Keratinocyte cancers–basal and cutaneous squamous cell carcinoma (BCC, cSCC)–are the most common forms of non-melanoma skin cancer and there has been a significant increase in their incidence globally in recent decades. Although the majority of BCC and cSCC are cured with conventional surgery or radiotherapy, certain tumour or patient-determined factors may result in these modalities being inadequate or inappropriate, for example, locally advanced or metastatic disease, high tumour multiplicity, patient comorbidities and patient preferences. Pathobiologically, activation of the Hedgehog (HH) signalling pathway has been shown to play a critical role in the majority of cases and is recognised as a valid therapeutic target. As such, hedgehog pathway inhibitors such as vismodegib and sonidegib are being investigated in high-risk cancers.

• Vismodegib is a small-molecule inhibitor of smoothened (SMO), a key component of the hedgehog signalling pathway that has been studied in BCC patients after failure of surgery and radiotherapy treatments. [1]
• Vismodegib has become an established treatment option for patients with advanced BCC in clinical practice.
• However, certain limitations of treatment with vismodegib should be kept in mind.
• Side effects lead to a significant rate of treatment discontinuation, thereby limiting overall drug exposure.
• Accordingly, continuous long-term treatment with vismodegib is not feasible in most patients.
• Clinical end points which may help to determine the optimal treatment duration (lifelong/continuous treatment vs treatment until best response) are lacking.
• Alternative dosing regimens may improve tolerability and dose exposure, but more studies are needed to optimise the dosing regimen. [2]
• Muscle cramps are an important side effect of vismodegib, but may be reduced with the administration of L-carnitine, based on a case report. [3]
• Other side effects include decreased sense of taste, hair loss, loss of appetite, weight loss and fatigue, as well as severe birth defects.
• Of note, it has been reported that in advanced BCC, patients who are resistant to treatment with vismodegib are also resistant to sonidegib. [4]

• Cemiplimab is a new anti-PD1 checkpoint inhibitor antagonist that is under development for SCC.
• Anti-PD1 agents are well known from their role in melanoma immunotherapy.
• PD-1 is a relevant target in cancer as malignant cells may develop a ligand towards the PD-1 receptor that allows them to avoid attack by cytotoxic T-cells.
• In addition to melanoma, SCC is another tumour type in which alterations in PD-1 are frequently found.
• The effects of PD-1 blockade with cemiplimab have been recently studied in advanced cutaneous SCC. [5]
• Response to cemiplimab was observed in 13 of 26 patients (50%; 95% CI, 30-70).
• In the metastatic-disease cohort of the phase II study, a response was observed in 28 of 59 patients (47%; 95% CI, 34-61).
• Among the 28 patients showing a response, duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at end of study.
• In a follow-up study of the same trial, estimated 1-year progression-free survival (PFS) was 53% and median PFS was 18.4 months.
• Adverse events include diarrhoea, fatigue, nausea, constipation and rash.
• Based on these results, cemiplimab has been approved by both the FDA and EMA for metastatic cutaneous SCC.

• Vismodegib and sonidegib are showing promise in treatment of BCC.
• Cemiplimab is a new treatment for SCC that was recently approved in Europe and the USA.