Efficacy and Safety of Sonidegib in Adult Patients with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome): Results from a Phase 2, Double-Blind, Randomized Trial.

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome, is a rare hereditary disease characterized by the development of multiple cutaneous basal cell carcinomas (BCCs) from a young age.1 Loss-of-function germline mutations in the hedgehog-related patched 1 (PTCH1) tumor suppressor gene are the most common cause of NBCCS.1 The hedgehog signaling pathway plays a major role in embryonic development, and in adulthood, is involved in the renewal and maintenance of distinct tissues, including hair follicles, muscle stem cells, and gastric epithelium.2 Its abnormal activation is thought to drive the formation of both sporadic BCCs and those resulting from NBCCS.1 Patients with NBCCS inherit one inactive copy of PTCH1 and then acquire a “second-hit” mutation, resulting in hedgehog pathway activation and BCC formation.1 Mutations in Suppressor of fused (SUFU) or the PTCH1 homolog PTCH2 have also been found in a subset of patients meeting criteria for NBCCS.1,3 Treatment of BCCs in patients with NBCCS can be extremely difficult due to the large number of tumors. Patients with a limited number of BCCs may benefit from surgical excision.3 However, patients with aggressive or recurrent tumors, as well as tumors in delicate or high-risk areas, may benefit from Mohs micrographic surgery, which is lengthy and costly.3 Multiple surgical procedures can be a source of discomfort, pain, and disfigurement for patients with NBCCS, leading to an unmet need for nonsurgical and minimally invasive treatment options. Sonidegib (Odomzo®; Sun Pharmaceutical Industries, Inc.; Cranbury, NJ), a hedgehog pathway inhibitor (HPI), is approved for the treatment of adult patients with locally advanced BCC (laBCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.4 Approval was based on results from the BOLT (BCC outcomes with LDE225 [sonidegib] treatment) study.5,6 Here we report the results of an exploratory study evaluating the safety, preliminary efficacy, and pharmacokinetics of sonidegib in patients with NBCCS after 12 weeks of treatment.