The primary goal of treatment in nonmelanoma skin cancer (NMSC) is tumor elimination with maximal preservation of function and cosmesis. Although this is often achieved by surgery and radiotherapy, some patients develop locally advanced, recurrent, and/or metastatic disease requiring a systemic approach. Such lesions can involve extensive areas of soft tissue, cartilage, and bone causing substantial destruction, disfigurement, and even death.
Cemiplimab and pembrolizumab are both approved for frontline use in advanced cutaneous squamous cell carcinoma (CSCC). Known as immune checkpoint inhibitors, these agents release the brakes on the body’s own immune system and allow it to destroy the tumor.
In advanced basal cell carcinoma (BCC), frontline therapy generally involves 1 of 2 currently approved Hedgehog pathway inhibitors (HPIs) – vismodegib and sonidegib. These agents are not without limitations; complete responses are uncommon, toxicities compromise quality of life, and most patients eventually experience disease progression. Cemiplimab represents an option for patients with intractable BCC who have previously received an HPI or for whom HPI therapy is not appropriate.
NMSCs are considered immunogenic given that UV exposure drives tumorigenesis, leading to an exceptionally high tumor mutational burden and neoantigen load. Despite immune recognition and response to neoantigens on malignant cells, the tumor microenvironment often becomes immunosuppressive; PD-L1 expression is common on tumor and immune cells.
Monoclonal antibodies that block PD-1, such as cemiplimab and pembrolizumab, prevent the immunosuppressive interaction with PD-L1 and restore immune function against malignant cells. Current data show early, deep, and durable responses.
All immunotherapy indications in NMSC specify its use in metastatic disease, or in locally advanced disease not amenable to surgery and/or radiation. Metastatic disease is more easily defined, but what constitutes locally advanced disease? While there is no consensus definition, locally advanced disease is generally considered as large, aggressive, or recurrent tumors or those that penetrate deeper into the skin or surrounding tissues. These lesions may not be amenable to radiation and can be difficult to treat surgically without causing morbidity, loss of function, or disfigurement. Factors to consider at decision forks include patient criteria (willingness, health/comorbidities, age) and clinical history (multiple recurrences, surgery, radiotherapy) in addition to surgical complexity and likelihood of clear margins. The complexity of such cases underscores the importance of a multidisciplinary team approach in determining candidacy for immunotherapy.
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Seeing Nonmelanoma Skin Cancers Through a New Lens: The Role and Place of Immunotherapy
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