Adjuvant therapy

Adjuvant therapeutic options are expanding for patients at high risk of recurrence after complete resection and include checkpoint inhibitors and combination signal transduction inhibitor therapy. Ipilimumab was the first checkpoint inhibitor to be approved by the FDA as adjuvant therapy. It has demonstrated improved OS when given at 10 mg/kg (ipi10), compared with placebo (EORTC 18071 [NCT00636168]).[22] However, ipi10 has significant toxicity at this dose. The North American Intergroup Trial E1609 (NCT01274338), designed with three treatment groups, compared ipi10 with ipilimumab at a lower dose of 3 mg/kg (ipi3) (approved for metastatic disease) and with high-dose interferon (HDI). Patients who received ipi3 had a significant improvement in OS compared with ipi10.[23] These data do not support HDI as an adjuvant treatment option for melanoma. As newer checkpoint inhibitors emerge, the role of ipi3 remains to be further defined.

Large randomized trials with the newer checkpoint inhibitors (nivolumab and pembrolizumab) and with combination signal transduction inhibitors (dabrafenib plus trametinib) showed a clinically significant impact on relapse-free survival (RFS). The CheckMate 238 (NCT02388906) trial compared nivolumab with ipi10 and found that nivolumab produced superior RFS and had a more tolerable safety profile.[24] Pembrolizumab produced superior RFS compared with placebo, with data on OS still maturing in the MK-3475-054/KEYNOTE-054 trial (NCT02362594).[25] Dabrafenib plus trametinib produced superior RFS compared with placebo, with data on OS still maturing in the COMBI-AD trial (NCT01682083).[26] Single-agent BRAF-inhibitor therapy with vemurafenib did not show improved RFS compared with placebo in the BRIM8 trial (NCT01667419).[27]

The benefit of immunotherapy with ipilimumab, nivolumab, and pembrolizumab has been seen regardless of programmed death-ligand 1 (PD-L1) expression or the presence of BRAF pathogenic variants. Combination signal transduction inhibitor therapy with dabrafenib plus trametinib is an additional option for patients with BRAF variants.

Patients should consider participating in clinical trials to identify treatments that will further extend RFS and OS with less toxicity and shorter treatment schedules.