Comparison of efficacy and tolerability of hedgehog pathway inhibitors for locally advanced basal cell carcinoma

Basal cell carcinoma (BCC) is the most diagnosed malignancy. While most cases are curable, a subset progresses to unresectable locally advanced (laBCC) or metastatic BCC (mBCC). The Smoothened inhibitors (SMOi) vismodegib and sonidegib have significantly improved outcomes in these cases. However, differences in trial design, pharmacokinetics, adverse effects (AEs), and real-world application warrant clinical comparison. This narrative review examines key clinical trials (ERIVANCE, BOLT, STEVIE, MIKIE), FDA labeling, and real-world data. Efficacy outcomes, AE profiles, pharmacokinetics, and resistance mechanisms are analyzed alongside expert recommendations for optimizing treatment. In expert opinion, sonidegib demonstrates a longer median duration of response and more durable disease control compared to vismodegib. Its delayed-onset AEs and deeper tissue penetration make it favorable for infiltrative or high-risk disease. Vismodegib, though more widely prescribed, is associated with earlier-onset AEs and challenges with treatment interruptions due to its shorter half-life. Tailored dosing and AE mitigation strategies as well as neoadjuvant applications of SMOi improve tolerability and outcomes for both agents. Both vismodegib and sonidegib remain essential tools in the management of advanced BCC. Understanding their pharmacologic and clinical differences enables more personalized treatment planning, enhancing long-term outcomes and expanding their use in neoadjuvant and maintenance settings.

Abstract from PubMed