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Merkel cell carcinoma is a rare, fast-growing skin cancer, usually caused by a common virus (Merkel cell polyomavirus) or by sun damage. Once it had spread there was no treatment that worked; PD-1/PD-L1 immunotherapy now gives lasting responses in about half of patients.
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.
Unsolved: primary and acquired immunotherapy resistance (about half of patients), immunosuppressed patients (transplant, CLL) who cannot receive checkpoint blockade safely, and the adjuvant standard.
Merkel cell carcinoma causes about 3,000 cases per year in the US and rising; median age is ~75; it is roughly 40 times rarer than melanoma and more likely to spread stage for stage, which is why immunotherapy's durable responses mattered so much.
Each skin cancer comes from a different cell layer: melanocytes and basal cells at the base of the epidermis, keratinocytes above them, Merkel cells and blood vessels in the dermis; depth of invasion decides the risk.
Same organ: Melanoma, Basal cell carcinoma, Cutaneous squamous cell carcinoma, Kaposi sarcoma, Skin cancer (all types), BRAF V600-mutant melanoma, Stage III melanoma (after surgery), Stage IIB and IIC melanoma, Advanced melanoma (unresectable stage III and stage IV), Mucosal melanoma, Acral melanoma, Advanced cutaneous squamous cell carcinoma, Locally advanced and metastatic basal cell carcinoma, Bowen's disease (squamous cell carcinoma in situ), Dermatofibrosarcoma protuberans
Wide local excision with sentinel node biopsy; adjuvant radiotherapy to the primary site (and nodal basin if node-positive); adjuvant nivolumab supported by ADMEC-O in selected patients.
Lymphadenectomy and/or nodal radiotherapy; neoadjuvant nivolumab (CheckMate 358) produced pathological complete responses in about half.
Avelumab, pembrolizumab or retifanlimab; ~50% response with most responses durable.
Platinum-etoposide chemotherapy (brief responses), radiotherapy, clinical trials (ipilimumab-nivolumab, T-VEC, adoptive T cells).
Avelumab, pembrolizumab and retifanlimab are all approved and none has been compared with another. First-line response was 39.7 per cent with avelumab in 116 patients, 56 per cent with pembrolizumab in 50 and 54.5 per cent with retifanlimab in 101. The retifanlimab study is the most fully reported: 17.8 per cent complete responses, median duration of response not reached in complete responders and 25.3 months in partial responders, median progression-free survival 16.0 months, and 63 per cent of patients alive at three years, in a disease where chemotherapy responses were measured in months. Grade 3 immune-related adverse events occurred in 10.9 per cent. Which antibody is used matters far less than that roughly half of patients respond and most responders keep responding.
ADMEC-O randomised 179 patients with completely resected Merkel cell carcinoma 2 to 1 to a year of nivolumab or to observation. Disease-free survival was 85 per cent at 12 months and 84 per cent at 24 with nivolumab against 77 and 73 per cent with observation, a hazard ratio of 0.58 whose 95 per cent confidence interval, 0.30 to 1.12, crosses one; the authors state it as an absolute risk reduction of 9 and 10 percentage points. Grade 3 or 4 adverse events occurred in 42 per cent against 11 per cent. Overall survival had ten events against six in a group half the size and is not mature. This is a phase 2 signal in a rare disease, not a proven standard, and the randomised phase 3 that would settle it, STAMP, has not reported.
NICE technology appraisal TA691 recommendation 1.1 recommends avelumab for metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease, under a commercial arrangement, on evidence collected in the Cancer Drugs Fund under TA517. TA517 recommendation 1.1 continues to cover its use after one or more lines of chemotherapy. Pembrolizumab and retifanlimab have no NICE appraisal for this disease.
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Query for this cancer: (TITLE:"Merkel cell carcinoma" OR ABSTRACT:"Merkel cell carcinoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Merkel cell carcinoma, not a curated reading list.
Feng, Chang and Moore find clonally integrated MCPyV in most MCC using digital transcriptome subtraction.
JAVELIN Merkel 200; accelerated approval March 2017.
179 patients randomised 2 to 1 to a year of nivolumab or observation; disease-free survival 84 against 73 per cent at 24 months, hazard ratio 0.58 with a confidence interval crossing one, and overall survival not mature.
Objective response 54.5 per cent in 101 chemotherapy-naive patients, median progression-free survival 16.0 months and 63 per cent alive at three years.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
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Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Immunotherapy can attack hormone-producing glands: most often the thyroid (usually ending in an under-active thyroid needing lifelong tablets), and less often the pituitary (hypophysitis) or adrenal glands, which can be life-threatening if missed.
Inflammation of the bowel caused by immunotherapy releasing the immune system against the gut lining, producing diarrhoea that can be severe. It is the commonest serious side effect of CTLA-4 antibodies and is treated with steroids and, if needed, infliximab.
See all on the product pages:AvelumabIpilimumabNivolumabPembrolizumabPlatinum + etoposide (EP / CE)Retifanlimab·Printable cards in the navigator
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