Advanced cutaneous squamous cell carcinoma
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.
Overview
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.
State of the art
- PD-1 blockade produces durable responses in about half of patients with advanced disease, where chemotherapy and cetuximab gave brief responses in a quarter.
- Neoadjuvant cemiplimab eliminates the tumour in about half of resectable high-risk cases and adjuvant cemiplimab (C-POST) is the first proven adjuvant therapy.
- Immunosuppressed patients remain the hardest group because the drugs that work best threaten the transplanted organ.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Check before combiningFood and drink: Everolimus
Avoid grapefruit. Live vaccines are contraindicated.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningKidneys: Carboplatin
Dose by Calvert formula using GFR (see the calculators).
- Check before combiningLiver: Everolimus
7.5 mg (mild), 5 mg (moderate), 2.5 mg (severe).
See all on the product pages:CarboplatinCemiplimabCosibelimabEverolimusPembrolizumab·Printable cards in the navigator
Anatomy and lymph node drainage
- Epidermis (in situ)
- Basal layer (melanocytes, basal cells)
- Keratinocytes (squamous)
- Dermis (invasive; Breslow depth)
- Merkel cells (dermal-epidermal)
- Dermal vessels (Kaposi)
- Acral and mucosal sites
- Nodes: sentinel node in the draining basin
- Nodes: regional basin (axilla, groin, neck)
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.
- Epidermis (in situ)
- Basal layer (melanocytes, basal cells)
- Keratinocytes (squamous)Locally advanced cutaneous squamous cell carcinoma (unresectable, not curable by radiotherapy) · Nodal metastatic cutaneous squamous cell carcinoma (parotid and cervical nodes) · Distant metastatic cutaneous squamous cell carcinoma · Cutaneous squamous cell carcinoma in organ-transplant recipients and other immunosuppressed patients · Keratinocyte cancer with perineural invasion
- Dermis (invasive; Breslow depth)
- Merkel cells (dermal-epidermal)High-risk resectable disease (neoadjuvant cemiplimab, adjuvant C-POST)
- Dermal vessels (Kaposi)
- Acral and mucosal sites
- sentinel node in the draining basin
- regional basin (axilla, groin, neck)
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, Dermatofibrosarcoma protuberans
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Subtypes & biomarkers
top- Locally advanced cutaneous squamous cell carcinoma (unresectable, not curable by radiotherapy)
- Nodal metastatic cutaneous squamous cell carcinoma (parotid and cervical nodes)
- Distant metastatic cutaneous squamous cell carcinoma
- High-risk resectable disease (neoadjuvant cemiplimab, adjuvant C-POST)
- Cutaneous squamous cell carcinoma in organ-transplant recipients and other immunosuppressed patients
- Keratinocyte cancer with perineural invasion
- Tumour mutational burden (very high; ultraviolet signature)
- Perineural and lymphovascular invasion
- Depth of invasion and differentiation grade
- Immunosuppression status (transplant, chronic lymphocytic leukaemia, HIV)
- PD-L1 expression (not required for treatment)
- Pathological response after neoadjuvant immunotherapy
How often this target appears
- 2011Cetuximab phase 2: responses in about a quarter of unresectable tumours
- 2018EMPOWER-CSCC-1: cemiplimab is the first approved systemic therapy
- 2020KEYNOTE-629: pembrolizumab approved for recurrent or metastatic disease
- 2022Neoadjuvant cemiplimab: pathological complete response in 51 percent (NEJM)
- 2024Cosibelimab approved
- 2025C-POST: adjuvant cemiplimab cuts recurrence after surgery and radiotherapy
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 13 changes by month →- 2026-09-17This recordAdvanced cutaneous squamous cell carcinomaFacts on this page last checked
When this page itself was last checked or edited.
- 2025GuidelineAdvanced cutaneous squamous cell carcinomaGuideline C-POST (NEJM 2025): Adjuvant after surgery and radiotherapy
Cemiplimab for high-risk disease (C-POST, 2025).
- 2025MilestoneCemiplimabC-POST: adjuvant cemiplimab cuts recurrence after surgery and radiotherapy
A milestone in how this cancer is treated.
- 2024ApprovalCosibelimabCosibelimab approved in US
Metastatic or locally advanced cutaneous SCC not curable by surgery or radiation
- 2024MilestoneCosibelimabCosibelimab approved
A milestone in how this cancer is treated.
- 2022MilestoneCemiplimabNeoadjuvant cemiplimab: pathological complete response in 51 percent (NEJM)
A milestone in how this cancer is treated.
What is in development for Advanced cutaneous squamous cell carcinoma, drawn from the whole corpus: 6 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 2 · 1
Trials under way · 3
- Study Evaluating Cemiplimab Alone and Combined With RP1 in Treating Advanced Squamous Skin Cancer · phase 2 · Replimune, Inc.
- An Open-label Study Using ASP-1929 Photoimmunotherapy in Combination With Anti-PD1 Therapy in EGFR Expressing Advanced Solid Tumors · phase 1/2 · Rakuten Medical, Inc.
- Study of Intralesional Cemiplimab in Adult Patients With Early Stage Cutaneous Squamous Cell Carcinoma · phase 3 · Regeneron Pharmaceuticals
Trials reported · 2
- EMPOWER-CSCC-1 · phase 2 · 2018 · positive
- KEYNOTE-629 · phase 2 · 2020 · positive
Open problems and what is being done
Transplant recipients, who have the highest incidence, cannot safely receive the most effective drugs.
About half of patients do not respond to PD-1 blockade and there is no approved second-line therapy.
How much surgery and radiotherapy can be omitted after a complete neoadjuvant response is unsettled.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Milan · cancer center | Italy | none recorded | 0 | 1,246 | 21,746 | #11 | |
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Pittsburgh, PA · cancer center | United States | 0 | 1,078 | 21,539 | - | ||
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - | |
Dresden · cancer center | Germany | none recorded | 0 | 728 | 7,984 | - | |
| United Kingdom | none recorded | 0 | 693 | 7,168 | - | ||
Aarhus · hospital | Denmark | none recorded | 0 | 624 | 4,497 | - | |
Freiburg im Breisgau · cancer center | Germany | none recorded | 0 | 549 | 5,261 | - | |
Lausanne · hospital | Switzerland | none recorded | 0 | 509 | 9,176 | - | |
Brussels · cancer center | Belgium | none recorded | 0 | 489 | 8,689 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Advanced cutaneous squamous cell carcinoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Advanced cutaneous squamous cell carcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Tumour mutational burden, Perineural and lymphovascular invasion, Depth of invasion and differentiation grade, Immunosuppression status, PD-L1 expression), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Locally advanced cutaneous squamous cell carcinoma, Nodal metastatic cutaneous squamous cell carcinoma, Distant metastatic cutaneous squamous cell carcinoma.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
High-risk resectable disease
- For my situation (high-risk resectable disease), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Cemiplimab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Adjuvant after surgery and radiotherapy
- For my situation (adjuvant after surgery and radiotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Cemiplimab for high-risk disease (C-POST, 2025).
- Am I a candidate for Cemiplimab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Locally advanced or metastatic, first line
- For my situation (locally advanced or metastatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: Cemiplimab (EMPOWER-CSCC-1), pembrolizumab (KEYNOTE-629) or cosibelimab; radiotherapy for symptomatic sites.
- Am I a candidate for Cemiplimab, Pembrolizumab, Cosibelimab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of EMPOWER-CSCC-1 and KEYNOTE-629 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Immunotherapy-ineligible or refractory
- For my situation (immunotherapy-ineligible or refractory), which of the standard options do you recommend and why?Why: Guideline options include: Cetuximab with or without radiotherapy, platinum-based chemotherapy, capecitabine; clinical trials of RP1 with cemiplimab or photoimmunotherapy.
- Am I a candidate for Cetuximab, Carboplatin, Vusolimogene oderparepvec, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Study Evaluating Cemiplimab Alone and Combined With RP1 in Treating Advanced Squamous Skin Cancer and An Open-label Study Using ASP-1929 Photoimmunotherapy in Combination With Anti-PD1 Therapy in EGFR Expressing Advanced Solid Tumors apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Transplant recipients
- For my situation (transplant recipients), which of the standard options do you recommend and why?Why: Guideline options include: Reduce immunosuppression and switch to sirolimus or everolimus where possible; PD-1 blockade only after weighing graft rejection risk; surgery and radiotherapy preferred.
- Am I a candidate for Everolimus, Cemiplimab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Study Evaluating Cemiplimab Alone and Combined With RP1 in Treating Advanced Squamous Skin Cancer, An Open-label Study Using ASP-1929 Photoimmunotherapy in Combination With Anti-PD1 Therapy in EGFR Expressing Advanced Solid Tumors, Study of Intralesional Cemiplimab in Adult Patients With Early Stage Cutaneous Squamous Cell Carcinoma, HMBD-001?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Transplant recipients, who have the highest incidence, cannot safely receive the most effective drugs”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “About half of patients do not respond to PD-1 blockade and there is no approved second-line therapy”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Advanced cutaneous squamous cell carcinoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
6drugs
8companies
7terms
4trials
5Latest papers
topQuery 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.
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