An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy

Simple Summary Merkel cell carcinoma (MCC) is a rare and highly aggressive type of skin neuroendocrine cancer that frequently recurs and metastasizes within a relatively short period. Despite rapid growth and characteristic skin color, MCC often goes undiagnosed in its early stage. Therefore, therapy is often initiated at the advanced stage, and selecting appropriate therapeutic interventions is critical. The emergence of novel immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), presents a promising treatment option for advanced MCC. Several biomarkers, such as PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI), showed significant potential as predictive biomarkers for treatment with ICI. Despite their predictive value, each has demonstrated limited value in MCC over recent years. Abstract Merkel cell carcinoma (MCC) is primarily a disease of the elderly Caucasian, with most cases occurring in individuals over 50. Immune checkpoint inhibitors (ICI) treatment has shown promising results in MCC patients. Although ~34% of MCC patients are expected to exhibit at least one of the predictive biomarkers (PD-L1, high tumor mutational burden/TMB-H/, and microsatellite instability), their clinical significance in MCC is not fully understood. PD-L1 expression has been variably described in MCC, but its predictive value has not been established yet. Our literature survey indicates conflicting results regarding the predictive value of TMB in ICI therapy for MCC. Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI.