Overview

Comprehensive FDA-approved therapies for Merkel Cell Carcinoma including targeted agents, immunotherapy, and combination regimens. Treatment approaches vary by molecular subtype, stage, and biomarker status.

Epidemiology & Impact

Merkel cell carcinoma is a rare aggressive neuroendocrine skin cancer with approximately 3,000 US cases annually. Incidence has tripled over 20 years. Approximately 80% are associated with Merkel cell polyomavirus (MCPyV). The disease predominantly affects elderly, fair-skinned, immunosuppressed individuals and has higher per-case mortality than melanoma (approximately 33%).

Molecular Biology & Biomarkers

Two molecular subtypes exist: virus-positive (80%, MCPyV T antigens inactivating Rb and p53, low mutational burden) and virus-negative (UV-driven high mutational burden, TP53 and RB1 mutations). Both demonstrate high immunogenicity explaining exceptional checkpoint immunotherapy responsiveness.

Merkel cell carcinoma has two distinct etiological pathways: Merkel cell polyomavirus (MCPyV)-positive (~80% of cases) and virus-negative (~20%). MCPyV-positive tumors have a low mutational burden but express viral T antigens that drive oncogenesis and serve as immune targets. Virus-negative tumors arise from UV-induced mutagenesis and carry extremely high tumor mutational burden (TMB), among the highest of any solid tumor. Both pathways converge on RB1 inactivation — via Large T antigen binding in virus-positive cases and via somatic mutation/deletion in virus-negative cases. TP53 mutations are enriched in virus-negative tumors. The high immunogenicity of both subtypes (viral antigens or neoantigen load) explains the exceptional responsiveness to immune checkpoint inhibitors.

Evolving Treatment Landscape

Avelumab was approved first-line for metastatic MCC with durable 62% response rates. Pembrolizumab shows similar activity. Chemotherapy achieves high initial responses but rarely durable. Surgery and radiation remain important for localized disease.

Early-stage MCC requires wide local excision with sentinel lymph node biopsy. Adjuvant radiation therapy reduces local recurrence risk and is recommended for most patients. For metastatic disease, immune checkpoint inhibitors have transformed outcomes: avelumab (JAVELIN Merkel 200), pembrolizumab (KEYNOTE-017), and retifanlimab (POD1UM-201) all achieve durable responses in 30-60% of patients. First-line immunotherapy is now preferred over chemotherapy, which achieves high initial response rates (60%) but short durations (typically 3-6 months). For immunotherapy-refractory disease, platinum/etoposide remains active. Emerging strategies include tumor-infiltrating lymphocyte (TIL) therapy, combination checkpoint inhibitors, and T-cell engaging bispecific antibodies targeting MCPyV T antigens.

Approved Merkel Cell Carcinoma Therapies

Bavencio
avelumab
FDA Approved 2017 Metastatic
Approved Indications (US/FDA)
Treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This was the first FDA-approved treatment for metastatic MCC.
Dosing Schedule
800 mg IV every 2 weeks
Drug Class
Checkpoint Inhibitor (Anti-PD-L1)
Manufacturer
Pfizer/Merck KGaA
Approval Year
2017
Pivotal Trial
NCT02155647 ↗
Key Publication
Kaufman et al. Lancet Oncol 2016 (JAVELIN Merkel 200) ↗
Keytruda
pembrolizumab
FDA Approved 2018 Recurrent/Metastatic
Approved Indications (US/FDA)
Treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.
Dosing Schedule
200 mg IV Q3W (adults) or 2 mg/kg Q3W (pediatric, max 200 mg)
Drug Class
Checkpoint Inhibitor (Anti-PD-1)
Manufacturer
Merck
Approval Year
2018
Pivotal Trial
NCT02267603 ↗
Key Publication
Nghiem et al. NEJM 2016 (KEYNOTE-017) ↗