Anti-programmed death (PD)-1 and PD-ligand (L)-1 checkpoint inhibitors have revolutionized the therapy of several cancers.,Immunotherapy of cancer can offer long-term durable benefit to patients, is active regardless of tumour histology, has a unique immune-related safety profile, and can be used in combination with other cancer treatments.,In addition, recent research has shown that immune-based therapy can be used as adjuvant therapy, that outcomes may be influenced by dose, and that clinical activity is observed in patients with brain metastases.,Despite our increased understanding of these agents, there are still several important questions that need to be answered.,These include strategies to overcome primary and acquired resistance, the influence of mutational status on treatment outcomes, the optimal duration of treatment, and the need to identify novel combination regimens that offer increased anti-tumour potency and/or reduced toxicity.,Here we review recent developments in these areas, with particular focus on new data reported at the 2017 ASCO Annual Meeting.
In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load.,The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway.,However, the prognostic significance of mutational stratification is unclear and needs further investigation.,Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies.,Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics.,We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature.,Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden.,We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis.,Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS  P = 0.03, OS  P = 0.06, respectively).,Melanoma genomic subtypes display different biological and clinical characteristics.,The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.