Elsevier

Dermatologic Clinics

Volume 41, Issue 1, January 2023, Pages 23-37
Dermatologic Clinics

Targeted Therapy and Immunotherapy in Nonmelanoma Skin Cancer

https://doi.org/10.1016/j.det.2022.07.009Get rights and content

Section snippets

Key points

  • Advanced nonmelanoma skin cancers include tumors that are poor candidates for surgery, radiation, or a combination of the two.

  • 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.

  • Future directions include intralesional therapy and combination therapy with other systemic medications or oncolytic viral therapy.

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.

First page preview

First page preview
Click to open first page preview

References (74)

  • R.C. DeConti

    Chemotherapy of squamous cell carcinoma of the skin

    Semin Oncol

    (2012)
  • W.N. William et al.

    Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial

    J Am Acad Dermatol

    (2017)
  • B.G.M. Hughes et al.

    Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial

    Ann Oncol

    (2021)
  • H. Chen et al.

    Pulmonary metastases of fibrosarcomatous dermatofibrosarcoma protuberans respond to apatinib-based angiogenesis and chemotherapy: a case report

    Ann Transl Med

    (2019)
  • M.C. Foote et al.

    Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma

    Ann Oncol

    (2014)
  • M.R. Migden et al.

    Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial

    Lancet Oncol

    (2020)
  • U. Leiter et al.

    Epidemiology of skin cancer

    Adv Exp Med Biol

    (2014)
  • K. Oda et al.

    A comprehensive pathway map of epidermal growth factor receptor signaling

    Mol Syst Biol

    (2005)
  • Q.T. Tran et al.

    EGFR regulation of epidermal barrier function

    Physiol Genomics

    (2012)
  • J. Cañueto et al.

    Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma

    Br J Dermatol

    (2017)
  • K. Chanprapaph et al.

    Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management

    Dermatol Res Pract

    (2014)
  • A.M. Skoda et al.

    The role of the Hedgehog signaling pathway in cancer: a comprehensive review

    Bosn J Basic Med Sci

    (2018)
  • B. Stecca et al.

    Hedgehog-Gli signaling in basal cell carcinoma and other skin cancers: prospects for therapy

    Res Rep Biol

    (2015)
  • R.L. Carpenter et al.

    Safety and tolerability of sonic hedgehog pathway inhibitors in cancer

    Drug Saf

    (2019)
  • J.L. Riley

    PD-1 signaling in primary T cells

    Immunol Rev

    (2009)
  • M. Robainas et al.

    Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy

    Onco Targets Ther

    (2017)
  • A. Akinleye et al.

    Immune checkpoint inhibitors of PD-L1 as cancer therapeutics

    Hematol Oncol

    (2019)
  • J.R. Brahmer et al.

    Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

    N Engl J Med

    (2012)
  • I. Baraibar et al.

    Safety and tolerability of immune checkpoint inhibitors (Pd-1 and pd-l1) in cancer

    Drug Saf

    (2019)
  • S. Wu et al.

    Basal-cell carcinoma incidence and associated risk factors in U.S. women and men

    Am J Epidemiol

    (2013)
  • S.-H. Seo et al.

    Pulmonary metastasis of Basal cell carcinoma

    Ann Dermatol

    (2011)
  • K. Moeholt et al.

    Platinum-Based Cytotoxic Therapy in Basal Cell Carcinoma a review of the literature

    Acta Oncol

    (1996)
  • M. Jefford et al.

    Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel

    ANZ J Surg

    (2004)
  • E. Chatelut et al.

    Toxicity patterns of cytotoxic drugs

    Invest New Drugs

    (2003)
  • A. Sekulic et al.

    Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study

    BMC cancer

    (2017)
  • S. Ikeda et al.

    Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy

    NPJ Genom Med

    (2016)
  • S.H. Omland et al.

    Immunosuppressive environment in basal cell carcinoma: the role of regulatory t cells

    Acta Derm Venereol

    (2016)
  • View full text