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Advanced cutaneous squamous cell carcinoma is a skin cancer that has grown beyond what surgery or radiotherapy can remove or has spread to lymph nodes or organs. Because sun damage gives it more mutations than almost any other cancer, immunotherapy works well: cemiplimab or pembrolizumab shrinks about half of tumours, often for years, and cemiplimab before surgery can make large tumours vanish.
Cutaneous squamous cell carcinoma arises from keratinocytes of sun-damaged skin and carries one of the highest mutation burdens of any human cancer, with TP53, NOTCH1 and CDKN2A mutations in most tumours. High-risk features are size over 2 centimetres, depth beyond fat, perineural or lymphovascular invasion, poor differentiation, ear or lip site and immunosuppression; these tumours recur, spread to parotid and cervical nodes and account for most deaths. Advanced disease is defined as locally advanced disease not curable by surgery or radiotherapy, or nodal or distant metastasis. Before 2018 the only systemic options were cetuximab, with responses in about a quarter of patients, and platinum-based chemotherapy with short-lived responses.
EMPOWER-CSCC-1 (2018) showed the PD-1 antibody cemiplimab produced responses in 47 percent of patients with metastatic disease and 46 percent in the pooled analysis of 193 patients, most of them durable, and it became the first approved drug for the disease in September 2018. KEYNOTE-629 (2020) found pembrolizumab produced responses in 34 percent of recurrent or metastatic and 50 percent of locally advanced tumours, and cosibelimab, a PD-L1 antibody, was approved in December 2024. Responses are less frequent in transplant recipients, in whom PD-1 blockade also risks graft rejection, and switching immunosuppression to a mammalian target of rapamycin inhibitor is one strategy.
Immunotherapy is now moving earlier. Neoadjuvant cemiplimab for stage II to IV resectable disease produced pathological complete responses in 51 percent and major pathological responses in 63 percent of 79 patients (2022), allowing smaller operations and sometimes omission of radiotherapy. C-POST (2025) randomised patients with high-risk disease after surgery and radiotherapy to adjuvant cemiplimab or placebo and cut the risk of recurrence or death by about two thirds, making it the first positive adjuvant trial in the disease. Intratumoural oncolytic virus RP1 with cemiplimab, photoimmunotherapy with cemiplimab, an EGFR-directed antibody-drug conjugate and intralesional cemiplimab for early lesions are in trials.
Cutaneous squamous cell carcinoma is the second commonest skin cancer and most are cured by excision, but a few percent recur locally beyond surgical control or spread to lymph nodes and distant sites; the risk is highest in organ-transplant recipients and other immunosuppressed people, in whom the disease is many times commoner and more aggressive.
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, Merkel 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, Locally advanced and metastatic basal cell carcinoma, Bowen's disease (squamous cell carcinoma in situ), Dermatofibrosarcoma protuberans
Excision with margin control or Mohs surgery, nodal evaluation, and postoperative radiotherapy for perineural invasion, positive margins or nodal disease; neoadjuvant cemiplimab to shrink large tumours before surgery.
Cemiplimab for high-risk disease (C-POST, 2025).
Cemiplimab (EMPOWER-CSCC-1), pembrolizumab (KEYNOTE-629) or cosibelimab; radiotherapy for symptomatic sites.
Cetuximab with or without radiotherapy, platinum-based chemotherapy, capecitabine; clinical trials of RP1 with cemiplimab or photoimmunotherapy.
Reduce immunosuppression and switch to sirolimus or everolimus where possible; PD-1 blockade only after weighing graft rejection risk; surgery and radiotherapy preferred.
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Adjuvant cemiplimab is a new standard for high-risk cutaneous squamous cell carcinoma after surgery and radiotherapy, particularly in patients with extracapsular nodal extension.
This cohort, with the locally advanced cohort in the label, is the evidence behind cosibelimab's December 2024 US approval. The response rate is of the same order as cemiplimab and pembrolizumab in this cancer, which gives patients a third checkpoint antibody option, though none of the three has been compared head to head.
Neoadjuvant cemiplimab is now used to shrink large or function-threatening cutaneous squamous cell carcinomas before surgery, and pathological response is being studied as a guide to omitting adjuvant radiotherapy.
Pembrolizumab is an approved first-line option for advanced cutaneous squamous cell carcinoma alongside cemiplimab.
PD-1 blockade is the first-line systemic treatment for advanced cutaneous squamous cell carcinoma, including on the lip, and cemiplimab has since moved into neoadjuvant and adjuvant use.
Query for this cancer: (TITLE:"Advanced cutaneous squamous cell carcinoma" OR ABSTRACT:"Advanced cutaneous squamous cell carcinoma" OR TITLE:"Locally advanced cutaneous squamous cell carcinoma" OR ABSTRACT:"Locally advanced cutaneous squamous cell carcinoma" OR TITLE:"Metastatic cutaneous squamous cell carcinoma" OR ABSTRACT:"Metastatic cutaneous squamous cell carcinoma" OR TITLE:"Advanced cSCC" OR ABSTRACT:"Advanced cSCC" OR TITLE:"Unresectable skin squamous cell carcinoma" OR ABSTRACT:"Unresectable skin squamous cell carcinoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Advanced cutaneous squamous cell carcinoma, not a curated reading list.
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.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Avoid grapefruit. Live vaccines are contraindicated.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Dose by Calvert formula using GFR (see the calculators).
7.5 mg (mild), 5 mg (moderate), 2.5 mg (severe).
See all on the product pages:CarboplatinCemiplimabCosibelimabEverolimusPembrolizumab·Printable cards in the navigator
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