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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 (Table 1).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. For primary and recurrent locally advanced cSCC, the guidelines recommend radiotherapy (RT) if surgery is not feasible, along with multidisciplinary discussion of concurrent systemic therapy in select cases (Table 2).2

Systemic Therapy

Systemic therapy is recommended if curative RT or surgery is not feasible for locally advanced, recurrent, or metastatic disease (Table 3).2

Targeted Therapy

EGFR inhibitors provide modest but clinically meaningful activity in advanced cSCC and represent a reasonable treatment option for patients who are ineligible for or progress after anti–PD-1 therapy, though responses are generally limited in durability.3

  • 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 months4
  • Panitumumab: Another monoclonal antibody with a 31% ORR in phase II trials5
  • Gefitinib: Tyrosine kinase inhibitor (TKI) with a 16% ORR in a single arm, phase II trial6
  • Erlotinib: TKI with a 10% ORR in a single-arm, phase II trial7
  • Dacomitinib: TKI with a response rate of 28%8

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

Immunotherapy

Cemiplimab

  • FDA-approved for metastatic and locally advanced cSCC that is not a candidate for surgery
  • Early data showed a 50% response rate with durable disease control in 65% of patients9
  • Ongoing long-term studies show an observed ORR in 62%, with 22% of patients achieving complete response and 40% achieving partial response at a median follow-up of 22.4 months10
  • NCCN guideline-recommended in the neoadjuvant setting
  • Adverse events include fatigue, diarrhea, and nausea/vomiting10
  • 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 setting11
  •  Phase 2 neoadjuvant study: Showed 2-year event-free survival was 86%, disease-free survival was 90% in patients who underwent surgery, and OS was 86%12

Pembrolizumab

  • FDA-approved for recurrent, metastatic, or locally advanced cSCC that is not a candidate for surgery
  • Keynote 629 Study: Showed an ORR of 40.9%, a complete response of 25%, and partial response of 40% at a median follow-up of more than 5 years13
  • CARSKIN Study: Reported an ORR of 47% at a follow-up of 26 months in patients with locally advanced or metastatic cSCC, with manageable adverse events14
  • Adverse events include fatigue, pruritus, and asthenia14

Nivolumab

  • Studied for advanced unresectable cSCC and as neoadjuvant therapy for resectable high-risk cSCC before major surgery.
  • CA209-9JC: In patients with treatment-naive advanced cSCC not eligible for curative surgery/RT, nivolumab achieved an ORR of 58.3%, disease control of 79%, median progression-free survival (PFS) of 12.7 months, and median OS of 20.7 months.15
  • MATISSE nivolumab arm: In resectable stage I–IVa cSCC requiring extensive surgery, 2 neoadjuvant nivolumab doses produced 45% major pathologic response, 10% partial pathologic response, and a 55% total pathologic response rate.16
  • MATISSE nivolumab + ipilimumab arm: In the same setting, nivolumab + ipilimumab produced 50% major pathologic response, 30% partial pathologic response, and an 80% total pathologic response rate.16
  • MATISSE clinical complete remissions: Among patients who forwent surgery after neoadjuvant treatment, 9 achieved clinical complete remission and all remained cancer free at median 34 months, with 100% 24-month disease-specific survival (DSS), relapse-free survival (RFS), and OS.16
  • Safety: Nivolumab had a manageable safety profile; in advanced cSCC, 25% had grade ≥3 treatment-related adverse events (AEs) and there were no treatment-related deaths.15,16

Cosibelimab

  • FDA-approved for adults with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation
  • Pivotal open-label study: Cosibelimab achieved ORRs of 50.0% in metastatic cSCC and 54.8% in locally advanced cSCC, with complete response rates of 12.8% and 25.8%, respectively, and durable responses with median duration not reached.17
  • Cosibelimab showed a manageable safety profile with low rates of severe immune-related adverse events (irAEs), which may be especially relevant in the older advanced cSCC population.17

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 2.2026. (https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf).
  3. Pham JP, Rodrigues A, Goldinger SM, Sim HW, Liu J. Epidermal growth factor receptor inhibitors in advanced cutaneous squamous cell carcinoma: A systematic review and meta-analysis. Exp Dermatol. 2024;33(1):e14978. doi:10.1111/exd.14978
  4. 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
  5. 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
  6. William WN Jr, Feng L, Ferrarotto R, et al. Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial. J Am Acad Dermatol. 2017;77(6):1110-1113.e2. doi:10.1016/j.jaad.2017.07.048
  7. Gold KA, Kies MS, William WN Jr, Johnson FM, Lee JJ, Glisson BS. Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial. Cancer. 2018;124(10):2169-2173. doi:10.1002/cncr.31346
  8. Cavalieri S, Perrone F, Miceli R, et al. Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer. Eur J Cancer. 2018;97:7-15. doi:10.1016/j.ejca.2018.04.004
  9. 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
  10. 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
  11. Rischin D, Porceddu S, Day F, et al. Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. N Engl J Med. doi:10.1056/NEJMoa2502449
  12. 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.

  13. 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

  14. Maubec E, Boubaya M, Deschamps L, et al. Final results of a phase II study of pembrolizumab as first-line treatment in advanced cutaneous squamous cell carcinomas (CSCCs). Ann Oncol. 2023;34(suppl 2):S682-S683.

  15. Munhoz RR, Nader-Marta G, de Camargo VP, et al. A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma. Cancer. 2022;128(24):4223-4231. doi:10.1002/cncr.34463

  16. Breukers SE, Traets JJH, van Dijk SW, et al. Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial. Nat Med. 2025;31(12):4055-4064. doi:10.1038/s41591-025-03943-w

  17. Ruiz ES, Muñoz-Couselo E, Montaudié H, et al. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: Results from a Pivotal Open-label Study with a median follow-up of ≥2 years. J Am Acad Dermatol. 2026;94(1):48-56. doi:10.1016/j.jaad.2025.09.009

ALL URLs accessed April 14, 2026

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