Eight Years of Real-Life Experience with Smoothened Inhibitors in a Swiss Tertiary Skin Referral Center

SIMPLE SUMMARY: Vismodegib and sonidegib are targeted therapies inhibiting the hedgehog pathway, a key driver in the pathogenesis of basal cell carcinoma (BCC). Hedgehog inhibitors (HhIs) are first-line therapy for locally advanced basal cell carcinoma (laBCC), metastatic basal cell carcinoma (mBCC) and multiple BCCs, when surgery and radiotherapy are no longer feasible. Safety and efficacy of the HhIs vismodegib and sonidegib have been shown in large prospective clinical trials. However, treatment of advanced basal cell carcinoma (aBCC) in daily practice includes patients who do not meet strict inclusion criteria and poses an additional challenge for treating physicians. This study aims to give an insight into a real-world experience in our tertiary skin referral center. ABSTRACT: Background: The hedgehog inhibitors vismodegib and sonidegib are approved for the treatment of advanced basal cell carcinoma. This study reports the experiences with these therapies in a tertiary skin referral center in daily practice. Methods: A retrospective, observational, single-center study analyzing medical records of patients with aBCC treated with a smoothened (SMO) inhibitor outside a clinical trial for at least one month between 2013 and 2021. Results: In total, 33 patients were included: 21 (64%) patients were treated with vismodegib, 3 (9%) patients with sonidegib and 9 (27%) patients with both treatments subsequently. With vismodegib, the best overall response was complete response (CR) in 33% cases, and partial response (PR) in 33% cases. Under sonidegib, 42% patients achieved CR and 17% PR. Mean duration to next treatment was 33 and 14 months for vismodegib and sonidegib, respectively. Adverse events varied in frequency between continuous and intermittent dosing and they were the most common reason for therapy discontinuation. Conclusions: Our real-world data illustrate the pitfalls and benefits of HhIs as well as the impact of different dosing regimens on adverse events, patient adherence and response. Treatment duration remains limited by adverse events and resistance. Additional treatment options, including immunotherapy and drug combinations, are needed.