The Current Successes (and Failures) in the Treatment of Cutaneous Metastatic Melanoma
Main Article Content
Abstract
The contemporaneous treatment of cutaneous metastatic melanoma (CMM) has been revolutionized in a process started decades ago with the better understanding of cancer genetics, cancer biology and the functioning mechanisms of the immune system, which were more recently translated from basic and clinical research into efficacious and effective new drugs. At the turn of the 21st century, patients with CMM had very few treatment options and their survival was measured in few months. Traditional chemotherapy or cytotoxic drugs had very limited non curative potential, with OS in the ranging from 6 to 12 months, at best.
Currently, the use of immune check point inhibitors (ICIs) and drugs directed at blocking mutated BRAF gene proteins as well as MEK inhibitors have transformed the landscape of CMM treatment, with immense positive impact on hard surrogates such as overall survival (OS) and disease-free survival (DFS) and on the quality of life (QoL) of such patients.
Our objective here is to review the last ten years of data regarding this evolution, as well as acknowledging its pitfalls and limitations, while trying to look forward in the search for biomarkers that could better tail treatment choices while preventing unnecessary toxicities.
Article Details
How to Cite
JC, Coelho et al.
The Current Successes (and Failures) in the Treatment of Cutaneous Metastatic Melanoma.
Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4751>. Date accessed: 16 may 2024.
doi: https://doi.org/10.18103/mra.v11i11.4751.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Agarwala SS. Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther. 2009;9(5):587-595. doi:10.1586/era.09.25
2. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination with Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Melanoma. J Clin Oncol. 2012;30(1):34-41. doi:10.1200/JCO.2011.34.6270
3. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
4. Atkins MB, Lotze MT, Dutcher JP, et al. High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993. J Clin Oncol. 1999;17(7):2105-2105. doi:10.1200/JCO.1999.17.7.2105
5. Atkins MB, Hsu J, Lee S, et al. Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26(35):5748-5754. doi:10.1200/JCO.2008.17.5448
6. Atkins MB, Buzaid AC, Houghton AN Jr. Chemotherapy and biochemotherapy. In: Cutaneous Melanoma. Balch C, Houghton A, Sober A, Soong S, Eds. 4th edition. Quality Medical Publishing; 2003:589.
7. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients. J Clin Oncol. 2007;25(34):5426-5434. doi:10.1200/JCO.2007.12.0253
8. García-Gutiérrez V, Hernández-Boluda JC. Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety. Front Oncol. 2019;9. Accessed October 1, 2023. https://www.frontiersin.org/articles/10.3389/fonc.2019.00603
9. Smyth MJ, Teng MW. 2018 Nobel Prize in physiology or medicine. Clin Transl Immunol. 2018;7(10):e1041. doi:10.1002/cti2.1041
10. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013
11. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
12. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98. doi:10.1097/COC.0000000000000239
13. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(22):6958-6962. doi:10.1158/1078-0432.CCR-11-1595
14. Ralli M, Botticelli A, Visconti IC, et al. Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions. J Immunol Res. 2020;2020:e9235638. doi:10.1155/2020/9235638
15. Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5-6):176-189. doi:10.18632/genesandcancer.180
16. Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8(62):106132-106142. doi:10.18632/oncotarget.22190
17. 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):711-723. doi:10.1056/NEJMoa1003466
18. Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N Engl J Med. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082
19. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093
20. Coelho JC, Rebelatto TF, Pereira RR, Liedke PER, Zanon AB, Azevedo SJ. Atezolizumab Monotherapy as First-line Treatment in Patients with Advanced BRAFV600 Wild-type Melanoma. J Clin Haematol. 2021;Volume 2(Issue 3):95-97. doi:10.33696/haematology.2.034
21. de Azevedo SJ, de Melo AC, Roberts L, Caro I, Xue C, Wainstein A. First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. Pigment Cell Melanoma Res. 2021;34(5):973-977. doi:10.1111/pcmr.12960
22. Hodi FS, Chiarion-Sileni V, Gonzalez R, 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):1480-1492. doi:10.1016/S1470-2045(18)30700-9
23. Wolchok JD, Chiarion-Sileni V, Gonzalez 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(2):127-137. doi:10.1200/JCO.21.02229
24. Daud AI, Wolchok JD, Robert C, et al. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(34):4102-4109. doi:10.1200/JCO.2016.67.2477
25. 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. doi:10.1056/NEJMoa2109970
26. Long GV, Stephen Hodi F, Lipson EJ, et al. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evid. 2023;2(4):EVIDoa2200239. doi:10.1056/EVIDoa2200239
27. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86-104. doi:10.3322/caac.21596
28. Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1-2):53-62. doi:10.1016/S0248-4900(01)01125-X
29. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. doi:10.1038/nature00766
30. Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8(1):67. doi:10.1186/1479-5876-8-67
31. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of Mutated, Activated BRAF in Metastatic Melanoma. N Engl J Med. 2010;363(9):809-819. doi:10.1056/NEJMoa1002011
32. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib. N Engl J Med. 2012;366(8):707-714. doi:10.1056/NEJMoa1112302
33. Chapman PB, Hauschild A, Robert C, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl J Med. 2011;364(26):2507-2516. doi:10.1056/NEJMoa1103782
34. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332. doi:10.1016/S1470-2045(14)70012-9
35. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. The Lancet. 2012;379(9829):1893-1901. doi:10.1016/S0140-6736(12)60398-5
36. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet. 2012;380(9839):358-365. doi:10.1016/S0140-6736(12)60868-X
37. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782-789. doi:10.1016/S1470-2045(12)70269-3
38. Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med. 2012;367(2):107-114. doi:10.1056/NEJMoa1203421
39. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 2012;367(18):1694-1703. doi:10.1056/NEJMoa1210093
40. Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690
41. Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Ann Oncol. 2016;27:vi575. doi:10.1093/annonc/mdw435.37
42. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639. doi:10.1093/annonc/mdx176
43. Larkin J, Ascierto PA, Dréno B, et al. Combined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868
44. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X
45. Dummer R, Ascierto PA, Gogas HJ, 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):603-615. doi:10.1016/S1470-2045(18)30142-6
46. Dummer R, Ascierto PA, Gogas HJ, 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):1315-1327. doi:10.1016/S1470-2045(18)30497-2
47. Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(15_suppl):3003-3003. doi:10.1200/jco.2015.33.15_suppl.3003
48. Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE-022 update: phase 1 study of first-line pembrolizumab (pembro) plus dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma. Ann Oncol. 2017;28:v430. doi:10.1093/annonc/mdx377.003
49. Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25(6):929-935. doi:10.1038/s41591-019-0474-7
50. Dummer R, Arance Fernández AM, Hansson J, et al. Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma. J Clin Oncol. 2018;36(5_suppl):189-189. doi:10.1200/JCO.2018.36.5_suppl.189
51. Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019;25(6):941-946. doi:10.1038/s41591-019-0448-9
52. Nathan P, Dummer R, Long GV, et al. LBA43 Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. Ann Oncol. 2020;31:S1172. doi:10.1016/j.annonc.2020.08.2273
53. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X
54. Robert C, Ribas A, Schachter J, 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;20(9):1239-1251. doi:10.1016/S1470-2045(19)30388-2
55. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836
56. Atkins MB, Lee SJ, Chmielowski B, 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. 2023;41(2):186-197. doi:10.1200/JCO.22.01763
57. Ascierto PA, Mandalà M, Ferrucci PF, 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(2):212-221. doi:10.1200/JCO.21.02961
58. Frederick DT, Piris A, Cogdill AP, 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):1225-1231. doi:10.1158/1078-0432.CCR-12-1630
59. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma. Clin Cancer Res. 2012;18(5):1386-1394. doi:10.1158/1078-0432.CCR-11-2479
60. Tawbi HA, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12):1692-1704. doi:10.1016/S1470-2045(21)00545-3
61. Haas L, Elewaut A, Gerard CL, et al. Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. Nat Cancer. 2021;2(7):693-708. doi:10.1038/s43018-021-00221-9
62. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708. doi:10.1001/jamanetworkopen.2021.4708
63. Ch’ng S, Uyulmaz S, Carlino MS, et al. Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies. Eur J Cancer. 2021;153:8-15. doi:10.1016/j.ejca.2021.04.037
64. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863-873. doi:10.1016/S1470-2045(17)30429-1
65. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. N Engl J Med. 2022;387(23):2113-2125. doi:10.1056/NEJMoa2210233
66. Adnan Khattak, Matteo Carlino, Tarek Meniawy, et al. A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. Abstract CT001 presented at: AACR Annual Meetin 2023; April 14, 2023; Orlando FL. Accessed October 1, 2023. https://www.aacr.org/wp-content/uploads/2023/05/AACR2023_LBA-Trials_AbstractsEbook.pdf
67. Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020;21(3):358-372. doi:10.1016/S1470-2045(20)30062-0
68. Rozeman EA, Hoefsmit EP, Reijers ILM, et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. 2021;27(2):256-263. doi:10.1038/s41591-020-01211-7
69. Robert C, Long GV, Brady B, et al. Five-Year Outcomes with Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020;38(33):3937-3946. doi:10.1200/JCO.20.00995
2. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination with Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Melanoma. J Clin Oncol. 2012;30(1):34-41. doi:10.1200/JCO.2011.34.6270
3. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
4. Atkins MB, Lotze MT, Dutcher JP, et al. High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993. J Clin Oncol. 1999;17(7):2105-2105. doi:10.1200/JCO.1999.17.7.2105
5. Atkins MB, Hsu J, Lee S, et al. Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26(35):5748-5754. doi:10.1200/JCO.2008.17.5448
6. Atkins MB, Buzaid AC, Houghton AN Jr. Chemotherapy and biochemotherapy. In: Cutaneous Melanoma. Balch C, Houghton A, Sober A, Soong S, Eds. 4th edition. Quality Medical Publishing; 2003:589.
7. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients. J Clin Oncol. 2007;25(34):5426-5434. doi:10.1200/JCO.2007.12.0253
8. García-Gutiérrez V, Hernández-Boluda JC. Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety. Front Oncol. 2019;9. Accessed October 1, 2023. https://www.frontiersin.org/articles/10.3389/fonc.2019.00603
9. Smyth MJ, Teng MW. 2018 Nobel Prize in physiology or medicine. Clin Transl Immunol. 2018;7(10):e1041. doi:10.1002/cti2.1041
10. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013
11. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
12. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98. doi:10.1097/COC.0000000000000239
13. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(22):6958-6962. doi:10.1158/1078-0432.CCR-11-1595
14. Ralli M, Botticelli A, Visconti IC, et al. Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions. J Immunol Res. 2020;2020:e9235638. doi:10.1155/2020/9235638
15. Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5-6):176-189. doi:10.18632/genesandcancer.180
16. Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8(62):106132-106142. doi:10.18632/oncotarget.22190
17. 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):711-723. doi:10.1056/NEJMoa1003466
18. Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N Engl J Med. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082
19. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093
20. Coelho JC, Rebelatto TF, Pereira RR, Liedke PER, Zanon AB, Azevedo SJ. Atezolizumab Monotherapy as First-line Treatment in Patients with Advanced BRAFV600 Wild-type Melanoma. J Clin Haematol. 2021;Volume 2(Issue 3):95-97. doi:10.33696/haematology.2.034
21. de Azevedo SJ, de Melo AC, Roberts L, Caro I, Xue C, Wainstein A. First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. Pigment Cell Melanoma Res. 2021;34(5):973-977. doi:10.1111/pcmr.12960
22. Hodi FS, Chiarion-Sileni V, Gonzalez R, 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):1480-1492. doi:10.1016/S1470-2045(18)30700-9
23. Wolchok JD, Chiarion-Sileni V, Gonzalez 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(2):127-137. doi:10.1200/JCO.21.02229
24. Daud AI, Wolchok JD, Robert C, et al. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(34):4102-4109. doi:10.1200/JCO.2016.67.2477
25. 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. doi:10.1056/NEJMoa2109970
26. Long GV, Stephen Hodi F, Lipson EJ, et al. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evid. 2023;2(4):EVIDoa2200239. doi:10.1056/EVIDoa2200239
27. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86-104. doi:10.3322/caac.21596
28. Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1-2):53-62. doi:10.1016/S0248-4900(01)01125-X
29. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. doi:10.1038/nature00766
30. Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8(1):67. doi:10.1186/1479-5876-8-67
31. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of Mutated, Activated BRAF in Metastatic Melanoma. N Engl J Med. 2010;363(9):809-819. doi:10.1056/NEJMoa1002011
32. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib. N Engl J Med. 2012;366(8):707-714. doi:10.1056/NEJMoa1112302
33. Chapman PB, Hauschild A, Robert C, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl J Med. 2011;364(26):2507-2516. doi:10.1056/NEJMoa1103782
34. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332. doi:10.1016/S1470-2045(14)70012-9
35. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. The Lancet. 2012;379(9829):1893-1901. doi:10.1016/S0140-6736(12)60398-5
36. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet. 2012;380(9839):358-365. doi:10.1016/S0140-6736(12)60868-X
37. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782-789. doi:10.1016/S1470-2045(12)70269-3
38. Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med. 2012;367(2):107-114. doi:10.1056/NEJMoa1203421
39. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 2012;367(18):1694-1703. doi:10.1056/NEJMoa1210093
40. Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690
41. Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Ann Oncol. 2016;27:vi575. doi:10.1093/annonc/mdw435.37
42. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639. doi:10.1093/annonc/mdx176
43. Larkin J, Ascierto PA, Dréno B, et al. Combined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868
44. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X
45. Dummer R, Ascierto PA, Gogas HJ, 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):603-615. doi:10.1016/S1470-2045(18)30142-6
46. Dummer R, Ascierto PA, Gogas HJ, 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):1315-1327. doi:10.1016/S1470-2045(18)30497-2
47. Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(15_suppl):3003-3003. doi:10.1200/jco.2015.33.15_suppl.3003
48. Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE-022 update: phase 1 study of first-line pembrolizumab (pembro) plus dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma. Ann Oncol. 2017;28:v430. doi:10.1093/annonc/mdx377.003
49. Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25(6):929-935. doi:10.1038/s41591-019-0474-7
50. Dummer R, Arance Fernández AM, Hansson J, et al. Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma. J Clin Oncol. 2018;36(5_suppl):189-189. doi:10.1200/JCO.2018.36.5_suppl.189
51. Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019;25(6):941-946. doi:10.1038/s41591-019-0448-9
52. Nathan P, Dummer R, Long GV, et al. LBA43 Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. Ann Oncol. 2020;31:S1172. doi:10.1016/j.annonc.2020.08.2273
53. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X
54. Robert C, Ribas A, Schachter J, 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;20(9):1239-1251. doi:10.1016/S1470-2045(19)30388-2
55. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836
56. Atkins MB, Lee SJ, Chmielowski B, 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. 2023;41(2):186-197. doi:10.1200/JCO.22.01763
57. Ascierto PA, Mandalà M, Ferrucci PF, 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(2):212-221. doi:10.1200/JCO.21.02961
58. Frederick DT, Piris A, Cogdill AP, 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):1225-1231. doi:10.1158/1078-0432.CCR-12-1630
59. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma. Clin Cancer Res. 2012;18(5):1386-1394. doi:10.1158/1078-0432.CCR-11-2479
60. Tawbi HA, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12):1692-1704. doi:10.1016/S1470-2045(21)00545-3
61. Haas L, Elewaut A, Gerard CL, et al. Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. Nat Cancer. 2021;2(7):693-708. doi:10.1038/s43018-021-00221-9
62. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708. doi:10.1001/jamanetworkopen.2021.4708
63. Ch’ng S, Uyulmaz S, Carlino MS, et al. Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies. Eur J Cancer. 2021;153:8-15. doi:10.1016/j.ejca.2021.04.037
64. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863-873. doi:10.1016/S1470-2045(17)30429-1
65. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. N Engl J Med. 2022;387(23):2113-2125. doi:10.1056/NEJMoa2210233
66. Adnan Khattak, Matteo Carlino, Tarek Meniawy, et al. A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. Abstract CT001 presented at: AACR Annual Meetin 2023; April 14, 2023; Orlando FL. Accessed October 1, 2023. https://www.aacr.org/wp-content/uploads/2023/05/AACR2023_LBA-Trials_AbstractsEbook.pdf
67. Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020;21(3):358-372. doi:10.1016/S1470-2045(20)30062-0
68. Rozeman EA, Hoefsmit EP, Reijers ILM, et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. 2021;27(2):256-263. doi:10.1038/s41591-020-01211-7
69. Robert C, Long GV, Brady B, et al. Five-Year Outcomes with Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020;38(33):3937-3946. doi:10.1200/JCO.20.00995