BACKGROUND: Patients with advanced basal cell carcinoma have limited treatment 
options. Hedgehog pathway signalling is aberrantly activated in around 95% of 
tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling 
inhibitor, in patients with advanced basal cell carcinoma.
METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 
trial. Eligible patients had locally advanced basal cell carcinoma not amenable 
to curative surgery or radiation or metastatic basal cell carcinoma. Patients 
were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 
mg oral sonidegib daily, stratified by disease, histological subtype, and 
geographical region. The primary endpoint was the proportion of patients who 
achieved an objective response, assessed in the primary efficacy analysis 
population (patients with fully assessable locally advanced disease and all 
those with metastatic disease) with data collected up to 6 months after 
randomisation of the last patient. This trial is registered with 
ClinicalTrials.gov, number NCT01327053.
FINDINGS: Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 
in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median 
follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis 
population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 
39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective 
response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who 
achieved an objective response, as assessed by central review, were noted among 
the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 
13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 
patients with locally advanced disease had an objective response, as assessed by 
central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer 
adverse events leading to dose interruptions or reductions (25 [32%] of 79 
patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) 
occurred in patients in the 200 mg group than in the 800 mg group. The most 
common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 
200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four 
[5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients 
in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.
INTERPRETATION: The benefit-to-risk profile of 200 mg sonidegib might offer a 
new treatment option for patients with advanced basal cell carcinoma, a 
population that is difficult to treat.
FUNDING: Novartis Pharmaceuticals Corporation.