Updates on the Systemic Treatment of Advanced Non-melanoma Skin Cancer

Abstract

Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.

Keywords: adnexal carcinoma; basal cell carcinoma; extramammary Paget's disease; merkel cell carcinoma; squamous cell carcinoma.

Figure 1

Targeting pathways and molecules in the treatment of NMSC. (A) Hedgehog signaling pathway. Activation of Hedgehog signaling is initiated by the cell-surface protein, SMO, which is inhibited by another cell-surface protein, PTCH1. Binding of the Hedgehog ligand to PTCH1 releases this inhibition and thereby activates the pathway. Mutations in PTCH1 result in loss of its inhibitory function, while mutations in SMO lead to constitutive signaling activation. Vismodegib and sonidegib are oral small molecule inhibitors of SMO, which block HH signaling activation. (B) Receptor tyrosine kinases and downstream MAPK and PI3-AKT signaling pathways. Aberrant overexpression or mutations of receptor tyrosine kinases, such as EGFR and HER2, cause activation of downstream signaling pathways, thus triggering several tumorigenic processes, including cell proliferation, cell survival, and resistance to apoptosis. The monoclonal antibodies, cetuximab and panitumumab, and the oral small molecules, gefitinib and erlotinib, inhibit the activity of EGFR. The monoclonal antibody, trastuzumab, inhibits the activity of HER2. (C) Interaction between T cells and tumor cells via the PD-1/PD-L1 axis. PD-1/PD-L1 interaction inhibits activation of T cell functions, including Th1 cytokine secretion, T cell proliferation, and cytotoxicity. Inhibition of PD-1/PD-L1 interaction with the anti-human PD-L1 antibody, avelumab, and anti-human PD-1 antibodies, nivolumab, pembrolizumab, and cemiplimab, releases these inhibitions and thereby activates the cytotoxic effects of T cells on tumor cells.