Update on Immunotherapeutics in the Management of Metastatic Melanoma

David Bulir, MD, PhD; Steven Liang, BHSc, PhD (Candidate); Maureen O'Malley, MD, FRCPC; Elaine McWhirter, MD, MSc


Skin Therapy Letter. 2019;24(1) 

In This Article

Immunotherapeutics for Adjuvant Therapy

Checkpoint immunotherapy and MEK/BRAF inhibition have also shown significant benefits in overall survival and recurrence-free survival in the adjuvant setting. Prior to checkpoint immunotherapy and MEK/BRAF inhibition, interferon was the only approved adjuvant treatment, and provided only modest benefit with significant toxicities.[32] A study comparing a higher dose of ipilimumab (10 mg/kg) to placebo for 3 years demonstrated significant benefits.[33] Three-year recurrence-free survival among patients receiving ipilimumab was 46.5% compared to 34.8% in the placebo group.[34] The median recurrence-free survival was significantly higher in the ipilimumab group compared to the placebo group, at 26.1 vs. 17.1 months, respectively. Of note, there were five deaths related to adverse events associated with ipilimumab and 46% of patients had grade 3 or higher adverse events leading to approximately 40% of patients discontinuing therapy before starting maintenance therapy.[33] Recently published updated results demonstrated a 5-year overall survival rate of 65.4% in the ipilimumab arm, compared to 54.4% for placebo (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001).[34] Due to the significant number of patients who discontinued ipilimumab after induction, there may be potential for greater benefit if patients continued with maintenance therapy.

In late 2017, the Food and Drug Administration in the United States approved nivolumab for adjuvant treatment in patients with melanoma and completely resected lymph nodes or metastases (stage IIIb/c or IV), based on the CheckMate-238 trial.[35] This randomized, phase III trial compared 1 year of treatment with nivolumab or ipilimumab in patients with resected melanoma.[35] The recurrence-free survival in patients who received nivolumab was 70.5%, compared to 60.8% in the ipilimumab arm. Six months after discontinuation of therapy (18 months after starting), recurrence-free survival in patients treated with nivolumab was 66.4% compared to 52.7% with ipilimumab.[35] Patients who received nivolumab had a considerably lower frequency of grade 3 or greater adverse events, 14.4% vs. 45.9% with ipilimumab. The discontinuation rate related to adverse events, regardless of severity, was only 9.7% with nivolumab compared to 42.6% with ipilimumab.[35]CheckMate-238 is presently ongoing and plans to assess longterm survival.

Combination MEK/BRAF inhibitors have also been studied in the adjuvant setting, with stage III BRAFV600E/V600K mutation positive melanoma. In the COMBI-AD trial, patients received dabrafenib and trametinib or placebo for 1 year.[36] With a median followup of 2.8 years, disease recurrence occurred in 37% of patients receiving dabrafenib and trametinib compared to 57% of patients in the placebo group, with a 3-year recurrence-free survival rate of 58% and 39%, respectively.[36] The 3-year overall survival among patients receiving active therapy was 86% vs. 77% in the placebo group.[36] Patients receiving combination treatment had a significantly reduced rate of distant metastases or deaths (25%) compared to those receiving placebo (35%).[36]