A new drug that targets the hedgehog signalling pathway and looks promising for patients with advanced basal cell carcinoma (BCC) was reported by Daniel van Hoff and colleagues at the annual meeting of the American Association for Cancer Research.

BCC is a common form of skin cancer and most patients are cured by surgery. However, a small fraction of patients have disease for which surgery is not an option and currently there are no therapies that can be used to effectively treat these patients. Mutations within the hedgehog signalling pathway are crucial in the development of BCC so van Hoff and colleagues set up a phase I clinical trial using GDC-0449 (Curis Inc.), a first-in-class, potent and orally available systemic inhibitor of hedgehog signal transduction pathways. Nine patients with advanced BCC (four with locally advanced or multifocal disease and five with metastatic disease) were enrolled in this first-in-human trial that used a 3+3 design with modified dose doubling to evaluate safety, tolerability, maximum tolerated dose, and pharmacokinetics and pharmacodynamics. The patients were recruited from the Scottsdale Healthcare Center, Arizona, the Karmanos Cancer Institute at Wayne State University, Michigan and the Sidney Kimmel Cancer Center at Johns Hopkins, California, USA.

In patients recruited to the dose escalation part of the trial, GDC-0449 was given as a 150, 270 or 540 mg single dose on day 1, followed by a 7-day break in which the pharmacokinetics of the drug were evaluated, and then patients received a once-daily dose for a continuous 28 day cycle (35 days in total). The expansion cohort of patients received 150 mg GDC-0449 daily starting on day 1 for 35 days.

In four out of five of the patients with metastatic disease, two had a partial response (confirmed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria), one had stable disease and one progressive disease. The fifth patient has not yet been assessed. Two of the four patients with locally advanced or multifocal disease had a complete response in subcutaneous masses (determined by physical examination), and the other two patients had stable disease in their skin lesions. Durable clinical benefit (mean 112+ days; range 56+ to 375+) was seen in eight of the nine patients. Importantly, expression of the hedgehog target gene GLI1 was reduced more than twofold in skin biopsy samples from all patients tested to date, indicating that GDC-0449 is able to target the hedgehog pathway when given orally as a systemic agent. This drug was also well-tolerated, with some patients losing their sense of taste and others showing a small amount of hair and weight loss.

GDC-0449 is being developed by Genentech under a collaboration agreement with Curis, and Genentech hope to start phase II trials later this year.