Vismodegib Treatment in Patients with Advanced Basal Cell Carcinoma: LongTerm Efficacy and Safety Data with Focus on Secondary Resistance and Underlying Resistance Mechanism

Background: The smoothened inhibitor vismodegib is an effective targeted therapy for basal cell carcinoma (BCC) witha manageable and consistent safety profile. The occurrence of secondary resistance during treatment is a major problemand is associated with hedgehog pathway reactivation, predominantly through Smoothened (SMO) gene mutations.Objectives: To analyse efficacy and safety data after long-term follow-up of patients treated with vismodegib foradvanced BCC in the University Hospital of Leuven, focusing on underlying genetic mechanisms of primary andsecondary resistance to vismodegib.Methods: Twenty seven patients were retrospectively included in the study. We performed targeted sequencing ofhedgehog pathway genes in 7 tumor samples from 4 patients with primary or secondary resistance to vismodegib.Results: Mean duration of follow-up was 29.9 months (1-77.7 months). Mean treatment duration was 13.3 months(1-64.5 months). The response rate to vismodegib was 93% (25/27 patients), with a partial response in 18/27 patientsand a complete response in 7/27 patients. One patient maintained a complete response up to >3 years after vismodegibdiscontinuation. Six out of 27 patients (24%) developed secondary resistance during treatment, in three of them wedetected acquired pathogenic SMO mutations in resistant tumor tissue. One patient with Bazex–Dupré–Christolsyndrome showed primary resistance to vismodegib. No unexpected safety signals were detected in our analysis,however progression of Multiple Sclerosis (MS) was observed in one patient.Conclusions: We deliver new data about the response duration after vismodegib discontinuation and describe MSprogression as a possible new adverse event to vismodegib. We describe for the first time vismodegib treatment andprimary resistance to vismodegib in a patient with Bazex–Dupré–Christol syndrome. We highlight the problem ofoccurrence of secondary resistance in >20% of responders and confirm the previously reported resistance mechanismthrough acquired SMO mutations.