Adjuvant Therapy for Melanoma
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In recent years, the number of patients with malignant melanoma has continued to increase globally; surgery remains the first treatment option for patients with resectable melanoma. Adjuvant therapy for patients with stage III and IV melanoma following surgical resection has gradually been approved. After complete resection, these patients can probably derive significant benefit from adjuvant therapy. New treatments that improve the long-term survival of patients with unresectable advanced or metastatic melanoma are currently under evaluation in adjuvant therapy to increase relapse-free survival and overall survival. We here review several relevant clinical trials of radiotherapy, systemic immune therapies, molecular-targeted therapies, and neoadjuvant therapies in order to shed light on most suitable adjuvant therapy. The findings of this review include the following: The use of interferon-α2b will be restricted for patients with ulcerated primary melanoma in countries with no access to new drugs in adjuvant therapy. Ipilimumab should not be considered as the first-line therapy due to its lower efficacy and severe toxicity. The use of anti-programmed death-1 antibody would be a relevant adjuvant therapy for patients without BRAF mutation. If the BRAF mutation status is positive, the combination of dabrafenib and trametinib is a plausible option. The establishment of appropriate therapeutic planning and clinical endpoints in adjuvant therapy should affect the standard of care. The choice of optimal adjuvant therapy for individual patients is an important issue.
KeywordsMelanoma Adjuvant therapy Radiotherapy Immune therapy Targeted therapy Neoadjuvant therapy
mitogen-activated protein kinase
randomized controlled trial
Food and Drug Administration
programmed cell death protein 1
Eastern Cooperative Oncology Group
European Medicines Agency
cytotoxic T lymphocyte-associated antigen 4
health-related quality of life
American Joint Committee on Cancer
Compliance with Ethical Standards
Conflict of Interest
Maiko Wada-Ohno, Takamichi Ito, and Masutaka Furue declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–68.CrossRefGoogle Scholar
- 9.• Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55 This study showed that durable responses under kinase inhibitors are possible. Baseline LDH and number of organ sites with metastasis associated with predictive of PFS and OS.CrossRefGoogle Scholar
- 14.Nakamura Y, Fujisawa Y, Tanaka R, Maruyama H, Ishitsuka Y, Okiyama N, et al. Use of immune checkpoint inhibitors prolonged overall survival in a Japanese population of advanced malignant melanoma patients: retrospective single institutional study. J Dermatol. 2018;45(11):1337–9.CrossRefGoogle Scholar
- 15.Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, et al. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017;18(3):393–403.CrossRefGoogle Scholar
- 16.•• Weber J, Mandala M, Del Vecchio M, et al. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35 This study showed that adjuvant therapy with nivolumab resulted in significantly longer RFS and a lower rate of high grade adverse events than adjuvant therapy with ipilimumab.CrossRefGoogle Scholar
- 17.•• Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813–23 This study showed that adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence compared with placebo and was not associated with new toxic effects.CrossRefGoogle Scholar
- 18.•• Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801 This study showed that adjuvant therapy with 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer RFS than placebo, with no new toxic effects identified.CrossRefGoogle Scholar
- 21.Balch C, Houghton A, Sober A. Radiotherapy for melanoma. In: Balch C, editor. Cutaneous melanoma. Philadelphia: J.B. Lippincott; 1992. p. 509.Google Scholar
- 27.Burmeister BH, Henderson MA, Ainslie J, Fisher R, di Iulio J, Smithers BM, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13(6):589–97.CrossRefGoogle Scholar
- 28.Henderson MA, Burmeister BH, Ainslie J, Fisher R, di Iulio J, Smithers BM, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):1049–60.CrossRefGoogle Scholar
- 30.Barbour S, Mark Smithers B, Allan C, Bayley G, Thomas J, Foote M, et al. Patterns of recurrence in patients with stage IIIB/C cutaneous melanoma of the head and neck following surgery with and without adjuvant radiation therapy: is isolated regional recurrence salvageable? Ann Surg Oncol. 2015;22(12):4052–9.CrossRefGoogle Scholar
- 51.•• Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55 This study showed that adjuvant therapy with ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of RFS, OS, and DFS than placebo. CrossRefGoogle Scholar
- 52.Tarhini AA, Lee SJ, Hodi FS, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): preliminary safety and efficacy of the ipilimumab arms. J Clin Oncol. 2017;35:9500. https://doi.org/10.1200/JCO.2017.35.15_suppl.9500.CrossRefGoogle Scholar
- 56.• Weber JS, D’Angelo SP, Minor 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(4):375–84 This study showed superiority of nivolumab (3 mg/kg every 2 weeks) versus chemotherapy in advanced melanoma patients. CrossRefGoogle Scholar
- 58.Kenneth FG, Megan O, Ahmad AT, et al. SWOG S1404: a phase III randomized trial comparing standard of care adjuvant therapy to pembrolizumab in patients with high risk resected melanoma. J Clin Oncol. 2016;34(15 suppl):e21032.Google Scholar
- 60.•• Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56 This study showed that significantly longer OS occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone among patients with advanced melanoma.CrossRefGoogle Scholar
- 65.Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, 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):1631–9.CrossRefGoogle Scholar
- 66.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:abstract LBA40.CrossRefGoogle Scholar
- 73.Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006;24(19):3164–71.CrossRefGoogle Scholar
- 74.Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One. 2014;9(2):e87705. https://doi.org/10.1371/journal.pone.0087705.CrossRefPubMedPubMedCentralGoogle Scholar
- 75.Tarhini AA, Lin Y, Lin H, Rahman Z, Vallabhaneni P, Mendiratta P, et al. Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-α2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire. J Immunother Cancer. 2018;6(1):112. https://doi.org/10.1186/s40425-018-0428-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018;19(2):181–93.CrossRefGoogle Scholar
- 80.Retseck J, VanderWeele R, Lin HM, Lin Y, Butterfield LH, Tarhini AA. Phenotypic and functional testing of circulating regulatory T cells in advanced melanoma patients treated with neoadjuvant ipilimumab. J Immunother Cancer. 2016;4:38. https://doi.org/10.1186/s40425-016-0141-1.CrossRefPubMedPubMedCentralGoogle Scholar
- 81.Tarhini AA, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield LH, et al. Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015;15(3):39. https://doi.org/10.1186/s40425-015-0081-1.CrossRefGoogle Scholar
- 82.National Institutes of Health. Neoadjuvant dabrafenib, trametinib and/or pembrolizumab in BRAF mutant resectable stage III melanoma (NeoTrio). Available at: https://clinicaltrials.gov/ct2/show/record/NCT02858921.
- 83.National Institutes of Health. ML29255 neoadjuvant vemurafenib and cobimetinib melanoma. Available at: https://clinicaltrials.gov/ct2/show/record/NCT03005639.
- 84.National Institutes of Health. Dabrafenib and trametinib before and after surgery in treating patients with stage IIIB-C melanoma with BRAF V600 mutation. Available at: https://clinicaltrials.gov/ct2/show/NCT02231775.
- 85.National Institutes of Health. Study of neo-adjuvant use of vemurafenib plus cobimetinib for BRAF mutant melanoma with palpable lymph node metastases. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02036086?view=record.
- 86.National Institutes of Health. Neoadjuvant dabrafenib + trametinib for AJCC stage IIIB-C BRAF V600 mutation positive melanoma. Available at: https://clinicaltrials.gov/ct2/show/record/NCT01972347.
- 87.National Institutes of Health. Neoadjuvant vemurafenib + cobimetinib in melanoma: NEO-VC. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02303951.
- 88.National Institutes of Health. Neoadjuvant pembrolizumab for unresectable stage III and unresectable stage IV melanoma (NeoPembroMel). Available at: https://clinicaltrials.gov/ct2/show/record/NCT02306850.
- 89.National Institutes of Health. Pembrolizumab in treating patients with stage III-IV high-risk melanoma before and after surgery. Available at: https://clinicaltrials.gov/ct2/show/NCT03698019.
- 90.National Institutes of Health. CMP-001 in combo with nivolumab in stage IIIB/C/D melanoma patients with clinically apparent lymph node disease. Available at: https://clinicaltrials.gov/ct2/show/record/NCT03618641.
- 91.National Institutes of Health. Neoadjuvant combination targeted and immunotherapy for patients with high-risk stage III melanoma (NeoACTIVATE). Available at: https://clinicaltrials.gov/ct2/show/NCT03554083.
- 92.National Institutes of Health. Neoadjuvant trial of nivolumab in combination with HF10 oncolytic viral therapy in resectable stage IIIB, IIIC, IVM1a melanoma. Available at: https://clinicaltrials.gov/ct2/show/record/NCT03259425.
- 93.National Institutes of Health. Nivolumab with or without ipilimumab or relatlimab before surgery in treating patients with stage IIIB-IV melanoma that can be removed by surgery. Available at: https://clinicaltrials.gov/ct2/show/NCT02519322.
- 94.National Institutes of Health. A tissue collection study of pembrolizumab (MK-3475) in subjects with resectable advanced melanoma. Available at: https://clinicaltrials.gov/ct2/show/NCT02434354.
- 95.National Institutes of Health. Neoadjuvant combination biotherapy with pembrolizumab and high dose IFN-alfa2b. Available at: https://clinicaltrials.gov/ct2/show/NCT02339324.
- 96.National Institutes of Health. Efficacy and safety of talimogene laherparepvec neoadjuvant treatment plus surgery versus surgery alone for melanoma. Available at: https://clinicaltrials.gov/ct2/show/NCT02211131
- 98.Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19(9):2370–80.CrossRefGoogle Scholar