Basal cell carcinoma (BCC) is the most frequent malignant neoplasm in humans and it accounts for 75% of all skin cancers. Its annual incidence is highest in Australia, followed by the United States, and Europe, and ranges from 70-150/100000 population, with increasing incidence with age.1 It is estimated that the incidence of BCC increases annually by 6.8% (95% CI, 5.3%-8.3%) in men and 7.9% (95% CI, 6.2%-9.7%) in women, due to increased exposure to ultraviolet (UV) radiation in sunlight and artificial light sources,2 increased outdoor sporting and recreational activities,3 increased life expectancy, and depletion of the ozone layer.4,5 In Spain, the estimated incidence of BCC in 2016 was 113.05/100000 population; this figure only includes histologically confirmed primary tumors in each patient.6 In addition to exposure to UV radiation and age, BCC has been associated with other risk factors, such as fair skin phototype (I and II), family history, exposure to ionizing radiation, arsenic intake, immunosuppression, and some genodermatoses.7

BCC is characterized as an extremely heterogeneous tumor with several clinical presentations and histologic subtypes. It generally does not follow an aggressive course, with slow and localized growth. It usually develops in parts of the body exposed to sun, with the head and neck being the most frequently affected (80%). The tumor is derived from undifferentiated and pluripotent stem cells in the basal cell layer of the epidermis and pilosebaceous follicles, regulated by the Hedgehog (Hh) signaling pathway. Basal epithelial tumor cells form groups surrounded by stroma with different growth patterns, giving rise either to slow-growing BCC with nodular and superficial subtypes or aggressive and invasive growth with morpheaform, invasive, micronodular, and basosquamous subtypes.7–9 The tumor can present with a single histologic pattern or a combination of patterns, in which case it is denoted as being of mixed histology.7

Prognosis for BCC is usually favorable and treatment is essentially surgical, although depending on different factors, radiotherapy, photodynamic therapy, and topical imiquimod can be used. However, BCC can at times progress locally, invading adjacent structures (locally advanced BCC [laBCC]) or metastasizing (metastatic BCC). It is estimated that up to 0.8% of all cases of BCC correspond to laBCC. In Spain, in 2017, laBCC was estimated to be present in at least 500 people.6 Patients with laBCC usually have a long history of untreated BCC or repeated treatment failures and recurrence, characterized by the difficulty or impossibility of eliminating the tumor by means of surgery or radiotherapy (Table 1).10,11 In these cases, the usual therapeutic options are ineffective, leading to major functional, emotional, and cosmetic impact, with a negative effect on the quality of life of the affected patients. Invasion of locoregional structures may lead to functional impotence, pain, and chronic insomnia that is difficult to control and a negative esthetic impact, often in the cephalic pole, causing anxiety, depression, and social exclusion.12 For these reasons, other tools are needed for control of the tumor, such as inhibitors of Hh signaling.

The Hh signaling pathway was first observed in 1980 in larvae of Drosophila melanogaster, in which mutations to the Patched and Hedgehog genes, which encode this signaling pathway, led to abnormal embryonic development.13 In different species, this pathway plays a crucial role in organogenesis during embryogenesis, but in adults, it is only active in hair follicles, skin, and stem cells, where it plays a major role in maintaining tissue homeostasis and cell repair.14

In the Hh pathway, the Patched 1 (PTCH1) transmembrane receptor, located in the primary cilia of the cells, in absence of ligand, inhibits the Smoothened (SMO) protein, a transmembrane receptor that acts as a signal transducer (Fig. 1A). When an Hh ligand binds to PTCH1, SMO inhibition disappears. SMO acts on the suppressor of fused homolog (SUFU) mediator protein, enhancing the activation of GLI transcription factors and inducing transcription of genes implicated in increased cell survival and mitosis (Fig. 1B).15

Figure 1.

Activation and deactivation of the Hedgehog (Hh) signaling pathway. A, In absence of Hh ligands, the PTCH1 receptor inhibits SMO, allowing the SUFU protein to bind and inhibit the GLI transcription factors. B, Binding of Hh ligands to PTCH1 suppresses SMO inhibition; as a result SUFU is inhibited, dissociating the complex and activating the GLI transcription factors, which translocate to the nucleus and transcription of genes associated with Hh signaling implicated in increased cell survival and mitosis is induced. C, In presence of Hh ligands, which activate the Hh pathway, inhibitors block SMO activation, allowing suppression of the GLI transcription factors by SUFU and transcription of genes associated with the Hh pathway.

Abbreviations: GLI, GLI transcription factor; Hh, Hedgehog ligand; I, SMO inhibitors such as sonidegib and vismodegib; PTCH1, Patched 1 transmembrane receptor; SMO, Smoothened protein; SUFU, suppressor of fused homolog protein.

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Aberrant activation of the Hh signaling pathway is the trigger for the pathogenic process in more than 90% of BCCs and is also responsible for triggering other types of tumor such as neuroblastomas, gliomas, and rhabdomyosarcomas.16 Abnormalities that can arise within the pathway include increased expression of the Hh ligand, which directly increases signaling, or genetic alteration of the regulatory proteins PTCH1 and SMO, giving rise to activated receptors, also leading to increased signal transduction. Most BCCs arise due to sporadic mutations in one of the implicated genes, with the most frequent being those in the PTCH1 (80%) and SMO (10%-20%) genes.16 There are also hereditary cases, such as Gorlin syndrome (GS) or basal cell nevus syndrome.17 GS is a hereditary disease of autosomal dominant transmission characterized by development of multiple BCCs at young ages, due mainly to mutations in the PTCH1 or SUFU gene.18 Most patients with GS are born with a mutation inherited from one of the alleles of PTCH1 and, subsequently, a second acquired mutation in a healthy allele because of external factors such as UV light, which is responsible for development of tumors.19

Inhibition of the Hh signaling pathway is a key therapeutic target in the treatment of laBCC, where surgery and radiotherapy cannot be used. Vismodegib and sonidegib inhibit the Hh pathway by binding to and deactivating the SMO protein, thus suppressing tumor growth (Fig. 1C). This review will summarize the efficacy, safety, and tolerability of sonidegib, as well as consider some points of importance in its use to treat patients with laBCC.

Sonidegib, marketed as Odomzo®, was approved by the United States Food and Drug Administration (FDA) and the European Commission after assessment by the European Medicines Agency (EMA) in July and August, respectively, of 2015. It is indicated for treatment of adult patients with laBCC who are not candidates for curative surgery or radiotherapy. The recommended dose is 200 mg of sonidegib, once a day, administered orally, separated from meals.

The frequency and importance of AEs associated with inhibition of the Hh pathway could be a limiting factor in treatment continuity. Dose adjustment or temporary treatment interruption are ready ways to improve patient compliance with treatment. During the BOLT trial, temporary dose interruptions or reductions did not have a negative impact on the efficacy of sonidegib.33 Specifically, similar ORRs assessed by central review were observed in subgroups with (50%) or without (57%) interruptions or dose reductions. Sonidegib is the only Hh inhibitor whose Summary of Product Characteristics includes a treatment regimen with dosing on alternate days to manage AEs.34

Sonidegib is an inhibitor of Hh signaling pathway that has been shown to be effective in the treatment of laBCC, with benefit observed in a significant proportion of patients, and short time to response to enable early detection of patients who respond and with favorable DoR and PFS. Its safety profile has been sustained in the long term, in the trial with the longest follow-up to date of an Hh inhibitor, while its tolerability is improved with a regimen of administration on alternative days, as stated in the Summary of Product Characteristics, thereby helping to reduce the number of treatment discontinuations.

Without doubt, sonidegib opens up a range of therapeutic possibilities for treatment of laBCC, although in absence of a head-to-head trial with the other molecule in its class, we need to wait for results of the 2 drugs in clinical practice to determine true differences and define the optimal profile of patients who respond to sonidegib, adjust dosing to minimizes adverse effects, and delay the onset of resistance to Hh inhibitors.

This article was funded by Sunpharma.

Rafael Botella-Estrada: Advisory board, and/or speaker, and/or participated in clinical trials for Pfizer, Abbvie, Almirall, Novartis, Janssen, Leo Pharma, Lilly, Celgene, Roche, SunPharma. Susana Puig: Advisory board or speaker or research grants or non-financial support or clinical trials for Abbvie, Almirall, Amgen, Avene, BMS, Canfield, Cantabria, ISDIN, La Roche Posay, Leo Pharma, MSD, Novartis, Pellepharma, Pfizer, Polychem, Regeneron, Roche, Sanofi. The remaining authors declare that they have no conflicts of interest.