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Advanced cSCC Management

Cutaneous squamous cell carcinoma (cSCC) is one of the most frequently diagnosed non-melanoma skin cancers, with a rising global incidence. Early-stage and low-risk cSCC are typically managed through surgery and, in some cases, localized therapeutic modalities. However, locally advanced or metastatic cSCC presents significant morbidity and mortality, necessitating a different therapeutic approach.1 Therapeutic recommendations are based on the extent of the disease and primarily consist of surgical resection, possible lymph node dissection, and consideration of adjuvant radiation therapy with or without concurrent systemic therapy.2

Cytotoxic Chemotherapy

Before modern therapies, cytotoxic chemotherapy and platinum-based agents were the mainstays of treatment for advanced cSCC. These agents included cisplatin, bleomycin, interferon, 5-fluorouracil, and doxorubicin, with varied response rates and significant side effects, such as nausea, emesis, and hematological toxicities. Combination with other modalities often confounded long-term efficacy data.1 The current guidelines recommend radiotherapy (RT) if surgery is not feasible, and multidisciplinary teams can consider concurrent systemic therapy in select cases (Table 1).2

Targeted Therapy

Epidermal growth factor receptor (EGFR) Inhibitors

  • Cetuximab: Monoclonal antibody targeting EGFR. Phase II studies showed an objective response rate (ORR) of 28%, with a mean overall survival (OS) of 8.1 months3
  • Panitumumab: Another monoclonal antibody with a 31% ORR in phase II trials4
  • Gefitinib and Erlotinib: Small molecule tyrosine kinase inhibitors (TKIs) with varying efficacy, often used in combination with surgery or radiation therapy1
  • Lapatinib: TKI targeting the HER2 receptor, with anecdotal effectiveness prompting further trials5

EGFR-targeted therapies are generally more tolerable than cytotoxic agents, but often come with side effects, such as cutaneous adverse events and diarrhea. Resistance to EGFR inhibitors is a known issue, with combination therapies being explored to combat this.1

Systemic Immunotherapy

Cemiplimab
  • FDA-approved for metastatic and locally advanced cSCC not candidates for surgery
  • Early data showed a 50% response rate with durable disease control in 65% of patients6
  • Ongoing long-term studies show an observed objective response rate in 62%, with 22% of patients achieving complete response and 40% achieving partial response at a median follow-up of 22.4 months7
  • NCCN guideline-recommended in the neoadjuvant setting
  • Adverse events include fatigue, diarrhea, and nausea/vomiting7
  • C-POST Study: Demonstrated improved disease-free survival (87.1% vs 64.1%) and reduced recurrences (9 events vs 40 for locoregional and 10 vs 26 for distant) in high-risk cSCC compared with placebo in the adjuvant setting.8
  • Phase 2 neoadjuvant study: Showed 2-year event-free survival was 86%, disease-free survival was 90% in patients who underwent surgery, and overall survival was 86%.9
Pembrolizumab
  • FDA-approved for recurrent, metastatic, or locally advanced cSCC not candidates for surgery
  • Keynote 629 Study: Showed an overall response rate of 40.9%, a complete response of 25%, and partial response of 40% at a median follow-up of more than 5 years10
  • CARSKIN Study: Reported an ORR of 41% at week 15 in patients with cSCC, with manageable adverse events3
  • Adverse events include fatigue, pruritus, and asthenia10
Given the published trial data supporting the efficacy and safety of these agents, the current guidelines recommend their use if curative surgery and curative RT are not feasible.2 See the immunotherapy in cSCC section of the portal for additional details about approved and emerging treatments as well as advancements in neoadjuvant and intralesional approaches.

Advanced cSCC requires a comprehensive, multidisciplinary approach for effective management. While traditional cytotoxic chemotherapy played a significant role in the past, modern therapies, including targeted therapies and systemic immunotherapies, have shown promise in improving outcomes and quality of life for patients with advanced cSCC. Ongoing research and clinical trials continue to refine these therapeutic strategies, offering hope for better management of this challenging condition.2 As such, clinicians must remain current on the latest evidence-based guideline recommendations and how to apply them to patient preferences for treatment.

References

  1. Aboul-Fettouh N, Morse D, Patel J, Migden MR. Immunotherapy and systemic treatment of cutaneous squamous cell carcinoma. Dermatol Pract Concept. 2021;11(suppl 2):e2021169S. doi:10.5826/dpc.11S2a169S
  2. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology. Squamous Cell Skin Cancer. Version 2.2025. (https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf).
  3. Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011;29:3419-3426. doi:10.1200/JCO.2010.34.1735
  4. Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol. 2014;25:2047-2052. doi:10.1093/annonc/mdu368
  5. Strickley JD, Spalding AC, Haeberle MT, Brown T, Stevens DA, Jung J. Metastatic squamous cell carcinoma of the skin with clinical response to lapatinib. Exp Hematol Oncol. 2018;7:20. doi:10.1186/s40164-018-0111-z
  6. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341-351. doi:10.1056/NEJMoa1805131

  7. Rischin D, Hughes BGM, Basset-Séguin N, et al. High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma. J Immunother Cancer. 2024;12(3):e008325. doi:10.1136/jitc-2023-008325

  8. Rischin D, Porceddu S, Day F, et al. Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. N Engl J Med. Published online May 31, 2025. doi:10.1056/NEJMoa2502449
  9. Rischin D, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II-IV cutaneous squamous cell carcinoma: 2-year follow-up and biomarker analysis. EJC Skin Cancer. 2025;Suppl_1:100702.
  10. Muñoz Couselo E, Hughes BGM, Mortier L, et al. Pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): Long-term results of the phase 2 KEYNOTE-629 study. J Clin Oncol. 2024;42(16_suppl):9554. doi:10.1200/JCO.2024.42.16_suppl.9554

All URLs accessed April 24, 2025

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