Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.