Basal cell carcinoma is the most common non-melanoma skin cancer in human beings, arising more frequently than all other cancers combined in adult patients.1, 2 Although most basal cell carcinomas follow an indolent course and can be treated curatively with surgery, a small proportion progress to an advanced stage.2 Advanced basal cell carcinoma is inconsistently classified, partly because of its rarity, the heterogeneity of complex cases of basal cell carcinoma, and the scarce treatment options available.3, 4, 5
Moreover, because 80% of sporadic basal cell carcinomas arise in the head and neck,6 advanced disease is often disfiguring and associated with substantial morbidity. Surgery and radiotherapy might be contraindicated for advanced basal cell carcinoma, either because of the extent of disease leading to risk of deformity or loss of function, or because of patients' medical history (eg, patients with basal cell naevus syndrome).7, 8 When surgery is inappropriate and patients cannot receive additional radiation therapy, Hedgehog pathway inhibitors can be a useful treatment option.
Research in context
Evidence before this study
Aberrant activation of the Hedgehog signalling pathway is a key driver in the pathogenesis of basal cell carcinoma, and vismodegib is the first Hedgehog pathway inhibitor approved for the treatment of advanced, inoperable basal cell carcinoma. The phase 2 study ERIVANCE BCC showed that vismodegib offered clinical activity in patients with advanced basal cell carcinoma who were not eligible for surgery. Recently, data have been presented for sonidegib, another Hedgehog pathway inhibitor. We searched Medline and Embase with the search terms “basal cell carcinoma”, “hedgehog pathway inhibitor”, “vismodegib”, “sonidegib”, and “LDE225” for peer reviewed papers and abstracts published in the past 5 years (between Jan 1, 2010, and March 1, 2015).
Added value of this study
In the STEVIE trial, comprising—to the best of our knowledge—the largest patient series reported with advanced basal cell carcinoma, the safety profile of vismodegib was consistent with that previously reported in other smaller vismodegib studies. Investigator-assessed responses were also consistent with those reported in the ERIVANCE BCC study, confirming proportions of tumour control.
Implications of all the available evidence
Vismodegib is tolerable and active in a population of patients with advanced basal cell carcinoma that is representative of patients treated in routine clinical practice. This study provides important safety and activity data associated with long-term vismodegib treatment.
Aberrant activation of the Hedgehog signalling pathway is a key driver in the pathogenesis of basal cell carcinoma, with most basal cell carcinomas showing genetic alterations in pathway components.9 Signalling mediated through the Hedgehog pathway is crucial for cell growth and differentiation during embryogenesis and early development, but is largely inactive in adults. The pathway is activated by the binding of Hedgehog ligand to PATCHED (PTCH1), a 12-pass transmembrane receptor, which relieves the inhibitory effects of PTCH1 on Smoothened (SMO), a seven-pass transmembrane protein and a member of the G-protein coupled receptor superfamily. Signal transduction by SMO leads to activation and nuclear localisation of GLI transcription factors and induction of target genes, many of which are involved in proliferation, survival, and differentiation. Most mutations in basal cell carcinoma are loss-of-function mutations in PTCH1 (80–90%) or activating mutations in SMO (about 10%), resulting in constitutive pathway activation.2, 6
Vismodegib is a first-in-class, oral, selective Hedgehog pathway inhibitor.9, 10 In a phase 2 study, 150 mg vismodegib once a day showed clinical benefit in patients with locally advanced or metastatic basal cell carcinoma who were not eligible for surgery, with 43% of patients achieving an objective response in locally advanced basal cell carcinoma and 30% in metastatic basal cell carcinoma by independent review (60% and 45%, respectively by investigator assessment), and median progression-free survival durations of 9·5 (IQR 7·2–12·8 for locally advanced basal cell carcinoma; 7·4–non-evaluable for metastatic basal cell carcinoma) months for both cohorts.11, 12 Although 51% of patients discontinued study treatment at data cutoff, a substantial proportion of patients achieved meaningful and durable responses with vismodegib. Vismodegib is the first Hedgehog pathway inhibitor approved for the treatment of advanced, inoperable basal cell carcinoma, and represents a promising new treatment option.13 More recently, data for another Hedgehog pathway inhibitor (sonidegib) have been presented in patients with locally advanced or metastatic basal cell carcinoma.14, 15, 16 Promising phase 1 data14 resulted in a multicentre, randomised, double-blind phase 2 trial.15
The SafeTy Events in VIsmodEgib (STEVIE) study was designed to further assess the safety and efficacy of vismodegib in patients without other satisfactory treatment options. We report results of an interim analysis in 499 patients with the potential to be followed up for 12 months or longer.
