Randomized, double-blind study of sonidegib (LDE225) in patients with advanced basal cell carcinoma

Background: The BOLT Phase 2 study, comparing two doses of sonidegib, a hedgehog pathway inhibitor (HhPI), in patients with advanced basal cell carcinoma (BCC) (aBCC; NCT01327053), met its primary endpoint of objective response rate ≥30 percent in both arms in analyses of data collected up to six months after randomization of the last patient (June 28, 2013, cutoff; median follow‐up [f/u], 13.9 mo; Migden, ASCO 2014). Associations of GLI1 (marker of Hh pathway activation) with clinical outcome (as of June 28, 2013) and updated 12‐month efficacy and safety data (Dec 31, 2013, cutoff; median f/u, 20.0 mo) are presented. Methods: Patients with locally advanced BCC (LaBCC; n=194) not amenable to curative surgery or radiation or metastatic BCC (mBCC; n=36) were randomized 1:2 to receive sonidegib 200 or 800mg daily. Clinical response was assessed by central review using modified RECIST (LaBCC) or RECIST 1.1 (mBCC). Exploratory analyses in a subset of patients (LaBCC, n=137; mBCC, n=13) assessed GLI1 levels by qRT‐PCR in tumor tissue collected at baseline, Week 9, and Week 17. Results: GLI1 levels decreased from baseline with both doses at Week 9 and 17 (median % changes [200mg], ‐91.07 and ‐93.75; P<0.0001 vs. baseline) and in patients with disease control (CR, PR, SD). Median percent changes (200mg) at Week 17 by response were CR, ‐99.47; PR, ‐90.79; SD, ‐96.58; PD, +10.19; unknown, ‐94.24. With an additional six‐month follow‐up, median exposure duration was 11.0 (200mg) and 6.6 months (800mg). More than half of patients with LaBCC in the 200mg arm responded, and tumor responses in both arms were durable. The safety profile of sonidegib was typical of HhPIs; the most common adverse events (200/800mg) were muscle spasms (52%/69%), alopecia (49%/57%), and dysgeusia (41%/60%). Conclusions: Reduced GLI1 levels versus baseline were seen in patients with disease control. With longer follow‐up, sonidegib continued to demonstrate clinically meaningful tumor shrinkage, sustained responses, and prolonged progression‐free survival in patients with aBCC. The 200mg dose had a better benefit‐risk profile.