A Smoothen Inhibitor for Advanced Basal Cell Carcinoma
Craig A. Elmets, MD reviewing Migden MR et al. Lancet Oncol 2015 Jun.
Small-molecule inhibitors of the Hedgehog pathway are an alternative for advanced BCCs in patients unsuited for surgery or radiation.
Although most basal cell carcinomas (BCCs) are easily treated with surgery, radiation, or medication, few options are available for locally advanced or metastatic disease. Recently, vismodegib, a small-molecule inhibitor of Smoothen (Smo), a protein activated in the Hedgehog signal transduction pathway, was approved for treating advanced, locally invasive, and metastatic BCC. More than 95% of BCCs have defects in the Hedgehog signal transduction pathway. Now, the safety and efficacy of sonidegib, a second Smo inhibitor, has been evaluated for locally advanced and metastatic BCC.
In this randomized, multicenter, double-blind, phase II trial, 79 patients received 200 mg of sonidegib daily and 151 received the 800-mg dose. Median follow-up was 13.9 months. Both local advanced and metastatic BCC were controlled in more than 90% of 200-mg recipients and in more than 80% of 800-mg recipients. Complete or partial response, as defined by investigators, was achieved in two thirds of patients with advanced local disease and almost one quarter of patients with metastatic disease, although responses were somewhat lower when a more rigorous assessment was made. The 200-mg dose was better tolerated. Adverse effects resembled those of other Smo inhibitors — specifically, muscle spasms, dysgeusia, alopecia, nausea, weight loss, fatigue, and increased serum creatine kinase. GLI1 expression is a marker of Hedgehog signal transduction pathway activity. Patients in whom sonidegib was successful had greater than 90% reduced GLI1 activity. In the one nonresponder in whom it could be evaluated, GLI1 expression increased.
Citation(s):
Migden MR et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015 Jun; 16:716.
