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Immune checkpoint inhibitors and BRAF and MEK inhibitors revolutionized the treatment of metastatic melanoma. More recently, the use of these agents has expanded into the adjuvant setting for patients with resectable stage III disease. Surgery, including wide local excision and lymph node dissection, is standard of care for patients with stage III melanoma where the disease has spread into the lymph nodes. Patients with stage III melanoma can be further divided into 4 substages—stages IIIA, IIIB, IIIC, and IIID—based on the depth of the primary melanoma, the presence or absence of ulceration in the primary melanoma, how many lymph nodes are involved, and whether the lymph nodes were palpable or detected with a biopsy. These different melanoma substages within the stage III category have distinct melanoma-specific survival outcomes with very poor prognosis shown for patients with stage IIID disease (10-year survival rate of 24%) and better prognosis for patients with stage IIIA disease (10-year survival rate of 88%).1 For patients with a poorer prognosis, adjuvant therapy can provide an opportunity for improved outcomes. Traditional adjuvant therapies for stage III resected melanoma included high-dose interferon or peginterferon. However, these drugs were associated with variable survival benefits and considerable toxicity. The first newer drug to be approved by the FDA for the adjuvant treatment of stage III melanoma was ipilimumab, a CTLA-4 inhibitor. Although ipilimumab was associated with improved survival vs placebo in patients with completely resected stage III melanoma, it was also associated with considerable toxicity.2 There are now studies that suggest greater benefits in the adjuvant setting with the PD-1 inhibitors nivolumab and pembrolizumab. Nivolumab was approved by the FDA in the adjuvant setting based on data from the phase III CheckMate 238 trial, which randomized patients with resected stage IIIB, IIIC, or IV melanoma to receive nivolumab or ipilimumab for 1 year and found that nivolumab treatment was associated with a 35% reduced risk of relapse compared with ipilimumab, along with much better tolerability.3 Pembrolizumab was approved earlier this year in the adjuvant setting based on the randomized phase III KEYNOTE‑054 study, which demonstrated that treatment with adjuvant pembrolizumab reduced the risk of relapse by 43% compared with placebo for patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma.4 The BRAF plus MEK inhibitor combination of dabrafenib plus trametinib has also been approved by the FDA as an adjuvant treatment for patients with BRAF V600E/K–mutated melanoma. This approval was based on the randomized phase III COMBI-AD study, in which patients with resected stage IIIA, IIIB, or IIIC BRAF-mutated melanoma were randomized to dabrafenib plus trametinib or placebo with treatment for up to 1 year.5 Adjuvant dabrafenib plus trametinib reduced the risk of relapse by 51% compared with placebo in this study. Numerous novel adjuvant strategies are currently being investigated; among these is the combination of nivolumab plus ipilimumab, which is being compared with nivolumab alone in an ongoing trial.6 Another exciting avenue of research concerns the use of neoadjuvant therapy with immunotherapy or targeted agents. Although this approach remains largely investigational, exciting data from early-phase trials have shown the potential of neoadjuvant therapy to improve outcomes for patients with resectable melanoma.7,8 For more detailed information on adjuvant therapy for stage III melanoma, see additional education resources such as Clinical Care Options.
1. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472-492. 2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845-1855. 3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835. 4. Eggermont AM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801. 5. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813-1823. 6. ClinicalTrials.gov. An investigational immuno-therapy study of nivolumab combined with ipilimumab compared to nivolumab by itself after complete surgical removal of stage IIIb/c/d or stage IV melanoma (CheckMate 915). Available at: https://clinicaltrials.gov/ct2/show/NCT03068455. Accessed August 2, 2019. 7. Rozeman EA, Menzies AM, van de Wiel BA, et al. OpACIN-neo—a multicenter phase 2 study to identify the optimal neo-adjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO). Program and abstracts of the 2018 European Society for Medical Oncology; October 19-23, 2018; Munich, Germany. Abstract LBA42. 8. Amaria RN, Prieto PA, Tetzlaff MT, 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;19:181-193.