Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun‐exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%–46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group. Implications for Practice Merkel cell carcinoma (MCC) is an uncommon aggressive skin cancer associated with advanced age, UV light exposure, and immunosuppression. Up to 80% are associated with Merkel cell polyomavirus. MCC is a chemosensitive disease, but tumor responses in the advanced setting are short‐lived with no long‐term survivors. Recent clinical trials with immune checkpoint inhibitors (i.e., pembrolizumab, avelumab, nivolumab) have shown promising results, with avelumab becoming the first drug to receive regulatory approval for this orphan indication. Further follow‐up is needed, however, to define more adequately the long‐term benefits of these drugs, and continued research is warranted to optimize immunotherapeutic strategies in this setting.

Merkel Cell Carcinoma of Unknown Primary: Immunohistochemical and Molecular Analyses Reveal Distinct UV-Signature/MCPyV-Negative and High Immunogenicity/MCPyV-Positive Profiles

“…Our findings support the role of immunotherapy in MCC-UP, which might include agents that block PD-1/PD-L1 axis and regulatory T-cell function or enhance T-cell activity. Several promising clinical trials of immune checkpoint inhibitors have demonstrated responses to anti-PD-L1 (avelumab, atezolizumab) and anti-PD1 (nivolumab, pembrolizumab) therapy [ 37 ]. In addition, a case of MCC-UP with a good response to avelumab has recently been reported [ 38 ].…”

Non-Melanoma Skin Cancers: Biological and Clinical Features

“…Chemotherapeutic regimens including platinum-based combinations, etoposide, topotecan, taxanes and anthracyclines were widely used until 2016, leading to response rates in the range of 30–75%, and to median PFS and OS of approximately 3 and 10 months, respectively, in the first-line setting [ 161 , 162 , 163 , 164 , 165 ]. The immunosuppressive effect of chemotherapy is currently regarded as a possible mechanism accounting for the early development of resistance following treatment with cytotoxic agents in the context of a highly immunogenic cancer [ 166 ].…”

Multidisciplinary team approach for Merkel cell carcinoma: the European Institute of Oncology experience with focus on radiotherapy

“…As a rare disease, MCC management requires MTB discussions to clarify any aspect of this complex scenario with dedicated specialists. Future improvement of MCC therapy, such as immune therapy 22 and other tailored treatment, requires multi-institutional collaborative groups and randomized trials.…”