The Expanding Role of Immunotherapies for Non-Melanoma Skin Cancers

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the 2 most common forms of non-melanoma skin cancers (NMSCs), with about 5.4 million diagnosed annually in the United States.¹ The incidence of these cancers continues to rise, with new annual cSCC diagnoses growing from 50% to 200% over the past 3 decades.^2,3 The majority of NMSCs are localized and can be treated with surgical interventions (Mohs surgery or wide local excision) or radiotherapy, but some patients present with advanced, inoperable, or metastatic disease for which treatment options are limited.⁴ These advanced forms, known as locally advanced BCC (laBCC), metastatic BCC (mBCC), locally advanced cSCC (laCSCC), and metastatic cSCC (mCSCC), can incur significant physical and psychological morbidity, from infections and limitation of function to depression, increased financial burden, and even death.^5,6 Because the tumors may not be well suited to conventional treatments such as surgery and radiation, systemic targeted therapies may be warranted. In recent years, the management of advanced BCC and cSCC has been transformed by the emergence of immunotherapy, particularly PD-1 and PD-L1 inhibitors, which have expanded treatment options and provided meaningful clinical benefit for patients beyond traditional approaches.

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Immunologic Rationale for Checkpoint Inhibition

NMSCs are typically driven by ultraviolet-induced DNA damage, leading to a high tumor mutational burden (TMB). As such, this elevated TMB promotes the generation of neoantigens that the immune system can recognize as targets on malignant cells. Checkpoint inhibitors and immunotherapies enhance immune recognition of tumor antigens, thereby eliminating malignant cells. Those with high TMB are more likely to respond to immunotherapy, possibly because of increased neoantigen expression.^7,8 

Immunotherapy in Cutaneous Squamous Cell Carcinoma

Systemic immunotherapy has fundamentally altered the management of advanced cSCC. Given the tumor’s high mutational burden and the link between immunosuppression and cSCC risk, blockade of the PD-1/PD-L1 axis prevents negative T-cell regulation and amplifies antitumor immune responses.^9-11 Three FDA-approved checkpoint inhibitors are now available for patients with laCSCC or mCSCC who are not amenable to curative surgery or radiation.

Cemiplimab (Libtayo; Regeneron), a high-affinity anti–PD-1 antibody, was the first FDA-approved therapy for advanced CSCC. In the pivotal phase 2 EMPOWER-CSCC-1 trial (NCT02760498), cemiplimab demonstrated durable antitumor activity across mCSCC and laCSCC cohorts in both weight-based and fixed dosing regimens.¹⁰ This was the largest prospective long-term dataset for anti–PD-1 therapy in advanced cSCC.¹⁰ The final analysis from this trial reported an objective response rate (ORR) of 47.2% at a median follow-up of 42.5 months, with a median progression-free survival of 26.0 months and an estimated 12-month duration of response of 88.3%.¹⁰ Subsequently, cemiplimab received additional FDA approval as an adjuvant therapy for high-risk cSCC following surgery and radiation.¹² Patients treated with cemiplimab had a reduced risk of recurrence or death vs placebo (HR, 0.32; P < .0001) and an estimated 24-month disease-free survival of 87.1% vs. 64.1% with placebo.¹² Cemiplimab also lowered the risk of locoregional recurrence by 80% and distant recurrence by 65%.¹²

Pembrolizumab (Keytruda; Merck), also an anti–PD-1 antibody, is FDA approved for laCSCC and recurrent/metastatic cSCC. In the phase 2 KEYNOTE-629 trial (NCT03284424), pembrolizumab demonstrated clinically meaningful, durable antitumor activity with an acceptable safety profile in primarily elderly patients with R/M cSCC.¹¹ ORR was 50.0% in laCSCC and 35.2% in R/M cSCC.¹¹

Cosibelimab (Unloxcyt; Checkpoint Therapeutics) was the first anti–PD-L1 antibody approved by the FDA for advanced cSCC in December 2024. This therapy has a proposed dual mechanism of action: PD-L1 blockade plus antibody-dependent cellular cytotoxicity (ADCC) via its functional Fc domain.¹³ In its pivotal phase 1 trial (NCT03212404), ORR (assessed by independent central review (ICR)) for mCSCC was 47.4% with a median follow-up of 15.4 months.^14,15 Of 31 patients with laCSCC, ORR was 48%.¹⁶ In the long-term analysis with a median follow-up duration of 29.3 months for those with mCSCC and 24.1 months for those with laCSCC, the ORR per ICR was 50.0% and 54.8%, respectively.¹⁷ PD-L1 inhibitors have demonstrated a lower incidence of grade 3 or higher treatment-related adverse events compared with PD-1 inhibitors.¹⁵

Immunotherapy in Basal Cell Carcinoma

Hedgehog pathway inhibitors (HHIs) vismodegib (Erivedge; Genentech) and sonidegib (Odomzo; Novartis) remain first-line systemic therapy for advanced BCC, but many patients develop resistance or experience intolerable toxicity, including muscle cramps, alopecia, dysgeusia, and creatine kinase (CK) elevation.¹⁸ For these cases, cemiplimab is the only FDA-approved immunotherapy option.¹⁸

Cemiplimab received FDA approval in 2021 for laBCC and mBCC following HHI failure or intolerance.¹⁹ In the pivotal open-label, multicenter, single-arm phase 2 trial (NCT05574101), patients with laBCC received cemiplimab 350 mg IV every 3 weeks for up to 93 weeks after HHI therapy.²⁰ Among 84 patients, ORR was 31%, with 6% achieving complete response and 25% partial response, and the estimated 12-month probability of maintained response was 85.2%.²⁰ In the extended follow-up analysis, overall ORR rose to 32.1%, with higher response rates in HHI-intolerant patients (38.1%) compared with those who progressed on HHIs (30.2%).²¹ For mBCC, a phase 2 trial of 54 patients reported an ORR of 22%.²² The final analysis of cemiplimab in mBCC after HHI treatment confirmed a clinically meaningful response with a manageable safety profile.

Cemiplimab is also indicated when HHIs are not appropriate, though the criteria defining this population remain incompletely established. Patients with pre-existing conditions that HHIs are known to exacerbate, such as muscle cramps, alopecia, or dysgeusia, may be better served by proceeding directly to cemiplimab. Similarly, those with baseline or elevated CK levels, or at heightened risk for myopathy, may not be suitable HHI candidates, making up-front cemiplimab a clinically reasonable choice.

Emerging Data and Evolving Treatment Paradigms

The therapeutic landscape for advanced NMSC continues to evolve rapidly. Neoadjuvant cemiplimab has emerged as an exciting treatment strategy for resectable, advanced cSCC. In a landmark phase 2 trial (NCT04154943), 79 patients with resectable stage II-IV cSCC received cemiplimab 350 mg every 3 weeks for up to 4 doses before surgery.²³ Pathological complete response (pCR) was achieved in 51% of patients and major pathological response in 13%, with an imaging-based ORR of 68%.²³ Further, an open-label, single-institution phase 2 trial (NCT05878288) confirmed that neoadjuvant cemiplimab achieved an excellent pCR rate in stage II-IV cSCC, and the extent of required surgery was reduced.²⁴

Combination strategies are also under active investigation, including cemiplimab with pulsed sonidegib in BCC (NCT04679480). First-line immunotherapy in BCC is emerging as a possible option, with early nivolumab data reporting a 52% ORR in treatment-naïve inoperable BCC, substantially exceeding second-line response rates.²⁵ These findings suggest that checkpoint inhibition may move earlier in the treatment sequence.

Another form of therapy for advanced SCC being investigated is intralesional immunotherapy. In an ongoing phase 1 clinical trial (NCT03889912), intralesional cemiplimab is being administered weekly for 12 weeks for patients with advanced cSCC and basal cell carcinoma.²⁶ Preliminary results show that intralesional cemiplimab results in a high rate of pathological response with evidence of tumor regression.²⁶

Safety Considerations and Immune-Related Adverse Events

The safety profiles of cemiplimab,²⁷ pembrolizumab, and cosibelimab are consistent with PD-1/PD-L1 class effects. For cemiplimab, rates of immune-related adverse events (irAEs) are reported to be 57.1%, with 12.5% being grade ≥3.27 Pembrolizumab-treated patients had irAEs at a rate of 22.6%, with 12.5% being grade ≥3 in the phase 2 clinical trial.¹¹ Cosibelimab demonstrated a comparatively favorable irAE burden, with irAEs in only 23.1% of patients, grade 3 irAEs in 2.6%, and no grade 4 or 5 irAEs.¹⁷

Clinicians and staff need to recognize that irAEs can affect any organ system, arise at any point during or after treatment, and range from mild to life-threatening.^28-30 Though most are mild or moderate, severe events have been described.^28-30 Notably, dermatologic toxicities are among the most frequent. One of the most critical factors to management is prompt recognition of an irAE,³¹ so patient education before therapy initiation is essential. Initiation of treatment with corticosteroids should be immediate, and in severe cases, treatment interruption is advised. Additionally, symptoms of irAEs can mimic metastatic or progressive disease, and dermatologists should initiate appropriate evaluation if this is suspected.

Practical Decision Considerations for Dermatologists

Dermatologists play a central role in identifying advanced NMSC and initiating timely referral for systemic therapy. Clinicians should consider referral when cSCC or BCC is unresectable, recurrent despite surgery or radiation, or presents with regional or distant metastasis. High-risk features include perineural invasion, diameter greater than 2 cm, immunosuppression, and head or neck location. Clinicians should also consider referral for systemic therapy when BCC progresses on or is intolerant to HHIs, or when comorbidities make traditional options inappropriate from the outset. Early dermatology-oncology collaboration is essential to optimize the timely selection of appropriate therapy and manage potential irAEs.

Looking Ahead

Immunotherapy is positioned to reshape the treatment paradigm for advanced NMSC. Neoadjuvant cemiplimab has demonstrated that pCR is achievable in resectable cSCC, potentially reducing morbidity and improving long-term outcomes. Adjuvant checkpoint inhibition is now an evidence-based option for high-risk disease following surgery and radiation. In BCC, first-line anti–PD-1 therapy and combination approaches are promising areas of investigation. As research continues to identify the ideal time to initiate treatment and biomarker technologies emerge, immunotherapy is poised to assume a more precise and expanded role in the management of advanced NMSCs.

Joshua Burshtein, MD, is a resident physician in the Department of Dermatology at the University of Illinois Chicago.

Todd Schlesinger, MD, is a dermatologist and Mohs surgeon at Epiphany Dermatology in South Carolina, as well as director of the Clinical Research Center of the Carolinas.

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