Metastatic melanoma is associated with poor outcomes and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand 1 (PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response. Despite these landmark changes in practice, the majority of patients are either intrinsically resistant or rapidly acquire resistance to MAPK pathway inhibitors and immune checkpoint blockade treatment.

• Immunotherapy is currently changing the landscape of oncology.
• Nowadays the standard of care in metastatic or unresectable melanoma patients includes immunomodulating modalities such as anti-PD-1 drugs (nivolumab, pembrolizumab) and the anti-CTLA-4 antibody ipilimumab.
• The improvements of progression free survival and overall survival connected with those treatments were unprecedented and have been confirmed in stage 3 trials.
• Nivolumab is associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. [1]

• PD-1/P-L1 blockade has promising effects in melanoma immunotherapy.
• Removing the so-called " brakes” on T cell immune responses by blocking the PD-1/PD-L1 check point should boost anti-tumour immunity and provide durable tumour regression for cancer patients.
• However, 30–60% of patients show no response to PD-1/PD-L1 blockade. [2]
• It is believed that mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumour site, immunosuppressive factors in the tumour microenvironment and a range of tumour-intrinsic factors.
• Tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance. [2]
• Treatment with an anti-PD-1 mAb also increases the frequency of IFN-gamma and TNF producing CD4+ T-cells specific for melanoma-associated antigens. [2]

• Biomarkers to predict outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence.
• Following pembrolizumab treatment in melanoma patients, high relative eosinophil count and relative lymphocyte count, low lactate dehydrogenase and absence of metastasis other than those involving the soft tissue/lung were found to be independent baseline characteristics associated with favourable overall survival. [3]
• In fact, the presence of these four factors in combination identifies a subgroup with excellent prognosis.
• In contrast, patients with no favourable factors present have poor prognosis.
• While not in melanoma, in colorectal cancer positive mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.
• Recent studies have indicated that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens. [4]
• In this regard, the use of a “cancer immunogram” has been proposed.
• This tool is based on a number of largely unrelated parameters such as tumour “foreignness” and T cell-inhibitory mechanisms.
• Furthermore, the “value” of these parameters can differ greatly between patients. [4]
• For example, in some patients, intratumoural inhibition of tumour-specific T cells will be the sole defect that needs to be addressed, whereas in other patients, the tumour may simply be insufficiently foreign to elicit a clinically relevant T cell response in the first place.
• Because of the multifactorial nature of cancer-immune interactions, combinations of biomarker assays will by definition be required.

• Several reported have strongly suggested that immune checkpoint blockade therapy leads to upregulation of IFN-γ and in turn clearance of tumour cells. [5]
• IFN-γ plays a dual and opposing role in cancer development.
• IFN-γ signalling inhibits tumour growth by arrest of tumour cell cycle, induction of tumour ischaemia and activation of effector cells while impairing suppressive immune cells.
• At the same time, it contributes to tumour growth via promotion of tumourigenesis and angiogenesis, upregulation of tolerant molecules and induction of a homeostasis program.
• The responses of melanoma to IFN-γ are heterogeneous and frequently downregulated in immune checkpoint inhibitor-naïve melanoma, which could possibly be used as a predictor of response to immunotherapy.

• Blocking PD-1 may enhance the durability of anti-tumour responses that are induced by the combined inhibition of BRAF and MEK1.
• Over 50% of melanomas harbour various BRAF mutations with the most common being the V600E.
• The BRAFV600E mutation gives rise to constitutive activation of the MAPK pathway leading to drug- and/or immune-resistance, apoptosis evasion, proliferation, survival and metastasis of melanomas.
• A randomised phase II trial in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor ‘dabrafenib’ and the MEK inhibitor ‘trametinib’ together with the PD-1-blocking antibody pembrolizumab or placebo. [6]
• Progression-free survival was numerically higher in the triplet group-16.0 months-compared with 10.3 months in the doublet group (HR 0.66; P = 0.043); however, the trial did not reach the planned benefit for statistically significant improvement.
• Median duration of response was 18.7 months and 12.5 months (95% confidence interval, 6.0-14.1).
• Thus, triplet therapy with dabrafenib, trametinib and pembrolizumab may be a promising treatment strategy that may help to overcome the problem of treatment resistance.

• Treatment resistance in malignant melanoma continues to be a major clinical obstacle.
• Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway have dramatically changed the treatment landscape.