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Advanced nonmelanoma skin cancers include tumors that are poor candidates for surgery, radiation, or a combination of the two.
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Hedgehog pathway inhibitors and programmed death-1 inhibitors have found the most success in systemic treatment of advanced nonmelanoma skin cancers within the last decade.
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Future directions include intralesional therapy and combination therapy with other systemic medications or oncolytic viral therapy.
Targeted Therapy and Immunotherapy in Nonmelanoma Skin Cancer
Section snippets
Key points
Patient selection and defining advanced tumors
There are currently no definitive objective criteria for advanced NMSC. In this review, advanced NMSC will refer to locally advanced or metastatic disease. Patients with locally advanced tumors tend to be poor candidates for surgery and/or radiation. At times, resecting locally advanced tumors may be technically feasible; however, it may result in significant morbidity and/or disfigurement for the patient. Even if feasible, some patients may be unwilling to endure extensive surgery for a
Basal cell carcinoma
BCC is the most common NMSC with an estimated age-adjusted incidence of 1488 and 1019 cases per 100,000 person-years for men and women, respectively.14 BCC has an estimated metastasis rate of 0.0028% to 0.55%.15,16 For locally advanced or metastatic BCC, systemic therapies should be considered. The sections below, Table 1 and Table 2 describe the systemic therapies used for the treatment of BCC.
Cutaneous squamous cell carcinoma
cSCC represents a significant health crisis for patients at high risk of NMSC because they have increased the incidence of cSCC and are at higher risk for aggressive and metastatic disease.35 Approximately 5% of tumors progress to advanced cSCC, an alarming percentage for a disease with an incidence between 9 and 96 per 100,000 men and 56 and 68 per 100,000 women in areas such as the United Kingdom, Sweden, and Germany.36, 37, 38 Although the majority of early cSCC are treated with surgery,
Combination therapy
Although this review focuses on monotherapy, it is worth noting that combination therapy with multiple systemic agents may increase response rates in a synergistic fashion. The percentage of clinical trials evaluating monotherapy with PD-1/PD-L1 inhibitors has decreased in recent years compared with an overall increase in those investigating combination therapy.54 When treating other types of advanced malignancies, PD-1 inhibitors are often combined with vascular endothelial growth factor
Rare tumors (Merkel cell carcinoma, sebaceous carcinoma, dermatofibrosarcoma protuberans)
Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm associated with Merkel cell polyoma virus. It has a high rate of nodal and distant metastases. PD-L1 inhibitor avelumab and PD-1 inhibitor pembrolizumab are USFDA-approved for advanced MCC. Major clinical trials investigating these agents as well as additional reports of immunotherapy for MCC are outlined in Table 5.58, 59, 60, 61, 62, 63
Sebaceous carcinoma (SC) rarely metastasizes, and there is no established first-line
Discussion
Compared with traditional cytotoxic chemotherapy, modern targeted therapies and immunotherapies have AE profiles better suited for the elderly population that presents with the majority of advanced cSCC. For advanced BCC, first-line HPIs and second-line PD-1 inhibitors have replaced antiquated cytotoxic agents. For advanced cSCC, PD-1 inhibitors are first-line based on their high benefit-to-risk ratio. PD-1 inhibitors demonstrate a higher ORR in advanced cSCC compared with BCC. Although both
Clinics care points
A multidisciplinary approach to advanced NMSC is vital because a combination of systemic, surgical, and radiation treatment options may be necessary to optimize treatment outcomes. For advanced BCC, HPIs, including vismodegib and sonidegib, are first-line therapy with suitable response rates and tolerability. PD-1 inhibitor cemiplimab was recently approved as second-line therapy for those who failed or are intolerant of an HPI. For advanced cSCC, PD-1 inhibitors cemiplimab and pembrolizumab are
Disclosure of interest
M. R Migden has participated on advisory boards and received honoraria from Regeneron Pharmaceuticals, Inc., Sun Pharmaceuticals, and Sanofi; advisory role with Rakuten Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article apart from those disclosed.
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