Guideline Updates Refine Management for Very High-Risk Squamous Cell Skin Cancer

The latest update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Squamous Cell Skin Cancer (Version 1.2026) introduces a significant change in the management of very high-risk cutaneous squamous cell carcinoma (CSCC).¹ A new category 1 preferred recommendation for adjuvant cemiplimab-rwlc (Libtayo; Regeneron) following adjuvant radiation therapy (RT) in certain very high-risk patients marks a shift toward intensified systemic intervention for patients with the highest risk of recurrence based on recent data.

Adjuvant Cemiplimab in Very High-Risk Disease

Version 1.2026 of the guidelines adds cemiplimab as a category 1 preferred option for patients with extremely high-risk nodal and nonnodal features who have undergone surgery with negative margins followed by adjuvant RT. This recommendation is supported by evidence from the phase 3, randomized C-POST trial (NCT03969004) evaluating adjuvant cemiplimab vs placebo in high-risk CSCC.²

In the trial, patients treated with cemiplimab experienced superior disease-free survival (24 vs 65 events [HR for disease recurrence or death, 0.32; 95% CI, 0.20-0.52; P < .001]). The cemiplimab group had an estimated 24-month disease-free survival rate of 87.1% (95% CI, 80.3-91.6), compared with 64.1% (95% CI, 55.9-71.1) in the placebo group.

Under the new guidelines, disease with an extremely high risk of recurrence is defined by specific clinical features¹:

• Nodal features: Extracapsular extension with the largest node measuring at least 20 mm or presence of at least 3 involved nodes.
• Nonnodal features: Presence of in-transit metastases, T4 lesions (involving bone invasion), perineural invasion, or locally recurrent tumors with at least 1 additional risk factor.

These traits align with the patient population in the C-POST trial of cemiplimab.²

Risk Stratification for Local CSCC

The guidelines also outline the stratification of local CSCC based on risk factors for recurrence or death.¹ Very high-risk disease includes any tumor larger than 4 cm regardless of location. Poorly differentiated tumors are explicitly categorized as very high risk. Subtypes such as acantholytic (adenoid), adenosquamous, or sarcomatoid (metaplastic) in any part of the tumor are also recognized as high-risk features.

During a preliminary workup of a lesion suspicious for skin cancer, the guidelines also now state that a biopsy should extend into the dermis to ensure accurate staging.

“The biopsy should include deep reticular dermis if the lesion is suspected to be more than a superficial process,” the guidelines explain. “This procedure is preferred because an infiltrative histology may sometimes be present only at the deeper, advancing margins of a tumor, and superficial biopsies will frequently miss this component.”

The Expanding Roles of Multidisciplinary Consultation and Neoadjuvant Therapy in CSCC

Version 1.2026 of the guidelines emphasizes the necessity of multidisciplinary consultation at centers with specialized expertise for both high-risk and very high-risk disease. This collaboration is particularly recommended for nonsurgical candidates to discuss definitive RT or systemic therapy.

The role of neoadjuvant therapy has also been expanded. Neoadjuvant cemiplimab is now an option for very high-risk tumors characterized by nonreactive, keratoacanthomatous rapid growth; in-transit metastasis; borderline resectability; or cases where surgery alone may result in significant functional impairment or may not be curative.

“Preliminary data and the clinical experience of NCCN Panel members suggest that other anti–PD-1 inhibitors may also be effective in this setting,” the guidelines noted, citing a retrospective study showing patients who received immunotherapy saw a statistically significant survival improvement vs those treated with other systemic therapies. However, the finding must be validated in prospective randomized studies, they added. “The use of immune checkpoint inhibitors might perhaps be extended to other indications, with early reports advocating its safety and efficacy concurrently with RT.”

Management of Locally Advanced and Field Disease

For locally advanced CSCC where curative surgery or RT is not feasible, the guidelines continue to recommend multidisciplinary consultation to discuss systemic therapy alone, with cemiplimab and pembrolizumab (Keytruda; Merck) remaining the preferred agents.

In the setting of field cancerization, the guidelines have updated preferred topical treatments, now listing topical calcipotriene/fluorouracil as a preferred option alongside fluorouracil, imiquimod (Aldara, Zyclara; Bausch Health US), and tirbanibulin (Klisyri; Almirall).

These updates collectively represent a move toward more aggressive, multimodality management for patients with very high-risk squamous cell skin cancer, leveraging immunotherapy earlier in the treatment continuum for this challenging disease.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 1.2026. Accessed February 27, 2026. https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf

2. Rischin D, Porceddu S, Day F, et al. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449

3. Amaral T, Osewold M, Presser D, Meiwes A, Garbe C, Leiter U. Advanced cutaneous squamous cell carcinoma: real world data of patient profiles and treatment patterns. J Eur Acad Dermatol Venereol. 2019;33(suppl 8):44-51. doi:10.1111/jdv.15845