Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.7 In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.
Hh Pathway in BCC
In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.8 The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.9 The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.10 Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.11,12
Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,13 subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.14 Many of these inhibitors have been clinically investigated.13,15,16
Systemic SMO Inhibitor: Vismodegib
Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.18,19
Adverse Effects of Vismodegib Therapy
Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.20 However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).20 In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.2 Apart from alopecia and possibly amenorrhea, these side effects are reversible.17 Alkeraye et al17 reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.7
Vismodegib is a pregnancy category D medication.4 Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.4
Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.21 Moreover, severe hepatotoxicity with vismodegib has been reported.22-24 A study conducted by Edwards et al25 concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.