Transforming Outcomes in Advanced Basal Cell Carcinoma: The Evolving Role of Systemic Therapy

Advanced basal cell carcinoma (aBCC) is an uncommon but severe presentation of basal cell carcinoma, including those with extensive local invasion and metastasis. Curative local treatments are often not feasible for patients with aBCC and the introduction of Hedgehog pathway inhibitors (HHIs) expanded the therapeutic landscape. First-line therapy with the HHIs, vismodegib and sonidegib, provides effective disease control, and may enable the preservation of function in locally complex cases. Also, it offers the possibility to simultaneously treat multiple tumors, such as in patients with basal cell nevus syndrome. However, long-term HHI therapy is limited by toxicity, heterogeneous responses and the emergence of resistance or tolerance. For selected patients with progression or limited tolerability under HHIs, immune checkpoint inhibition has emerged as an established second-line option, offering durable responses in a subset of patients. However, immune-related adverse events remain a concern. To address the shortcomings of systemic therapy and improve the long-term disease control of patients with aBCC, ongoing research focuses on alternative dosing strategies, integration of combination or novel systemic agents and the development of predictive biomarkers. This review provides a comprehensive, clinically oriented overview of the evidence on systemic treatment for aBCC, emphasizing efficacy, safety, resistance mechanisms, and therapeutic strategies.