R.; Ugurel, S.; Becker, J.C.; Trefzer, U.; Degen, A.; Schenck, F.; Frey, L.; Wilhelm, T.; Hassel, J.C.; et al. Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: A multicenter phase II DeCOG trial. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2011, 22, 1667–1674. [Google Scholar] [CrossRef]
- Takahara, Y.; Kan, T.; Teshima, Y.; Matsubara, D.; Takahagi, S.; Tanaka, A.; Hide, M. Malignant melanoma with in-transit metastases refractory to programmed cell death-1 inhibitor successfully treated with local interferon-β injections: A case report. Mol. Clin. Oncol. 2021, 15, 212. [Google Scholar] [CrossRef]
- Aoyagi, S.; Hata, H.; Homma, E.; Shimizu, H. Sequential local injection of low-dose interferon-beta for maintenance therapy in stage II and III melanoma: A single-institution matched case-control study. Oncology 2012, 82, 139–146. [Google Scholar] [CrossRef]
- Fujimura, T.; Okuyama, R.; Ohtani, T.; Ito, Y.; Haga, T.; Hashimoto, A.; Aiba, S. Perilesional treatment of metastatic melanoma with interferon-beta. Clin. Exp. Dermatol. 2009, 34, 793–799. [Google Scholar] [CrossRef]
- Kakizaki, A.; Fujimura, T.; Furudate, S.; Kambayashi, Y.; Yamauchi, T.; Yagita, H.; Aiba, S. Immunomodulatory effect of peritumorally administered interferon-beta on melanoma through tumor-associated macrophages. Oncoimmunology 2015, 4, e1047584. [Google Scholar] [CrossRef]
- Fujimura, T.; Hidaka, T.; Kambayashi, Y.; Furudate, S.; Kakizaki, A.; Tono, H.; Tsukada, A.; Haga, T.; Hashimoto, A.; Morimoto, R.; et al. Phase I study of nivolumab combined with IFN-β for patients with advanced melanoma. Oncotarget 2017, 8, 71181–71187. [Google Scholar] [CrossRef] [PubMed]
- The Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161, 1681–1696. [Google Scholar] [CrossRef] [PubMed]
- Smalley, K.S.M. Understanding melanoma signaling networks as the basis for molecular targeted therapy. J. Investig. Dermatol. 2010, 130, 28–37. [Google Scholar] [CrossRef] [PubMed]
- Hawryluk, E.B.; Tsao, H. Melanoma: Clinical features and genomic insights. Cold Spring Harb Perspect Med. 2014, 4, a015388. [Google Scholar] [CrossRef]
- Robert, C.; Grob, J.J.; Stroyakovskiy, D.; Karaszewska, B.; Hauschild, A.; Levchenko, E.; Chiarion Sileni, V.; Schachter, J.; Garbe, C.; Bondarenko, I.; et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N. Engl. J. Med. 2019, 381, 626–636. [Google Scholar] [CrossRef]
- Dummer, R.; Ascierto, P.A.; Gogas, H.J.; Arance, A.; Mandala, M.; Liszkay, G.; Garbe, C.; Schadendorf, D.; Krajsova, I.; Gutzmer, R.; 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, 1315–1327. [Google Scholar] [CrossRef]
- Kroeze, S.G.; Fritz, C.; Hoyer, M.; Lo, S.S.; Ricardi, U.; Sahgal, A.; Stahel, R.; Stupp, R.; Guckenberger, M. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review. Cancer Treat. Rev. 2017, 53, 25–37. [Google Scholar] [CrossRef]
- Ascierto, P.A.; McArthur, G.A.; Dréno, B.; Atkinson, V.; Liszkay, G.; Di Giacomo, A.M.; Mandalà, M.; Demidov, L.; Stroyakovskiy, D.; Thomas, L.; 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, 1248–1260. [Google Scholar] [CrossRef]
- Eroglu, Z.; Ribas, A. Combination therapy with BRAF and MEK inhibitors for melanoma: Latest evidence and place in therapy. Ther. Adv. Med. Oncol. 2016, 8, 48–56. [Google Scholar] [CrossRef]
- Nazarian, R.; Shi, H.; Wang, Q.; Kong, X.; Koya, R.C.; Lee, H.; Chen, Z.; Lee, M.-K.; Attar, N.; Sazegar, H.; et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010, 468, 973–977. [Google Scholar] [CrossRef]
- Larkin, J.; Ascierto, P.A.; Dréno, B.; Atkinson, V.; Liszkay, G.; Maio, M.; Mandalà, M.; Demidov, L.; Stroyakovskiy, D.; Thomas, L.; et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 2014, 371, 1867–1876. [Google Scholar] [CrossRef] [PubMed]
- Long, G.V.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; de Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; Grob, J.J.; et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014, 371, 1877–1888. [Google Scholar] [CrossRef] [PubMed]
- da Silva, I.P.; Wang, K.Y.; Wilmott, J.S.; Holst, J.; Carlino, M.S.; Park, J.J.; Quek, C.; Wongchenko, M.; Yan, Y.; Mann, G.; et al. Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 1272–1279. [Google Scholar] [CrossRef] [PubMed]
- Zengarini, C.; Mussi, M.; Veronesi, G.; Alessandrini, A.; Lambertini, M.; Dika, E. BRAF V600K vs. BRAF V600E: A comparison of clinical and dermoscopic characteristics and response to immunotherapies and targeted therapies. Clin. Exp. Dermatol. 2022, 47, 1131–1136. [Google Scholar] [CrossRef]
- Goto, K.; Yoshikawa, S.; Takai, T.; Tachibana, K.; Honma, K.; Isei, T.; Kukita, Y.; Oishi, T. Clinicopathologic and genetic characterization of invasive melanoma with BRAF V600K mutation: A study of 16 cases. J. Cutan. Pathol. 2023, 50, 739–747. [Google Scholar] [CrossRef]
- Patel, M.; Eckburg, A.; Gantiwala, S.; Hart, Z.; Dein, J.; Lam, K.; Puri, N. Resistance to Molecularly Targeted Therapies in Melanoma. Cancers 2021, 13, 1115. [Google Scholar] [CrossRef]
- Welsh, S.J.; Rizos, H.; Scolyer, R.A.; Long, G.V. Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next? Eur. J. Cancer Oxf. Engl. 1990 2016, 62, 76–85. [Google Scholar] [CrossRef]
- Sullivan, R.J.; Flaherty, K.T. Resistance to BRAF-targeted therapy in melanoma. Eur. J. Cancer 2013, 49, 1297–1304. [Google Scholar] [CrossRef]
- Haist, M.; Stege, H.; Kuske, M.; Bauer, J.; Klumpp, A.; Grabbe, S.; Bros, M. Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better? Cancer Metastasis Rev. 2023, 42, 481–505. [Google Scholar] [CrossRef]
- Ribas, A.; Lawrence, D.; Atkinson, V.; Agarwal, S.; Miller, W.H.; Carlino, M.S.; Fisher, R.; Long, G.V.; Hodi, F.S.; Tsoi, J.; et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 2019, 25, 936–940. [Google Scholar] [CrossRef]
- Estrela, J.M.; Salvador, R.; Marchio, P.; Valles, S.L.; Lopez-Blanch, R.; Rivera, P.; Benlloch, M.; Alcacer, J.; Perez, C.L.; Pellicer, J.A.; et al. Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma. Am. J. Cancer Res. 2019, 9, 2580–2598. [Google Scholar] [PubMed]
- Wang, V.E.; Xue, J.Y.; Frederick, D.T.; Cao, Y.; Lin, E.; Wilson, C.; Urisman, A.; Carbone, D.P.; Flaherty, K.T.; Bernards, R.; et al. Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 7202–7217. [Google Scholar] [CrossRef] [PubMed]
- Theodosakis, N.; Micevic, G.; Langdon, C.G.; Ventura, A.; Means, R.; Stern, D.F.; Bosenberg, M.W. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. J. Investig. Dermatol. 2017, 137, 2187–2196. [Google Scholar] [CrossRef] [PubMed]
- Aida, S.; Sonobe, Y.; Tanimura, H.; Oikawa, N.; Yuhki, M.; Sakamoto, H.; Mizuno, T. MITF suppression improves the sensitivity of melanoma cells to a BRAF inhibitor. Cancer Lett. 2017, 409, 116–124. [Google Scholar] [CrossRef]
- Gong, H.Z.; Zheng, H.Y.; Li, J. The clinical significance of KIT mutations in melanoma: A meta-analysis. Melanoma Res. 2018, 28, 259–270. [Google Scholar] [CrossRef]
- Millán-Esteban, D.; García-Casado, Z.; Manrique-Silva, E.; Virós, A.; Kumar, R.; Furney, S.; López-Guerrero, J.A.; Requena, C.; Bañuls, J.; Traves, V.; et al. Distribution and clinical role of KIT gene mutations in melanoma according to subtype: A study of 492 Spanish patients. Eur. J. Dermatol. EJD 2021, 31, 830–838. [Google Scholar] [CrossRef]
- Beadling, C.; Jacobson-Dunlop, E.; Hodi, F.S.; Le, C.; Warrick, A.; Patterson, J.; Town, A.; Harlow, A.; Cruz, F.; Azar, S.; et al. KIT gene mutations and copy number in melanoma subtypes. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2008, 14, 6821–6828. [Google Scholar] [CrossRef]
- Steeb, T.; Wessely, A.; Petzold, A.; Kohl, C.; Erdmann, M.; Berking, C.; Heppt, M.V. 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, 348–357. [Google Scholar] [CrossRef]
- Kim, K.B.; Alrwas, A. Treatment of KIT-mutated metastatic mucosal melanoma. Chin. Clin. Oncol. 2014, 3, 35. [Google Scholar]
- Pham, D.D.M.; Guhan, S.; Tsao, H. KIT and Melanoma: Biological Insights and Clinical Implications. Yonsei Med. J. 2020, 61, 562–571. [Google Scholar] [CrossRef]
- Hodi, F.S.; Corless, C.L.; Giobbie-Hurder, A.; Fletcher, J.A.; Zhu, M.; Marino-Enriquez, A.; Fisher, D.E. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2013, 31, 3182–3190. [Google Scholar] [CrossRef] [PubMed]
- Han, Y.; Gu, Z.; Wu, J.; Huang, X.; Zhou, R.; Shi, C.; Tao, W.; Wang, L.; Wang, Y.; Zhou, G.; et al. Repurposing Ponatinib as a Potent Agent against KIT Mutant Melanomas. Theranostics 2019, 9, 1952–1964. [Google Scholar] [CrossRef] [PubMed]
- Johnson, D.B.; Puzanov, I. Treatment of NRAS-mutant melanoma. Curr. Treat. Options Oncol. 2015, 16, 15. [Google Scholar] [CrossRef] [PubMed]
- Jenkins, R.W.; Sullivan, R.J. NRAS mutant melanoma: An overview for the clinician for melanoma management. Melanoma Manag. 2016, 3, 47–59. [Google Scholar] [CrossRef]
- Kelleher, F.C.; McArthur, G.A. Targeting NRAS in melanoma. Cancer J. Sudbury Mass. 2012, 18, 132–136. [Google Scholar] [CrossRef]
- Dummer, R.; Schadendorf, D.; Ascierto, P.A.; Arance, A.; Dutriaux, C.; Di Giacomo, A.M.; Rutkowski, P.; Del Vecchio, M.; Gutzmer, R.; Mandala, M.; et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017, 18, 435–445. [Google Scholar] [CrossRef]
- Muñoz-Couselo, E.; Adelantado, E.Z.; Ortiz, C.; García, J.S.; Perez-Garcia, J. NRAS-mutant melanoma: Current challenges and future prospect. OncoTargets Ther. 2017, 10, 3941–3947. [Google Scholar] [CrossRef]
- Zhao, J.; Galvez, C.; Beckermann, K.E.; Johnson, D.B.; Sosman, J.A. Novel insights into the pathogenesis and treatment of NRAS mutant melanoma. Expert Rev. Precis. Med. Drug Dev. 2021, 6, 281–294. [Google Scholar] [CrossRef]
- Randic, T.; Kozar, I.; Margue, C.; Utikal, J.; Kreis, S. NRAS mutant melanoma: Towards better therapies. Cancer Treat. Rev. 2021, 99, 102238. [Google Scholar] [CrossRef]
- Vu, H.L.; Aplin, A.E. Targeting mutant NRAS signaling pathways in melanoma. Pharmacol. Res. 2016, 107, 111–116. [Google Scholar] [CrossRef]
- Bergethon, K.; Shaw, A.T.; Ou, S.-H.I.; Katayama, R.; Lovly, C.M.; McDonald, N.T.; Massion, P.P.; Siwak-Tapp, C.; Gonzalez, A.; Fang, R.; et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2012, 30, 863–870. [Google Scholar] [CrossRef] [PubMed]
- Davies, K.D.; Doebele, R.C. Molecular pathways: ROS1 fusion proteins in cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2013, 19, 4040–4045. [Google Scholar] [CrossRef] [PubMed]
- Shaw, A.T.; Ou, S.H.; Bang, Y.J.; Camidge, D.R.; Solomon, B.J.; Salgia, R.; Riely, G.J.; Varella-Garcia, M.; Shapiro, G.I.; Costa, D.B.; et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 2014, 371, 1963–1971. [Google Scholar] [CrossRef] [PubMed]
- Drilon, A.; Siena, S.; Dziadziuszko, R.; Barlesi, F.; Krebs, M.G.; Shaw, A.T.; de Braud, F.; Rolfo, C.; Ahn, M.-J.; Wolf, J.; et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020, 21, 261–270. [Google Scholar] [CrossRef]
- Ma, S.-C.; Zhu, H.-B.; Wang, J.; Zhang, Y.-P.; Guo, X.-J.; Long, L.-L.; Guo, Z.-Q.; Wu, D.-H.; Dong, Z.-Y.; Bai, X. De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma. Front. Oncol. 2021, 11, 666145. [Google Scholar] [CrossRef]
- Couts, K.L.; McCoach, C.E.; Murphy, D.; Christiansen, J.; Turner, J.; Lewis, K.D.; Robinson, W.A.; Doebele, R.C. Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion with Clinical Response to Entrectinib. JCO Precis. Oncol. 2017, 1, 1–7. [Google Scholar] [CrossRef]
- Cao, J.; Yu, Y.; Zhou, Y.; Ji, Q.; Qian, W.; Jia, D.; Jin, G.; Qi, Y.; Li, X.; Li, N.; et al. Case report: Complete remission with crizotinib in ROS1 fusion-positive sinonasal mucosal melanoma. Front. Oncol. 2022, 12, 942258. [Google Scholar] [CrossRef]
- Lezcano, C.; Shoushtari, A.N.; Ariyan, C.; Hollmann, T.J.; Busam, K.J. Primary and Metastatic Melanoma with NTRK Fusions. Am. J. Surg. Pathol. 2018, 42, 1052–1058. [Google Scholar] [CrossRef]
- Forschner, A.; Forchhammer, S.; Bonzheim, I. NTRK gene fusions in melanoma: Detection, prevalence and potential therapeutic implications. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2020, 18, 1387–1392. [Google Scholar] [CrossRef]
- Yan, J.; Deng, L.; Yu, J.; Wu, X.; Wang, S.; Cang, S. Multi-cohort analysis identifies somatic NTRK mutations as a biomarker for immune checkpoint inhibitor use in cutaneous melanoma. Clin. Transl. Med. 2023, 13, e1478. [Google Scholar] [CrossRef]
- Cocco, E.; Scaltriti, M.; Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 2018, 15, 731–747. [Google Scholar] [CrossRef] [PubMed]
- Kheder, E.S.; Hong, D.S. Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018, 24, 5807–5814. [Google Scholar] [CrossRef] [PubMed]
- Drilon, A.; Siena, S.; Ou, S.-H.I.; Patel, M.; Ahn, M.J.; Lee, J.; Bauer, T.M.; Farago, A.F.; Wheler, J.J.; Liu, S.V.; et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017, 7, 400–409. [Google Scholar] [CrossRef] [PubMed]
- Drilon, A.; Laetsch, T.W.; Kummar, S.; Dubois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef]
- Leach, D.R.; Krummel, M.F.; Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271, 1734–1736. [Google Scholar] [CrossRef]
- Linsley, P.S.; Greene, J.L.; Tan, P.; Bradshaw, J.; Ledbetter, J.A.; Anasetti, C.; Damle, N.K. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J. Exp. Med. 1992, 176, 1595–1604. [Google Scholar] [CrossRef]
- Walunas, T.L.; Bakker, C.Y.; Bluestone, J.A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 1996, 183, 2541–2550. [Google Scholar] [CrossRef]
- Robert, C.; Thomas, L.; Bondarenko, I.; O’Day, S.; Weber, J.; Garbe, C.; Lebbe, C.; Baurain, J.-F.; Testori, A.; Grob, J.-J.; et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 2011, 364, 2517–2526. [Google Scholar] [CrossRef]
- Yamazaki, N.; Uhara, H.; Fukushima, S.; Uchi, H.; Shibagaki, N.; Kiyohara, Y.; Tsutsumida, A.; Namikawa, K.; Okuyama, R.; Otsuka, Y.; et al. Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma. Cancer Chemother. Pharmacol. 2015, 76, 969–975. [Google Scholar] [CrossRef]
- Boussiotis, V.A. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N. Engl. J. Med. 2016, 375, 1767–1778. [Google Scholar] [CrossRef]
- Parry, R.V.; Chemnitz, J.M.; Frauwirth, K.A.; Lanfranco, A.R.; Braunstein, I.; Kobayashi, S.V.; Linsley, P.S.; Thompson, C.B.; Riley, J.L. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 2005, 25, 9543–9553. [Google Scholar] [CrossRef] [PubMed]
- Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2015, 372, 2521–2532. [Google Scholar] [CrossRef] [PubMed]
- Robert, C.; Carlino, M.S.; McNeil, C.; Ribas, A.; Grob, J.-J.; Schachter, J.; Nyakas, M.; Kee, D.; Petrella, T.M.; Blaustein, A.; et al. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 3998–4003. [Google Scholar] [CrossRef]
- Ribas, A.; Puzanov, I.; Dummer, R.; Schadendorf, D.; Hamid, O.; Robert, C.; Hodi, F.S.; Schachter, J.; Pavlick, A.C.; Lewis, K.D.; et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol. 2015, 16, 908–918. [Google Scholar] [CrossRef] [PubMed]
- Robert, C.; Long, G.V.; Brady, B.; Dutriaux, C.; Maio, M.; Mortier, L.; Hassel, J.C.; Rutkowski, P.; McNeil, C.; Kalinka-Warzocha, E.; et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015, 372, 320–330. [Google Scholar] [CrossRef]
- Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.-J.; Rutkowski, P.; Lao, C.D.; Cowey, C.L.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Long-Term Outcomes with Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients with Advanced Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022, 40, 127–137. [Google Scholar] [CrossRef]
- Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 2015, 372, 2006–2017. [Google Scholar] [CrossRef]
- Kitano, S.; Nakayama, T.; Yamashita, M. Biomarkers for Immune Checkpoint Inhibitors in Melanoma. Front. Oncol. 2018, 8, 270. [Google Scholar] [CrossRef]
- Di Donato, M.; Cristiani, C.M.; Capone, M.; Garofalo, C.; Madonna, G.; Passacatini, L.C.; Ottaviano, M.; Ascierto, P.A.; Auricchio, F.; Carbone, E.; et al. Role of the androgen receptor in melanoma aggressiveness. Cell Death Dis. 2025, 16, 34. [Google Scholar] [CrossRef]
- Kleffel, S.; Posch, C.; Barthel, S.R.; Mueller, H.; Schlapbach, C.; Guenova, E.; Elco, C.P.; Lee, N.; Juneja, V.R.; Zhan, Q.; et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell 2015, 162, 1242–1256. [Google Scholar] [CrossRef]
- Workman, C.J.; Cauley, L.S.; Kim, I.J.; Blackman, M.A.; Woodland, D.L.; Vignali, D.A.A. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 2004, 172, 5450–5455. [Google Scholar] [CrossRef] [PubMed]
- Baixeras, E.; Huard, B.; Miossec, C.; Jitsukawa, S.; Martin, M.; Hercend, T.; Auffray, C.; Triebel, F.; Piatier-Tonneau, D. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 1992, 176, 327–337. [Google Scholar] [CrossRef] [PubMed]
- Huard, B.; Prigent, P.; Tournier, M.; Bruniquel, D.; Triebel, F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur. J. Immunol. 1995, 25, 2718–2721. [Google Scholar] [CrossRef] [PubMed]
- Tawbi, H.A.; Schadendorf, D.; Lipson, E.J.; Ascierto, P.A.; Matamala, L.; Gutiérrez, E.C.; Rutkowski, P.; Gogas, H.J.; Lao, C.D.; De Menezes, J.J.; et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 2022, 386, 24–34. [Google Scholar] [CrossRef]
- Kaufman, H.L.; Ruby, C.E.; Hughes, T.; Slingluff, C.L. Current status of granulocyte-macrophage colony-stimulating factor in the immunotherapy of melanoma. J. Immunother. Cancer 2014, 2, 11. [Google Scholar] [CrossRef]
- Shalhout, S.Z.; Miller, D.M.; Emerick, K.S.; Kaufman, H.L. Therapy with oncolytic viruses: Progress and challenges. Nat. Rev. Clin. Oncol. 2023, 20, 160–177. [Google Scholar] [CrossRef]
- Chesney, J.; Puzanov, I.; Collichio, F.; Singh, P.; Milhem, M.M.; Glaspy, J.; Hamid, O.; Ross, M.; Friedlander, P.; Garbe, C.; et al. Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination with Ipilimumab Versus Ipilimumab Alone in Patients with Advanced, Unresectable Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 1658–1667. [Google Scholar] [CrossRef]
- Andtbacka, R.H.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients with Advanced Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef]
- Chi, Z.; Li, S.; Sheng, X.; Si, L.; Cui, C.; Han, M.; Guo, J. Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: A study of 522 consecutive cases. BMC Cancer 2011, 11, 85. [Google Scholar] [CrossRef]
- Fujisawa, Y.; Yoshikawa, S.; Minagawa, A.; Takenouchi, T.; Yokota, K.; Uchi, H.; Noma, N.; Nakamura, Y.; Asai, J.; Kato, J.; et al. Clinical and histopathological characteristics and survival analysis of 4594 Japanese patients with melanoma. Cancer Med. 2019, 8, 2146–2156. [Google Scholar] [CrossRef]
- Roh, M.R.; Kim, J.; Chung, K.Y. Treatment and outcomes of melanoma in acral location in Korean patients. Yonsei Med. J. 2010, 51, 562–568. [Google Scholar] [CrossRef] [PubMed]
- Bai, X.; Kong, Y.; Chi, Z.; Sheng, X.; Cui, C.; Wang, X.; Mao, L.; Tang, B.; Li, S.; Lian, B.; et al. MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2017, 23, 6120–6127. [Google Scholar] [CrossRef] [PubMed]
- Tomizuka, T.; Namikawa, K.; Higashi, T. Characteristics of melanoma in Japan: A nationwide registry analysis 2011–2013. Melanoma Res. 2017, 27, 492–497. [Google Scholar] [CrossRef] [PubMed]
- Pt, B.; Am, G.; Ml, M.; Ma, T. Acral lentiginous melanoma: Incidence and survival patterns in the United States, 1986–2005. Arch. Dermatol. 2009, 145, 427–434. [Google Scholar]
- Bishop, K.D.; Olszewski, A.J. Epidemiology and survival outcomes of ocular and mucosal melanomas: A population-based analysis. Int. J. Cancer 2014, 134, 2961–2971. [Google Scholar] [CrossRef]
- Mori, T.; Izumi, T.; Doi, R.; Kamimura, A.; Takai, S.; Teramoto, Y.; Nakamura, Y. Immune checkpoint inhibitor-based therapy for advanced acral and mucosal melanoma. Exp. Dermatol. 2023, 32, 276–289. [Google Scholar] [CrossRef]
- Ribas, A.; Hamid, O.; Daud, A.; Hodi, F.S.; Wolchok, J.D.; Kefford, R.; Joshua, A.M.; Patnaik, A.; Hwu, W.-J.; Weber, J.S.; et al. Association of Pembrolizumab with Tumor Response and Survival Among Patients with Advanced Melanoma. JAMA 2016, 315, 1600–1609. [Google Scholar] [CrossRef]
- Schachter, J.; Ribas, A.; Long, G.V.; Arance, A.; Grob, J.-J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; 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, 1853–1862. [Google Scholar] [CrossRef]
- Rawson, R.V.; Johansson, P.A.; Hayward, N.K.; Waddell, N.; Patch, A.-M.; Lo, S.; Pearson, J.V.; Thompson, J.F.; Mann, G.J.; Scolyer, R.A.; et al. Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas. Lab. Investig. J. Tech. Methods Pathol. 2017, 97, 130–145. [Google Scholar] [CrossRef]
- Park, S.E.; Park, K.; Lee, E.; Kim, J.-Y.; Ahn, J.S.; Im, Y.-H.; Lee, C.; Jung, H.; Cho, S.Y.; Park, W.-Y.; et al. Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer. Oncoimmunology 2018, 7, e1466768. [Google Scholar] [CrossRef]
- Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015, 372, 2509–2520. [Google Scholar] [CrossRef] [PubMed]
- Huang, F.; Li, J.; Wen, X.; Zhu, B.; Liu, W.; Wang, J.; Jiang, H.; Ding, Y.; Li, D.; Zhang, X. Next-generation sequencing in advanced Chinese melanoma reveals therapeutic targets and prognostic biomarkers for immunotherapy. Sci. Rep. 2022, 12, 9559. [Google Scholar] [CrossRef] [PubMed]
- Hida, T.; Idogawa, M.; Kato, J.; Kiniwa, Y.; Horimoto, K.; Sato, S.; Sawada, M.; Tange, S.; Okura, M.; Okuyama, R.; et al. Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan. Cancer Med. 2024, 13, e70360. [Google Scholar] [CrossRef] [PubMed]
- Hayward, N.K.; Wilmott, J.S.; Waddell, N.; Johansson, P.A.; Field, M.A.; Nones, K.; Patch, A.-M.; Kakavand, H.; Alexandrov, L.B.; Burke, H.; et al. Whole-genome landscapes of major melanoma subtypes. Nature 2017, 545, 175–180. [Google Scholar] [CrossRef]
- Nakamura, Y.; Namikawa, K.; Kiniwa, Y.; Kato, H.; Yamasaki, O.; Yoshikawa, S.; Maekawa, T.; Matsushita, S.; Takenouchi, T.; Inozume, T.; et al. Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients. Eur. J. Cancer 2022, 176, 78–87. [Google Scholar] [CrossRef]
- Bhave, P.; Ahmed, T.; Lo, S.N.; Shoushtari, A.; Zaremba, A.; Versluis, J.M.; Mangana, J.; Weichenthal, M.; Si, L.; Lesimple, T.; et al. Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma. J. Immunother. Cancer 2022, 10, e004668. [Google Scholar] [CrossRef]
- Namikawa, K.; Ito, T.; Yoshikawa, S.; Yoshino, K.; Kiniwa, Y.; Ohe, S.; Isei, T.; Takenouchi, T.; Kato, H.; Mizuhashi, S.; et al. Systemic therapy for Asian patients with advanced BRAF V600-mutant melanoma in a real-world setting: A multi-center retrospective study in Japan (B-CHECK-RWD study). Cancer Med. 2023, 12, 17967–17980. [Google Scholar] [CrossRef]
- Atkins, M.B.; Lee, S.J.; Chmielowski, B.; Tarhini, A.A.; Cohen, G.I.; Truong, T.-G.; Moon, H.H.; Davar, D.; O’Rourke, M.; Stephenson, J.J.; et al. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 186–197. [Google Scholar] [CrossRef]
- Ascierto, P.A.; Mandalà, M.; Ferrucci, P.F.; Guidoboni, M.; Rutkowski, P.; Ferraresi, V.; Arance, A.; Guida, M.; Maiello, E.; Gogas, H.; et al. Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2023, 41, 212–221. [Google Scholar] [CrossRef]
- Wang, M.; Fukushima, S.; Sheen, Y.-S.; Ramelyte, E.; Cruz-Pacheco, N.; Shi, C.; Liu, S.; Banik, I.; Aquino, J.D.; Acosta, M.S.; et al. The genetic evolution of acral melanoma. Nat. Commun. 2024, 15, 6146. [Google Scholar] [CrossRef]
- Chesney, J.; Lewis, K.D.; Kluger, H.; Hamid, O.; Whitman, E.; Thomas, S.; Wermke, M.; Cusnir, M.; Domingo-Musibay, E.; Phan, G.Q.; 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, 10, e005755. [Google Scholar] [PubMed]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef] [PubMed]
- Park, J.H.; Rivière, I.; Gonen, M.; Wang, X.; Sénéchal, B.; Curran, K.J.; Sauter, C.; Wang, Y.; Santomasso, B.; Mead, E.; et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 449–459. [Google Scholar] [CrossRef] [PubMed]
- Schuster, S.J.; Svoboda, J.; Chong, E.A.; Nasta, S.D.; Mato, A.R.; Anak, Ö.; Brogdon, J.L.; Pruteanu-Malinici, I.; Bhoj, V.; Landsburg, D.; et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N. Engl. J. Med. 2017, 377, 2545–2554. [Google Scholar] [CrossRef]
- Wang, M.; Munoz, J.; Goy, A.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl. J. Med. 2020, 382, 1331–1342. [Google Scholar] [CrossRef]
- Shah, P.D.; Huang, A.C.; Xu, X.; Orlowski, R.; Amaravadi, R.K.; Schuchter, L.M.; Zhang, P.; Tchou, J.; Matlawski, T.; Cervini, A.; et al. Phase I Trial of Autologous RNA-electroporated cMET-directed CAR T Cells Administered Intravenously in Patients with Melanoma and Breast Carcinoma. Cancer Res. Commun. 2023, 3, 821–829. [Google Scholar] [CrossRef]
- Murisier, F.; Beermann, F. Genetics of pigment cells: Lessons from the tyrosinase gene family. Histol. Histopathol. 2006, 21, 567–578. [Google Scholar]
- Murisier, F.; Guichard, S.; Beermann, F. A conserved transcriptional enhancer that specifies Tyrp1 expression to melanocytes. Dev. Biol. 2006, 298, 644–655. [Google Scholar] [CrossRef]
- Jilani, S.; Saco, J.D.; Mugarza, E.; Pujol-Morcillo, A.; Chokry, J.; Ng, C.; Abril-Rodriguez, G.; Berger-Manerio, D.; Pant, A.; Hu, J.; et al. CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes. Nat. Commun. 2024, 15, 1244. [Google Scholar] [CrossRef]
- Ozbay Kurt, F.G.; Lasser, S.; Arkhypov, I.; Utikal, J.; Umansky, V. Enhancing immunotherapy response in melanoma: Myeloid-derived suppressor cells as a therapeutic target. J Clin Investig. 2023, 133, e170762. [Google Scholar] [CrossRef]
- Procureur, A.; Simonaggio, A.; Bibault, J.E.; Oudard, S.; Vano, Y.A. Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments. Cancers 2021, 13, 678. [Google Scholar] [CrossRef] [PubMed]
- Knisely, J.P.S.; Yu, J.B.; Flanigan, J.; Sznol, M.; Kluger, H.M.; Chiang, V.L.S. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J. Neurosurg. 2012, 117, 227–233. [Google Scholar] [CrossRef] [PubMed]
- Kiess, A.P.; Wolchok, J.D.; Barker, C.A.; Postow, M.A.; Tabar, V.; Huse, J.T.; Chan, T.A.; Yamada, Y.; Beal, K. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: Safety profile and efficacy of combined treatment. Int. J. Radiat. Oncol. Biol. Phys. 2015, 92, 368–375. [Google Scholar] [CrossRef] [PubMed]
- Bristol-Myers Squibb. A Randomized, Double-Blind Phase 2/3 Study of Relatlimab Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Metastatic or Unresectable Melanoma [Internet]. Clinicaltrials.gov; March 2025. Report No.: NCT03470922. Available online: https://clinicaltrials.gov/study/NCT03470922 (accessed on 27 April 2025).
- Abramson Cancer Center at Penn Medicine. A Randomized Phase 2 Trial of Ipilumumab and Nivolumab with or Without Hypofractionated Radiotherapy in Patients with Metastatic Melanoma [Internet]. Clinicaltrials.gov; February 2025. Report No.: NCT03646617. Available online: https://clinicaltrials.gov/study/NCT03646617 (accessed on 25 April 2025).
- Khan, M.K. Pilot Study of Pembrolizumab and Stereotactic Radio-Surgery (SRS) for Patients with Melanoma or Non-Small Cell Lung Cancer (NSCLC) Brain Metastases (BM) [Internet]. Clinicaltrials.gov; May 2024. Report No.: NCT02858869. Available online: https://clinicaltrials.gov/study/NCT02858869 (accessed on 25 April 2025).
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. A Pilot Study of Stereotactic Radiosurgery Combined with Nivolumab in Patients with Newly Diagnosed Melanoma Metastases in the Brain and Spine [Internet]. Clinicaltrials.gov; November 2021. Report No.: NCT02716948. Available online: https://clinicaltrials.gov/study/NCT02716948 (accessed on 25 April 2025).
- Gérard, A.; Doyen, J.; Cremoni, M.; Bailly, L.; Zorzi, K.; Ruetsch-Chelli, C.; Brglez, V.; Picard-Gauci, A.; Troin, L.; Esnault, V.L.; et al. Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients. J. Immunother. Cancer 2021, 9, e002512. [Google Scholar] [CrossRef]
- Centre Hospitalier Universitaire de Nice. Nivolumab in Combination with High Dose Radiotherapy at Varied Tumor Sites in Advanced Melanoma and no Prior Antitumoral Treatment [Internet]. Clinicaltrials.gov; November 2023. Report No.: NCT02799901. Available online: https://clinicaltrials.gov/study/NCT02799901 (accessed on 27 April 2025).
- Spaas, M.; Sundahl, N.; Kruse, V.; Rottey, S.; De Maeseneer, D.; Duprez, F.; Lievens, Y.; Surmont, V.; Brochez, L.; Reynders, D.; et al. Checkpoint Inhibitors in Combination with Stereotactic Body Radiotherapy in Patients with Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial. JAMA Oncol. 2023, 9, 1205–1213. [Google Scholar] [CrossRef]
- University Hospital, Ghent. CHEckpoint Inhibition in Combination with an Immunoboost of External Beam Radiotherapy in Solid Tumors: CHEERS-Trial [Internet]. Clinicaltrials.gov; January 2024. Report No.: NCT03511391. Available online: https://clinicaltrials.gov/study/NCT03511391 (accessed on 25 April 2025).
- Miller, W. A Phase II Study of Pembrolizumab with Carboplatin/Paclitaxel in Patients with Metastatic Melanoma [Internet]. clinicaltrials.gov; February 2021. Report No.: NCT02617849. Available online: https://clinicaltrials.gov/study/NCT02617849 (accessed on 27 April 2025).
- Robinson, C.; Xu, M.M.; Nair, S.K.; Beasley, G.M.; Rhodin, K.E. Oncolytic viruses in melanoma. Front. Biosci. Landmark Ed. 2022, 27, 63. [Google Scholar] [CrossRef]
- Ribas, A.; Chesney, J.; Long, G.V.; Kirkwood, J.M.; Dummer, R.; Puzanov, I.; Hoeller, C.; Gajewski, T.F.; Gutzmer, R.; Rutkowski, P.; et al. 1037O MASTERKEY-265: A phase III, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL). Ann. Oncol. 2021, 32, S868–S869. [Google Scholar] [CrossRef]
- Wong, M.K.; Sacco, J.J.; Robert, C.; Michels, J.; Bowles, T.L.; In, G.K.; Tsai, K.K.; Lebbe, C.; Gaudy-Marqueste, C.; Couselo, E.M.; et al. Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J. Clin. Oncol. 2024, 42 (Suppl S16), 9517. [Google Scholar] [CrossRef]
- Weber, J.S.; Carlino, M.S.; Khattak, A.; Meniawy, T.; Ansstas, G.; Taylor, M.H.; Kim, K.B.; McKean, M.; Long, G.V.; Sullivan, R.J.; et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): A randomised, phase 2b study. Lancet 2024, 403, 632–644. [Google Scholar] [CrossRef]
- Long, G.V.; Ferrucci, P.F.; Khattak, A.; Meniawy, T.M.; Ott, P.A.; Chisamore, M.; Trolle, T.; Hyseni, A.; Heegaard, E. KEYNOTE—D36: Personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma. Future Oncol. 2022, 18, 3473–3480. [Google Scholar] [CrossRef]
- Iovance Biotherapeutics, Inc. A Phase 3, Multicenter, Randomized, Open-label, Parallel Group, Treatment Study to Assess the Efficacy and Safety of the Lifileucel (LN-144, Autologous Tumor Infiltrating Lymphocytes [TIL]) Regimen in Combination with Pembrolizumab Compared with Pembrolizumab Monotherapy in Participants with Untreated, Unresectable or Metastatic Melanoma [Internet]. Clinicaltrials.gov; April 2025. Report No.: NCT05727904. Available online: https://clinicaltrials.gov/study/NCT05727904 (accessed on 22 April 2025).
- University of California, San Francisco. Immunotherapy with or Without Radiation Therapy in Treating Patients with Recurrent or Second Primary Head and Neck Cancer [Internet]. Clinicaltrials.gov; February 2024. Report No.: NCT03340129. Available online: https://clinicaltrials.gov/study/NCT03340129 (accessed on 25 April 2025).
- A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination with Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265) [Internet]. ClinicalTrials.gov; April 2021. Report No.: NCT02263508. Available online: https://clinicaltrials.gov/study/NCT02263508 (accessed on 25 April 2025).
- AstraZeneca. Study of Durvalumab and/or Tremelimumab in Combination with Radiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC) [Internet]. Clinicaltrials.gov; April 2024. Report No.: NCT03897881. Available online: https://clinicaltrials.gov/study/NCT03897881 (accessed on 25 April 2025).
- Garofalo, C.; De Marco, C.; Cristiani, C.M. NK Cells in the Tumor Microenvironment as New Potential Players Mediating Chemotherapy Effects in Metastatic Melanoma. Front. Oncol. 2021, 11, 754541. [Google Scholar] [CrossRef] [PubMed]
- Cristiani, C.M.; Turdo, A.; Ventura, V.; Apuzzo, T.; Capone, M.; Madonna, G.; Mallardo, D.; Garofalo, C.; Giovannone, E.D.; Grimaldi, A.M.; et al. Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway. Cancer Immunol. Res. 2019, 7, 841–852. [Google Scholar] [CrossRef] [PubMed]
- Dobos, J.; Mohos, A.; Tóvári, J.; Rásó, E.; Lőrincz, T.; Zádori, G.; Tímár, J.; Ladányi, A. Sex-dependent liver colonization of human melanoma in SCID mice--role of host defense mechanisms. Clin. Exp. Metastasis 2013, 30, 497–506. [Google Scholar] [CrossRef] [PubMed]
- Gupta, S.; Artomov, M.; Goggins, W.; Daly, M.; Tsao, H. Gender Disparity and Mutation Burden in Metastatic Melanoma. J. Natl. Cancer Inst. 2015, 107, djv221. [Google Scholar] [CrossRef]
- Joosse, A.; de Vries, E.; Eckel, R.; Nijsten, T.; Eggermont, A.M.; Hölzel, D.; Coebergh, J.W.W.; Engel, J. Gender differences in melanoma survival: Female patients have a decreased risk of metastasis. J. Investig. Dermatol. 2011, 131, 719–726. [Google Scholar] [CrossRef]
- Robinson, J.K.; Mallett, K.A.; Turrisi, R.; Stapleton, J. Engaging patients and their partners in preventive health behaviors: The physician factor. Arch. Dermatol. 2009, 145, 469–473. [Google Scholar] [CrossRef]
- Swetter, S.M.; Johnson, T.M.; Miller, D.R.; Layton, C.J.; Brooks, K.R.; Geller, A.C. Melanoma in middle-aged and older men: A multi-institutional survey study of factors related to tumor thickness. Arch. Dermatol. 2009, 145, 397–404. [Google Scholar] [CrossRef]
- Nebhan, C.A.; Johnson, D.B. Predictive biomarkers of response to immune checkpoint inhibitors in melanoma. Expert Rev. Anticancer. Ther. 2020, 20, 137–145. [Google Scholar] [CrossRef]
- Larkin, J.; Hodi, F.S.; Wolchok, J.D. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N. Engl. J. Med. 2015, 373, 1270–1271. [Google Scholar] [CrossRef]
- Ning, B.; Liu, Y.; Wang, M.; Li, Y.; Xu, T.; Wei, Y. The Predictive Value of Tumor Mutation Burden on Clinical Efficacy of Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Meta-Analysis. Front. Pharmacol. 2022, 13, 748674. [Google Scholar] [CrossRef]
- Roccuzzo, G.; Sarda, C.; Pala, V.; Ribero, S.; Quaglino, P. Prognostic biomarkers in melanoma: A 2023 update from clinical trials in different therapeutic scenarios. Expert Rev. Mol. Diagn. 2024, 24, 379–392. [Google Scholar] [CrossRef] [PubMed]
- Tumeh, P.C.; Harview, C.L.; Yearley, J.H.; Shintaku, I.P.; Taylor, E.J.M.; Robert, L.; Chmielowski, B.; Spasic, M.; Henry, G.; Ciobanu, V.; et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014, 515, 568–571. [Google Scholar] [CrossRef] [PubMed]
- Moldoveanu, D.; Ramsay, L.; Lajoie, M.; Anderson-Trocme, L.; Lingrand, M.; Berry, D.; Perus, L.J.; Wei, Y.; Moraes, C.; Alkallas, R.; et al. Spatially mapping the immune landscape of melanoma using imaging mass cytometry. Sci. Immunol. 2022, 7, eabi5072. [Google Scholar] [CrossRef] [PubMed]
- Berry, S.; Giraldo, N.A.; Green, B.F.; Cottrell, T.R.; Stein, J.E.; Engle, E.L.; Xu, H.; Ogurtsova, A.; Roberts, C.; Wang, D.; et al. Analysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade. Science 2021, 372, eaba2609. [Google Scholar] [CrossRef]
- Laino, A.S.; Woods, D.; Vassallo, M.; Qian, X.; Tang, H.; Wind-Rotolo, M.; Weber, J. Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition. J. Immunother. Cancer 2020, 8, e000842. [Google Scholar] [CrossRef]
- Reschke, R.; Enk, A.H.; Hassel, J.C. Prognostic Biomarkers in Evolving Melanoma Immunotherapy. Am. J. Clin. Dermatol. 2025, 26, 213–223. [Google Scholar] [CrossRef]
- Imani, S.; Roozitalab, G.; Emadi, M.; Moradi, A.; Behzadi, P.; Jabbarzadeh Kaboli, P. The evolution of BRAF-targeted therapies in melanoma: Overcoming hurdles and unleashing novel strategies. Front. Oncol. 2024, 14, 1504142. [Google Scholar] [CrossRef]
- Revythis, A.; Shah, S.; Kutka, M.; Moschetta, M.; Ozturk, M.A.; Pappas-Gogos, G.; Ioannidou, E.; Sheriff, M.; Rassy, E.; Boussios, S. Unraveling the Wide Spectrum of Melanoma Biomarkers. Diagnostics 2021, 11, 1341. [Google Scholar] [CrossRef]
Treatment Approach | Protocol | Efficacy | Key Considerations |
---|---|---|---|
Chemotherapy | Dacarbazine (DTIC) | ORR: 5–12% | Limited efficacy; standard before targeted therapy |
Temozolomide | ORR: 13.4% | No significant survival benefit over DTIC | |
nab-Paclitaxel | ORR: 15% | No significant difference in OS compared to DTIC | |
CBDCA + PTX (Carboplatin + Paclitaxel) | ORR: 18% | No significant difference from DTIC | |
CVD (Cisplatin + Vindesine + DTIC) | ORR: 20–35% | No OS benefit over DTIC monotherapy | |
Cytokine Therapy | IL-2 (High-Dose Interleukin-2) | ORR: 15–20%; combined with SBRT: 54% | Durable response possible, but toxicity is high |
IFN-α (Interferon-Alpha) | ORR: low; no OS benefit | Used as adjuvant therapy but limited in recent use | |
IFN-β (Interferon-Beta, Intralesional) | Complete response in case reports | Effective for in-transit/cutaneous metastases |
Year | Phase | Trial Name | Intervention vs. Control | Patient Population | ORR (%) | Reference |
---|---|---|---|---|---|---|
2010 | III | MDX010-20 | Ipilimumab + gp100 vs. gp100 | Advanced, previously treated | 10.9 vs. 5.7 | [5] |
2011 | III | CA184-024 | Ipilimumab + Dacarbazine vs. Dacarbazine | Treatment-naïve advanced | 15.2 vs. 10.3 | [89] |
2014 | III | CheckMate 066 | Nivolumab vs. Dacarbazine | Treatment-naïve advanced BRAF WT | 40.0 vs. 13.9 | [96] |
2014 | III | CheckMate 037 | Nivolumab vs. Chemotherapy | Advanced after ipilimumab or BRAF inhibitor | 31.7 vs. 10.6 | [6] |
2014 | II | KEYNOTE-002 | Pembrolizumab vs. Chemotherapy | Advanced refractory to ipilimumab | 25.0 vs. 4.0 | [95] |
2015 | III | KEYNOTE-006 | Pembrolizumab vs. Ipilimumab | Advanced (≤1 prior therapy) | 33.7 vs. 11.9 | [94] |
2015 | III | CheckMate 067 | Nivolumab + Ipilimumab vs. Nivolumab vs. Ipilimumab | Treatment-naïve advanced | 58 combo, 45 Nivo, 19 Ipi | [97,98] |
2022 | II/III | RELATIVITY-047 | Nivolumab + Relatlimab vs. Nivolumab | Treatment-naïve advanced | 43.1 vs. 32.6 | [105] |
Therapeutic Strategy | Description |
---|---|
Inhibition of proliferative signaling pathways | Targeting constitutively active mutations (e.g., BRAF, KIT, NRAS, TERT, CCND1) to suppress melanoma proliferation; TERT and CCND1 alterations are notable in acral melanoma. |
Adoptive cell therapy using TILs | Lifileucel, an FDA-approved TIL therapy, shows efficacy after ICI and BRAF/MEK failure; limited by complexity, cost, and toxicity. |
Melanoma antigen-targeted CAR-T therapy | TYP1-targeted CAR-T cells demonstrate promising preclinical efficacy; clinical translation in melanoma is ongoing. |
Combining immune checkpoint inhibitors (ICIs) with other modalities | Strategies include dual checkpoint blockade, ICI with radiotherapy, oncolytic viruses, cancer vaccines, and TIL-ICI combinations. |
Natural killer (NK) cell-based approaches | AR blockade may restore NK cell cytotoxicity and enhance ICI efficacy; under preclinical investigation. |
Identification and validation of biomarkers | Biomarkers such as PD-L1, TMB, IFN-γ signature, TILs, LAG-3, HLA genotypes, and gut microbiota are critical for predicting treatment response. |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kado, S.; Komine, M. Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations. Int. J. Mol. Sci. 2025, 26, 5370. https://doi.org/10.3390/ijms26115370
Kado S, Komine M. Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations. International Journal of Molecular Sciences. 2025; 26(11):5370. https://doi.org/10.3390/ijms26115370
Chicago/Turabian StyleKado, Soichiro, and Mayumi Komine. 2025. "Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations" International Journal of Molecular Sciences 26, no. 11: 5370. https://doi.org/10.3390/ijms26115370
APA StyleKado, S., & Komine, M. (2025). Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations. International Journal of Molecular Sciences, 26(11), 5370. https://doi.org/10.3390/ijms26115370