Teaching pack: Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of older, fair-skinned and immunosuppressed people. About 80% of cases in the Northern Hemisphere are driven by clonally integrated Merkel cell polyomavirus (MCPyV, discovered 2008); the remainder are UV-induced with a very high tumour mutational burden. Both forms are immunogenic, which explains why MCC responded to checkpoint blockade when chemotherapy gave only brief responses.

Localised disease is treated with wide excision, sentinel node biopsy and adjuvant radiotherapy; the STAMP and ADMEC-O trials tested adjuvant PD-1 blockade, with ADMEC-O (nivolumab) showing a disease-free survival benefit in 2023. Metastatic disease is treated first line with avelumab (JAVELIN Merkel 200, first approval 2017), pembrolizumab (KEYNOTE-017, 2018) or retifanlimab (POD1UM-201, 2023); durable responses occur in about half, and chemotherapy is reserved for immunotherapy failure. Circulating MCPyV oncoprotein antibodies (AMERK) allow surveillance in seropositive patients.

• Three approved PD-1/PD-L1 antibodies; about half of metastatic patients respond and most responders stay in remission for years.
• Virus-driven biology makes MCPyV antigens an appealing target for vaccines and TCR-T.
• Adjuvant immunotherapy has its first positive trial (ADMEC-O) and is entering guidelines.
• Serologic surveillance (MCPyV oncoprotein antibodies) reduces imaging in seropositive patients.

1. 1972Toker describes 'trabecular carcinoma of the skin'
2. 2008Merkel cell polyomavirus discovered
3. 2016Pembrolizumab first-line phase 2 (KEYNOTE-017, NEJM)
4. 2017Avelumab: first approved therapy for MCC
5. 2018Pembrolizumab approved
6. 2023Retifanlimab approved; ADMEC-O adjuvant nivolumab positive

• Nivolumab (product)
• Retifanlimab (product)
• Ipilimumab (product)

• Half of patients do not respond to PD-1 blockade and have no effective second line.
• Immunosuppressed patients: high incidence, poor outcomes, contraindications to immunotherapy.
• No validated adjuvant standard yet despite ADMEC-O.
• Rarity limits trial size; registries (e.g. Seattle) carry much of the evidence.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
3. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.

• NCCN Guidelines: Merkel Cell Carcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444
• Merkelcell.org (UW/Fred Hutch): https://merkelcell.org/
• NCI PDQ: Merkel cell carcinoma: https://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Merkel-cell_carcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444