Melanoma - Emerging treatments | BMJ Best Practice US

Adjuvant nivolumab and ipilimumab combination therapy for advanced resectable disease

Phase 2/3 trials have demonstrated that adjuvant nivolumab plus ipilimumab significantly improved survival in patients with resected stage IV melanoma with no evidence of disease compared with placebo, but no significant difference was found between combination treatment compared with nivolumab alone for patients with resected stage IIIB-D or IV melanoma.[168][169] However, while there has been no demonstrable benefit of adjuvant treatment with nivolumab plus ipilimumab compared with nivolumab alone in resected stage 3 disease, there are some data to suggest benefit in the resected stage 4 setting.[168][169] Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group at lower doses, but when higher doses were used in the trial stage 2 and 4 adverse effects increased to 71%, and 29% of patients, respectively.[168][169]

Binimetinib for NRAS-mutant melanoma

The NEMO trial assessed the efficacy and safety of the mitogen-activated protein kinase (MEK) inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma and found that binimetinib improved progression-free survival compared with dacarbazine and was tolerable.[170] The National Comprehensive Cancer Network (NCCN) guidelines recommend binimetinib as useful in certain circumstances for patients with NRAS-mutated tumors who experience progression following immune checkpoint inhibitor therapy.[14]

Targeted therapy against KIT-mutant melanoma

Mutations in KIT oncogene are characteristic for acral and mucous melanoma subtypes. The therapeutic value of KIT inhibitors (imatinib, nilotinib, dasatinib, and sunitinib) has been evaluated in a systematic review and one-arm meta-analysis.[171] The pooled objective response rate (ORR) of KIT inhibitors for unresectable or metastatic mucosal, acral, or chronically sun-damaged melanoma was 15%. Subgroup analysis revealed the highest ORR for nilotinib (20%).[171] In a single-arm phase 2 trial of patients with KIT-mutated metastatic or inoperable melanoma, 10 of the 11 patients who responded to nilotinib had mutations in exon 11 of the KIT gene, suggesting that nilotinib may be an effective treatment for patients with specific KIT mutations.[172]

Targeted and immunotherapy combinations

The Food and Drug Administration (FDA) has approved combination therapy with the anti-programmed death-1 (PD-1) antibody atezolizumab in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. In a randomized controlled phase 3 trial, the combination of atezolizumab, cobimetinib, and vemurafenib was associated with longer median progression-free survival, and increased toxicity, in patients with unresectable or metastatic disease, compared with cobimetinib plus vemurafenib.[173] However, follow-up data reported that the triplet regimen did not significantly improve overall survival compared with placebo.[174] The NCCN guidelines recommend pembrolizumab plus lenvatinib as a potential treatment for patients with BRAF V600 mutation melanoma who have progressed on systemic immunotherapy, or who have progressed following treatment with BRAF/MEK inhibitor if not previously received.[14] This combination is also recommended as a potential treatment for patients without BRAF V600 mutation who have progressed on anti-PD1 monotherapy if not already received.[14]

Novel molecular and immune targets

The interleukin-2 pathway agonist bempegaldesleukin (BEMPEG/NKTR-214) is under investigation in phase 3 trials, in combination with nivolumab.[175] Bempegaldesleukin preferentially activates CD8+ T cells and natural killer cells, which destroy cancer cells. Other immune cell receptor checkpoints are also under study, including LAG3 and GITR. The Food and Drug Administration has granted fast track designation to alrizomadlin, which targets the p53 pathway. Alrizomadlin binds to, and inactivates, MDM2. In healthy cells, MDM2 binds to and inactivates p53. By blocking this process, alrizomadlin induces the p53 tumor suppression pathway. A phase 2 clinical trial of alrizomadlin plus pembrolizumab for refractory/relapsed melanoma is underway.[176]

Lifileucel

The FDA has granted accelerated approval for lifileucel, a tumor infiltrating lymphocyte therapy, for the treatment of patients with unresectable or metastatic melanoma who have progressed on or after anti-PD-1 therapy, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. Phase 2 trials have demonstrated that lifileucel improved tumor response for patients with advanced melanoma who have been heavily pretreated; one trial reported participants had received at least three prior therapies including PD-1 and PD-L1 inhibitors.[177][178]

Vusolimogene oderparepvec

Vusolimogene oderparepvec is a modified herpes virus which selectively infects and lyses tumor cells.[179] Early results from phase 1 and 2 trials suggest that nivolumab plus vusolimogene oderparepvec is safe and effective in patients with advanced melanoma who have not responded to anti-PD-1 or anti-CTLA4 therapy.[180] A phase 3 trial is in progress.[181] Vusolimogene oderparepvec (in combination with nivolumab) has been granted breakthrough therapy by the FDA.

T-cell receptor therapies

T-cell receptor therapies equip activated T cells with specific receptors that target their complementary cancer antigens. One systematic review demonstrated that for patients with cutaneous melanoma, T-cell receptor therapy improves antitumor activity and survival rates similar to those reported for tumor-inflitrating lymphocyte therapy with a significantly higher benefit for cancer/testis antigens targeting cells.[182]