Melanoma - Emerging treatments

Cancer vaccines plus immunotherapy

IO102-IO103, an investigational immune-modulatory therapeutic cancer vaccine designed to target both tumour cells and immune-suppressive cells within the tumour microenvironment by stimulating activation and expansion of T cells against IDO1+ and/or programmed death-ligand-1 (PD-L1)-positive cells, is being tested to treat patients with advanced melanoma. One open-label, randomised phase 3 trial with treatment-naive advanced melanoma patients compared IO102-IO103 in combination with pembrolizumab or pembrolizumab alone. The initial results, which were presented in a conference abstract, demonstrated that combination treatment improved progression-free survival compared with pembrolizumab alone. ESMO: IO102–IO103 cancer vaccine plus pembrolizumab for first-line (1L) advanced melanoma: primary phase III results (IOB-013/KN-D18) Opens in new window One ongoing single arm phase 2 trial is testing nivolumab plus ipilimumab in combination with the DNA-based melanoma vaccines SCIB1and iSCIB1+, or SCIB1 in combination with pembrolizumab, for untreated patients with unresectable stage III/IV melanoma.[179] Initial results reported in a conference abstract stated that 23 patients have received the combination of SCIB1 with nivolumab plus ipilimumab, and that for the 13 patients that have reached the first imaging timepoint of 13 weeks, the objective response rate is 11/13 (85%), response rates were confirmed in a subsequent scan (one complete response and 10 partial responses); the disease control rate was 12/13 (92%) and 1 partial disease control. Patients showed a 40% to 100% reduction in tumour volume at 13 and/or 25 weeks.[180]

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.[181][182] 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.[181][182] 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.[181][182]

Binimetinib for NRAS-mutant melanoma

The NEMO trial assessed the efficacy and safety of the mitogen-activated extracellular 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.[183] The National Comprehensive Cancer Network (NCCN) guidelines recommend binimetinib as useful in certain circumstances for patients with NRAS-mutated tumours who experience progression following immune checkpoint inhibitor therapy.[13]

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.[184] 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%).[184] 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.[185]

Targeted and immunotherapy combinations

The US Food and Drug Administration (FDA) has approved combination therapy with the PD-L1 inhibitor atezolizumab in combination with cobimetinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. In a randomised 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.[186] However, follow-up data reported that the triplet regimen did not significantly improve overall survival compared with placebo.[187] The NCCN guidelines recommend pembrolizumab plus lenvatinib (a tyrosine kinase inhibitor) 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.[13] This combination is also recommended as a potential treatment for patients without BRAF V600 mutation who have progressed on anti-PD-1 monotherapy if not already received.[13]

Novel molecular and immune targets

The interleukin-2 pathway agonist bempegaldesleukin is under investigation in phase 3 trials, in combination with nivolumab.[188] 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 US FDA 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 tumour suppression pathway. A phase 2 clinical trial of alrizomadlin plus pembrolizumab for refractory/relapsed melanoma is underway.[189]

Lifileucel

The FDA has granted accelerated approval to lifileucel, a tumour 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 tumour response for patients with advanced melanoma who have been heavily pre-treated; one trial reported participants had received at least three prior therapies including PD-1 and PD-L1 inhibitors.[190][191] The 5 year analysis of the C-144 -01 study assessed the long- term efficacy and safety of lifileucel.[190][192] The results demonstrated a 31.4% objective response in pretreated patients with no additional long-term safety concerns.[192]

Vusolimogene oderparepvec

Vusolimogene oderparepvec is a modified herpes virus which selectively infects and lyses tumour cells.[193] 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.[194] A phase 3 trial is in progress.[195] The FDA is currently reviewing the treatment for approval.

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 antitumour activity and survival rates similar to those reported for tumour-inflitrating lymphocyte therapy with a significantly higher benefit for cancer/testis antigens targeting cells.[196] The interim data from a first-in-human, multicentre, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME) directed TCR T cell therapy, in HLA-A*02+ patients with PRAME, recurrent and/or refractory melanoma showed promising anti-tumour activity in multiple solid tumours, including refractory melanoma.[197]