AUTHOR=Rubatto Marco , Sciamarrelli Nadia , Borriello Silvia , Pala Valentina , Mastorino Luca , Tonella Luca , Ribero Simone , Quaglino Pietro 

TITLE=Classic and new strategies for the treatment of advanced melanoma and non-melanoma skin cancer

JOURNAL=Frontiers in Medicine

VOLUME=Volume 9 - 2022

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.959289

DOI=10.3389/fmed.2022.959289

ISSN=2296-858X

ABSTRACT=Advanced melanoma and NMSCs are burdened with a dismal prognosis. To improve the survival of these patients, studies on immunotherapy and target therapies in melanoma and NMSCs are rapidly increasing. 
BRAF and MEK inhibitors improves clinical outcomes, and anti-PD1 therapy demonstrates better results than chemotherapy or anti-CTLA4 therapy in terms of survival of patients with advanced melanoma. 
In recent years, the combination therapy of Nivolumab plus Ipilimumab has gained ground in studies for its survival and response rate benefits in patients with advanced melanoma. 
In addition, neoadjuvant treatment for stage III and IV melanoma, either as monotherapy or combination therapy, has recently been discussed.
Another promising strategy evaluated in recent studies is the triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy. 
On the other hand, in advanced and metastatic BCC, successful therapeutic strategies, such as Vismodegib and Sonidegib, are based on inhibition of aberrant activation of the Hedgehog signaling pathway. 
In these patients, anti PD-1 therapy with Cemiplimab should be reserved as second-line therapy in case of disease progression or poor response. 
In patients with locally advanced or metastatic SCC who are not candidates for surgery or radiotherapy, anti-PD1 agents such as Cemiplimab, Pembrolizumab and Cosibelimab (CK-301) have shown significant results in terms of response rate. 
PD-1/PD-L1 inhibitors, such as Avelumab, have also been used in Merkel carcinoma, achieving responses in half of patients with advanced disease. 
The latest prospect emerging for MCC is the locoregional approach involving injection of drugs that can stimulate the immune system. Two of the most promising molecules used in combination with immunotherapy are Cavrotolimod (a Toll-like receptor 9 agonist) and a Toll-like receptor 7/8 agonist. 
Another area of study is cellular immunotherapy with natural killer cells stimulated with an IL15 analog or CD4/CD8 cells stimulated with tumor neoantigens.
Neoadjuvant treatment with Cemiplimab in CSCCs and Nivolumab in MCCs have shown promising results. 
Despite the successes of these new drugs, the new challenges ahead will be to select patients who will benefit from these treatments, based on biomarkers and parameters of the tumor microenvironment.