Guideline-Based Clinical Approach

1 · Diagnosis & risk stratification

Confirm and stage cSCC

Obtain adequate histology and document differentiation, depth, perineural or lymphovascular invasion, and margins. Examine regional nodes; use imaging when high-risk, nodal, or locally advanced disease is suspected. Incorporate immunosuppression and transplant status into risk assessment.

Reference: NCCN Squamous Cell Skin Cancer, Version 1.2026; Stratigos et al., European consensus-based interdisciplinary guideline for invasive cSCC, Part 1, European Journal of Cancer 2023.

Classify BCC before treatment

Confirm histology when the diagnosis or subtype is uncertain, then assess site, size, borders, recurrence, aggressive histology, prior radiation, and host factors. Discuss difficult-to-treat tumors in a multidisciplinary setting.

Reference: NCCN Basal Cell Skin Cancer, Version 2.2024; Peris et al., European consensus-based interdisciplinary guideline for BCC, European Journal of Cancer 2023.

2 · Localized disease

Surgery first for localized cSCC

Use standard excision for suitable lower-risk disease and margin-controlled surgery for high-risk, recurrent, poorly defined, or functionally critical tumors. Consider nodal assessment in selected very-high-risk cases.

Reference: NCCN Squamous Cell Skin Cancer, Version 1.2026; American Academy of Dermatology cSCC recommendations; European consensus cSCC treatment update, 2026.

Match local BCC therapy to risk

Complete surgical removal is preferred; use micrographic or margin-controlled surgery for high-risk, recurrent, or critical-site tumors. Selected superficial low-risk tumors may receive topical, destructive, or photodynamic therapy; radiation is an alternative when surgery is unsuitable.

Reference: NCCN Basal Cell Skin Cancer, Version 2.2024; Peris et al., European Journal of Cancer 2023; ASTRO skin-cancer radiation guideline, 2020.

3 · Radiation & perioperative cSCC

Use definitive or postoperative radiation selectively

Use definitive radiation when surgery is contraindicated or excessively morbid. Consider postoperative radiation for unresectable positive margins, extensive perineural invasion, T4 or recurrent disease, and high-risk nodal features.

Reference: NCCN Squamous Cell Skin Cancer, Version 1.2026; Likhacheva et al., ASTRO clinical practice guideline, Practical Radiation Oncology 2020; European consensus cSCC treatment update, 2026.

Consider adjuvant cemiplimab after surgery and radiation

For adults with extremely high-risk cSCC after margin-negative surgery and adjuvant radiation, NCCN lists cemiplimab as a Category 1 preferred option. Apply the C-POST risk criteria and review immune, autoimmune, and transplant factors.

Reference: NCCN Squamous Cell Skin Cancer, Version 1.2026.

4 · Advanced systemic therapy

Use checkpoint therapy for advanced cSCC

When curative surgery or radiation is not feasible, use an approved PD-1 or PD-L1 therapy. Individualize treatment for solid-organ transplant or autoimmune disease; consider cetuximab or a clinical trial after checkpoint therapy.

Reference: NCCN Squamous Cell Skin Cancer, Version 1.2026; European consensus cSCC treatment update, 2026.

Sequence systemic therapy for advanced BCC

Use vismodegib or sonidegib when locally advanced or metastatic BCC is not amenable to curative local therapy. Use cemiplimab after Hedgehog-inhibitor progression or intolerance, or when Hedgehog inhibition is inappropriate.

Reference: NCCN Basal Cell Skin Cancer, Version 2.2024; Peris et al., European Journal of Cancer 2023.

Perioperative cutaneous squamous cell carcinoma

1 · Neoadjuvant systemic therapy

Selected / evidence-based

Neoadjuvant cemiplimab

A multidisciplinary option when response may reduce the morbidity of planned surgery in resectable stage II–IV cSCC.

Details

Clinical outcomes

Outcome	Result
Pathologic complete response	50.6%
Major pathologic response	12.7%
Radiologic objective response rate	68.4%

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, severe skin reactions, and infusion reactions can occur. Treatment can delay surgery if clinically significant immune toxicity develops.

Reference: Gross et al., New England Journal of Medicine 2022.

2 · Adjuvant systemic therapy

FDA approvedFDA

Adjuvant cemiplimab

For adults at high risk of recurrence after surgery and radiation, following the current label and multidisciplinary review.

Not routine

Adjuvant pembrolizumab

KEYNOTE-630 did not establish adjuvant pembrolizumab as a routine substitute for the approved C-POST cemiplimab strategy in high-risk resected cSCC.

Details

Clinical interpretation

Keep this as a negative/uncertain treatment boundary rather than an active adjuvant option.

Reference: KEYNOTE-630.

Details

Clinical outcomes

Outcome	Result	Comparator result	Comparator
24-month disease-free survival	87.1%	64.1%	Placebo
Disease recurrence or death	HR 0.32	Reference	Placebo

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, and infusion reactions can occur. In the adjuvant setting, toxicity must be weighed against recurrence risk in a patient without measurable disease.

Reference: Rischin et al., New England Journal of Medicine 2025, C-POST; FDA approval, October 8, 2025.

3 · Adjuvant local therapy

Selected

Adjuvant radiation therapy

Consider for persistently positive margins, extensive perineural invasion, T4 disease, recurrence, or high-risk nodal features.

Not routine

Adjuvant RT + carboplatin

Do not routinely add carboplatin to postoperative radiation for high-risk cSCC; TROG 05.01 did not establish a benefit over radiation alone.

Details

Safety signals

Carboplatin adds myelosuppression, thrombocytopenia, nausea, renal and hypersensitivity risks without a demonstrated routine adjuvant benefit in this setting.

Reference: TROG 05.01.

Details

Safety signals

Acute dermatitis, pain, edema, fatigue, and temporary alopecia are common site-dependent effects. Late fibrosis, telangiectasia, lymphedema, neuropathy, wound-healing difficulty, cartilage or bone injury, and rare secondary malignancy can occur.

Reference: Ruiz et al., Journal of the American Academy of Dermatology 2022; Harris et al., JAMA Otolaryngology–Head & Neck Surgery 2019.

Advanced or unresectable cutaneous squamous cell carcinoma

1 · PD-1 therapy

FDA approvedFDA

Cemiplimab

A systemic standard when locally advanced or metastatic cSCC is not curable with surgery or radiation.

Details

Clinical outcomes

Outcome	Result
Objective response rate — locally advanced	44%
Complete response — locally advanced	13%
Objective response rate — metastatic	47%

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, severe skin reactions, and infusion reactions can occur. Review autoimmune disease, transplant history, and baseline organ function before treatment.

Reference: Migden et al., Lancet Oncology 2020; Migden et al., New England Journal of Medicine 2018; EMPOWER-CSCC-1.

FDA approvedFDA

Pembrolizumab

An approved PD-1 option for recurrent, metastatic, or locally advanced cSCC in the applicable label setting.

Details

Clinical outcomes

Outcome	Result
Objective response rate — recurrent/metastatic	34.3%
Median progression-free survival — recurrent/metastatic	6.9 months
Objective response rate — locally advanced	50.0%

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, severe skin reactions, and infusion reactions can occur. Immune toxicity may arise during treatment or after discontinuation.

Reference: Grob et al., Journal of Clinical Oncology 2020, KEYNOTE-629; Hughes et al., Annals of Oncology 2021.

2 · PD-L1 therapy

FDA approvedFDA

Cosibelimab

An approved PD-L1 option for metastatic or locally advanced cSCC not amenable to curative surgery or radiation.

Details

Clinical outcomes

Outcome	Result
Objective response rate — metastatic	47.4%
Objective response rate — locally advanced	48.4%

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, and infusion reactions can occur. Fatigue, rash, diarrhea, pruritus, musculoskeletal symptoms, and thyroid dysfunction are clinically relevant.

Reference: CK-301-101; Clingan et al., Journal for ImmunoTherapy of Cancer 2023; FDA UNLOXCYT prescribing information.

3 · PD-1 unsuitable or later line

Selected

Cetuximab-based therapy

Consider when checkpoint therapy is unsafe or as a later-line EGFR-directed strategy after multidisciplinary review.

Details

Clinical outcomes

Outcome	Result
Objective response rate	28%
Disease control rate	69%
Median progression-free survival	4.1 months
Median overall survival	8.1 months

Safety signals

Acneiform rash, xerosis, fissures, paronychia, diarrhea, infusion reactions or anaphylaxis, hypomagnesemia, and other electrolyte abnormalities can occur. Rare interstitial lung disease and serious cardiopulmonary reactions require vigilance.

Reference: Maubec et al., Journal of Clinical Oncology 2011. The efficacy data predate routine PD-1 therapy.

Localized basal cell carcinoma

1 · Lower-risk local disease

Standard

Excision, curettage, topical, or destructive therapy

Select the modality by subtype, site, size, border definition, recurrence risk, and patient priorities.

Details

Safety signals

Toxicity is modality-specific. Procedures can cause bleeding, infection, pain, scarring, pigment change, and recurrence. Topical therapies commonly cause local erythema, crusting, erosion, pain, and prolonged inflammation.

Reference: Drucker et al., Annals of Internal Medicine 2018; Bath-Hextall et al., Cochrane Database of Systematic Reviews 2007.

2 · High-risk local disease

Standard

Mohs surgery or margin-controlled excision

Preferred when the site, borders, recurrence, or histology makes complete tissue-sparing margin control important.

Details

Safety signals

Bleeding, infection, pain, scarring, delayed healing, and site-specific nerve or functional injury can occur. Reconstruction can add flap- or graft-related complications.

Reference: van Loo et al., European Journal of Cancer 2014; Mosterd et al., Lancet Oncology 2008.

3 · Selected downstaging

Selected

Neoadjuvant vismodegib

A specialist option for locally advanced BCC when tumor shrinkage may permit less morbid surgery.

Details

Clinical outcomes

Outcome	Result
Surgical downstaging	80%
Three-year recurrence among downstaged patients	36.4% (16/44)

Safety signals

Muscle spasms, dysgeusia, alopecia, weight loss, decreased appetite, fatigue, nausea, and diarrhea are frequent class effects. Embryo-fetal toxicity requires strict pregnancy precautions and blood-donation restrictions.

Reference: Bertrand et al., EClinicalMedicine 2021, VISMONEO.

4 · Nonsurgical local therapy

Selected

Radiation therapy

A definitive local option when surgery is unsuitable or would cause unacceptable morbidity.

Details

Safety signals

Acute dermatitis, pain, edema, fatigue, and alopecia can occur. Late pigment change, telangiectasia, fibrosis, wound-healing difficulty, cartilage or bone injury, and rare secondary malignancy are site- and dose-dependent.

Reference: Zaorsky et al., Radiotherapy and Oncology 2018; Locke et al., International Journal of Radiation Oncology Biology Physics 2001.

Advanced basal cell carcinoma

1 · Hedgehog-pathway inhibitors

FDA approvedFDA

Vismodegib

A first systemic option for locally advanced or metastatic BCC when curative surgery or radiation is not appropriate.

Details

Clinical outcomes

Outcome	Result
Objective response rate — locally advanced	60.3%
Objective response rate — metastatic	48.5%
Median duration of response — locally advanced	26.2 months
Median duration of response — metastatic	14.8 months
Median overall survival — metastatic	33.4 months

Safety signals

Muscle spasms, dysgeusia, alopecia, weight loss, decreased appetite, fatigue, nausea, and diarrhea frequently accumulate over time. Embryo-fetal toxicity requires strict pregnancy precautions and blood-donation restrictions.

Reference: Sekulic et al., BMC Cancer 2017, ERIVANCE final update; FDA ERIVEDGE prescribing information.

FDA approvedFDA

Sonidegib

An approved Hedgehog-pathway inhibitor for locally advanced BCC that has recurred or is not suitable for surgery or radiation.

Details

Clinical outcomes

Outcome	Result
Objective response rate — locally advanced	56%
Objective response rate — metastatic	8%

Safety signals

Muscle spasms, alopecia, dysgeusia, fatigue, nausea, diarrhea, weight loss, and creatine-kinase elevation can occur. Monitor for clinically important muscle toxicity. Embryo-fetal toxicity requires strict pregnancy precautions.

Reference: Dummer et al., British Journal of Dermatology 2020, BOLT 42-month analysis; FDA ODOMZO prescribing information.

2 · After Hedgehog therapy

FDA approvedFDA

Cemiplimab

Use after Hedgehog-inhibitor exposure, or when a Hedgehog inhibitor is not appropriate, in the applicable advanced-BCC setting.

Details

Clinical outcomes

Outcome	Result
Objective response rate — locally advanced	31%
Complete response — locally advanced	6%
Objective response rate — metastatic	22%
Median progression-free survival — metastatic	10 months
Median overall survival — metastatic	50 months

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, severe skin reactions, and infusion reactions can occur. Transplant history and autoimmune disease can materially change the risk-benefit assessment.

Reference: Stratigos et al., Lancet Oncology 2021; Lewis et al., Annals of Oncology 2024; Study 1620.

3 · Combined local and systemic therapy

Selected

Vismodegib + radiation therapy

A specialist combined-modality option for selected locally advanced BCC when durable local control is the priority.

Investigational

Pembrolizumab ± vismodegib

Investigational checkpoint ± Hedgehog-inhibitor strategy in advanced BCC; reported response rates are approximately 38–44%, but this has not replaced standard HHI → cemiplimab sequencing.

Details

Clinical outcomes

Outcome	Result
Objective response rate	~38–44%

Safety signals

Immune-mediated toxicities from pembrolizumab may overlap with Hedgehog-inhibitor muscle spasms, dysgeusia, alopecia, weight loss, fatigue and gastrointestinal effects.

Reference: Advanced BCC pembrolizumab ± vismodegib study context; NCT02690948.

Details

Clinical outcomes

Outcome	Result
One-year locoregional control	91%

Safety signals

Hedgehog-inhibitor muscle spasms, dysgeusia, alopecia, weight loss, and gastrointestinal effects can overlap with radiation dermatitis, pain, fatigue, fibrosis, and wound-healing risks. Coordinate timing and supportive care closely.

Reference: Barker et al., Journal of Clinical Oncology 2024.

Emerging and investigational strategies

1 · Perioperative cSCC

Investigational

Neoadjuvant nivolumab + ipilimumab

A research strategy for resectable cSCC; the MATISSE trial was randomized but not designed for formal comparison between cohorts.

Details

Clinical outcomes

Outcome	Result
Total pathologic response	80%
Major pathologic response	50%
Partial pathologic response	30%
Two-year disease-specific survival among pathologic responders	100%

Safety signals

Dual checkpoint blockade can cause immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, myocarditis, neurologic toxicity, and severe skin reactions. Toxicity may delay surgery and can require systemic immunosuppression.

Reference: Breukers et al., Nature Medicine 2025, MATISSE.

2 · Checkpoint strategies in BCC

Investigational

Nivolumab → add relatlimab after progression

A sequential PD-1/LAG-3 research approach in advanced BCC; the cohorts were noncomparative.

Details

Clinical outcomes

Outcome	Result
Objective response rate — first-line nivolumab	52%
Objective response rate — relatlimab added after nivolumab progression	31%

Safety signals

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, myocarditis, neurologic toxicity, severe skin reactions, and infusion reactions can occur. Combination checkpoint blockade may increase immune toxicity.

Reference: Warrier et al., ESMO 2025 abstract 1667P.

3 · EGFR after checkpoint resistance

Investigational

Pembrolizumab → add cetuximab at progression

The I-TACKLE phase II strategy tested EGFR blockade after primary resistance to pembrolizumab in advanced cSCC.

Details

Clinical outcomes

Outcome	Result
Objective response rate after cetuximab was added	38%

Safety signals

Cetuximab adds acneiform rash, xerosis, fissures, paronychia, infusion reactions, diarrhea, hypomagnesemia, and rare lung toxicity to the immune-mediated risks of pembrolizumab.

Reference: Bossi et al., European Journal of Cancer 2025, I-TACKLE.

4 · Biomarker-guided BCC case

Case report

PTCH1-mutant BCC with squamous differentiation · vismodegib + pembrolizumab

Biology-guided salvage in metastatic BCC with squamous differentiation after limited objective response to nivolumab + ipilimumab despite ultra-high TMB.

Details

Molecular / diagnostic context

Feature	Finding
TMB	95 mutations/Mb
PD-L1	CPS 0; TPS 0%
Microsatellite status	MS-stable
PTCH1	Y977fs*16 truncating alteration
Initial nivolumab + ipilimumab	Stable disease without objective regression

Response after treatment change

Pembrolizumab 200 mg every 3 weeks plus vismodegib 150 mg daily produced a near-complete response within 3–4 months. Complete metabolic response of the hepatic lesion was documented by June 2023; sustained metabolic remission was still present on PET/CT in November 2025.

Clinical interpretation

The case supports integrated histologic and genomic reassessment when conventional biomarkers and clinical behavior are discordant. It does not establish synergy between Hedgehog inhibition and PD-1 blockade; the relative contribution of vismodegib, pembrolizumab, and prior checkpoint exposure cannot be separated.

Safety signals

Therapy was stopped in June 2025 because of grade 2 pneumonitis. Respiratory symptoms resolved after treatment interruption; subsequent rechallenge with vismodegib was followed by recurrent symptoms and permanent systemic-treatment discontinuation.

Reference: Aydın E, Tokat ÜM, Adibi A, et al. Front Immunol. 2026;17:1814345. doi:10.3389/fimmu.2026.1814345.

1 · Diagnosis & risk stratification

Confirm and stage cSCC

Classify BCC before treatment

2 · Localized disease

Surgery first for localized cSCC

Match local BCC therapy to risk

3 · Radiation & perioperative cSCC

Use definitive or postoperative radiation selectively

Consider adjuvant cemiplimab after surgery and radiation

4 · Advanced systemic therapy

Use checkpoint therapy for advanced cSCC

Sequence systemic therapy for advanced BCC

1 · Lower-risk local disease

Excision or Mohs surgery

Safety signals

2 · High-risk local disease

Mohs or wide excision ± nodal evaluation

Safety signals

3 · Nonsurgical local therapy

Definitive radiation therapy

Safety signals

1 · Neoadjuvant systemic therapy

Neoadjuvant cemiplimab

Clinical outcomes

Safety signals

2 · Adjuvant systemic therapy

Adjuvant cemiplimab

Adjuvant pembrolizumab

Clinical interpretation

Clinical outcomes

Safety signals

3 · Adjuvant local therapy

Adjuvant radiation therapy

Adjuvant RT + carboplatin

Safety signals

Safety signals

1 · PD-1 therapy

Cemiplimab

Clinical outcomes

Safety signals

Pembrolizumab

Clinical outcomes

Safety signals

2 · PD-L1 therapy

Cosibelimab

Clinical outcomes

Safety signals

3 · PD-1 unsuitable or later line

Cetuximab-based therapy

Clinical outcomes

Safety signals

1 · Lower-risk local disease

Excision, curettage, topical, or destructive therapy

Safety signals

2 · High-risk local disease

Mohs surgery or margin-controlled excision

Safety signals

3 · Selected downstaging

Neoadjuvant vismodegib

Clinical outcomes

Safety signals

4 · Nonsurgical local therapy

Radiation therapy

Safety signals

1 · Hedgehog-pathway inhibitors

Vismodegib

Clinical outcomes

Safety signals

Sonidegib

Clinical outcomes

Safety signals

2 · After Hedgehog therapy

Cemiplimab

Clinical outcomes

Safety signals

3 · Combined local and systemic therapy

Vismodegib + radiation therapy

Pembrolizumab ± vismodegib

Clinical outcomes

Safety signals