Hedgehog Inhibitor Sonidegib Active in Advanced Basal Cell Carcinoma
In the phase II BOLT trial reported in The Lancet Oncology, Migden et al found that the hedgehog pathway signaling inhibitor sonidegib produced responses in patients with locally advanced or metastatic basal cell carcinoma at 200-mg and 800-mg dose levels. The lower dose appeared to be associated with a better benefit-risk profile.
Study Details
In the study, 230 patients with locally advanced disease not amenable to curative surgery or radiation or metastatic disease for which all available treatment options had been exhausted were randomly assigned 1:2 between July 2011 and January 2013 to receive sonidegib 200 mg/d (n = 79, 13 with metastatic disease) or 800 mg/d (n = 151, 23 with metastatic disease). The primary endpoint was the proportion of patients who achieved an objective response on central review among those with fully assessable (by modified RECIST criteria) locally advanced tumors and all patients with metastatic disease.
Response Rates
Median follow-up was 13.9 months. In the primary efficacy analysis, objective response was observed in 20 (36%) of 55 evaluable patients receiving 200 mg and 39 (34%) of 116 receiving 800 mg. Response rates were 43% in 42 patients with locally advanced disease and 15% in 13 patients with metastatic disease in the 200-mg group and 38% in 93 patients with locally advanced disease and 17% in 23 with metastatic disease in the 800-mg group. In the intent-to-treat analysis, response rates on central review were 47% in locally advanced disease in the 200-mg group and 35% in locally advanced disease in the 800-mg group.
Adverse Events
The most common adverse events of any grade were muscle spasms (49% in 200-mg group vs 67% in 800-mg group), dysgeusia (38% vs 59%), alopecia (43% vs 55%), nausea (33% vs 45%), and increased serum creatine kinase (29% vs 37%). The most common grade 3 or 4 adverse events were increased creatine kinase (6% vs 13%) and increased lipase concentration (5% vs 5%). Serious adverse events occurred in 14% vs 30% of patients. Adverse events led to dose interruption or reduction in 32% vs 60% and treatment discontinuation in 22% vs 36%. The most common adverse events leading to treatment discontinuation were muscle spasms (4% vs 9%), dysgeusia (3% vs 5%), weight decrease (3% vs 5%), and nausea (3% vs 4%).
The investigators concluded: “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.”
Michael R. Migden, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author of The Lancet Oncology article.
The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit www.thelancet.com.
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