{"entity":{"id":"advanced-cutaneous-scc","kind":"cancer","name":"Advanced cutaneous squamous cell carcinoma","aka":["Locally advanced cutaneous squamous cell carcinoma","Metastatic cutaneous squamous cell carcinoma","Advanced cSCC","Unresectable skin squamous cell carcinoma"],"tldr":"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.","summary":"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.\n\nEMPOWER-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.\n\nImmunotherapy 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_skin","links":[{"label":"EMPOWER-CSCC-1 (NEJM 2018)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1805131"},{"label":"Neoadjuvant cemiplimab (NEJM 2022)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2209813"},{"label":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_skin"}],"tags":["subtype-page"],"related":["cutaneous-scc","head-and-neck"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","mohs-surgery","imrt-igrt","superficial-radiotherapy","oncolytic-virus","photoimmunotherapy"],"targets":["pd1","pdl1","egfr"],"drugs":["cemiplimab","pembrolizumab","cosibelimab","cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","neoadjuvant-adjuvant","pcr"],"trials":["empower-cscc-1","keynote-629","nct04050436"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"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.","subtypes":["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"],"biomarkers":["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"],"standardOfCare":[{"setting":"High-risk resectable disease","approach":"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.","refs":["mohs-surgery","imrt-igrt","cemiplimab","sentinel-node"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Adjuvant after surgery and radiotherapy","approach":"Cemiplimab for high-risk disease (C-POST, 2025).","refs":["cemiplimab"],"guideline":{"version":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"}},{"setting":"Locally advanced or metastatic, first line","approach":"Cemiplimab (EMPOWER-CSCC-1), pembrolizumab (KEYNOTE-629) or cosibelimab; radiotherapy for symptomatic sites.","refs":["empower-cscc-1","keynote-629","cemiplimab","pembrolizumab","cosibelimab","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Immunotherapy-ineligible or refractory","approach":"Cetuximab with or without radiotherapy, platinum-based chemotherapy, capecitabine; clinical trials of RP1 with cemiplimab or photoimmunotherapy.","refs":["cetuximab","carboplatin","nct04050436","nct04305795","vusolimogene-oderparepvec"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Transplant recipients","approach":"Reduce immunosuppression and switch to sirolimus or everolimus where possible; PD-1 blockade only after weighing graft rejection risk; surgery and radiotherapy preferred.","refs":["everolimus","cemiplimab"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}}],"stateOfArt":["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."],"history":[{"year":2011,"title":"Cetuximab phase 2: responses in about a quarter of unresectable tumours","refs":["cetuximab"]},{"year":2018,"title":"EMPOWER-CSCC-1: cemiplimab is the first approved systemic therapy","refs":["empower-cscc-1","cemiplimab"]},{"year":2020,"title":"KEYNOTE-629: pembrolizumab approved for recurrent or metastatic disease","refs":["keynote-629","pembrolizumab"]},{"year":2022,"title":"Neoadjuvant cemiplimab: pathological complete response in 51 percent (NEJM)","refs":["cemiplimab"]},{"year":2024,"title":"Cosibelimab approved","refs":["cosibelimab"]},{"year":2025,"title":"C-POST: adjuvant cemiplimab cuts recurrence after surgery and radiotherapy","refs":["cemiplimab"]}],"pipeline":["nct04050436","nct04305795","nct06585410","hmbd-001","cosibelimab","vusolimogene-oderparepvec","cemiplimab"],"openProblems":["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."],"parent":"cutaneous-scc"},"route":"/cancers/advanced-cutaneous-scc/","neighbours":{"cancer":[{"id":"cutaneous-scc","kind":"cancer","name":"Cutaneous squamous cell carcinoma","route":"/cancers/cutaneous-scc/"},{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"oncolytic-virus","kind":"technology","name":"Oncolytic viruses","route":"/technologies/oncolytic-virus/"},{"id":"photoimmunotherapy","kind":"technology","name":"Photoimmunotherapy & photodynamic therapy","route":"/technologies/photoimmunotherapy/"},{"id":"sentinel-node","kind":"technology","name":"Sentinel lymph node biopsy","route":"/technologies/sentinel-node/"},{"id":"superficial-radiotherapy","kind":"technology","name":"Superficial and orthovoltage radiotherapy for skin cancer","route":"/technologies/superficial-radiotherapy/"}],"term":[{"id":"mohs-surgery","kind":"term","name":"Mohs surgery","route":"/terms/mohs-surgery/"},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/"},{"id":"pcr","kind":"term","name":"Pathologic complete response (pCR)","route":"/terms/pcr/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cemiplimab","kind":"drug","name":"Cemiplimab","route":"/drugs/cemiplimab/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"cosibelimab","kind":"drug","name":"Cosibelimab","route":"/drugs/cosibelimab/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"hmbd-001","kind":"drug","name":"HMBD-001","route":"/drugs/hmbd-001/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"vusolimogene-oderparepvec","kind":"drug","name":"Vusolimogene oderparepvec","route":"/drugs/vusolimogene-oderparepvec/"}],"trial":[{"id":"nct04305795","kind":"trial","name":"An Open-label Study Using ASP-1929 Photoimmunotherapy in Combination With Anti-PD1 Therapy in EGFR Expressing Advanced Solid Tumors","route":"/trials/nct04305795/"},{"id":"empower-cscc-1","kind":"trial","name":"EMPOWER-CSCC-1","route":"/trials/empower-cscc-1/"},{"id":"keynote-629","kind":"trial","name":"KEYNOTE-629","route":"/trials/keynote-629/"},{"id":"nct04050436","kind":"trial","name":"Study Evaluating Cemiplimab Alone and Combined With RP1 in Treating Advanced Squamous Skin Cancer","route":"/trials/nct04050436/"},{"id":"nct06585410","kind":"trial","name":"Study of Intralesional Cemiplimab in Adult Patients With Early Stage Cutaneous Squamous Cell Carcinoma","route":"/trials/nct06585410/"}]}}