Itraconazole Has Activity in Patients with Basal Cell Carcinoma

Aberrant activation of the Hedgehog pathway is a hallmark of basal cell carcinoma (BCC). Vismodegib, an antagonist of the Hedgehog component Smoothened (SMO), has been approved by the FDA for treatment of inoperable or metastatic BCC, but some patients have vismodegib resistance. Surgical excision can be used to treat most nonadvanced BCCs but can cause scarring and morbidity. Preclinical studies have identified itraconazole, a widely used, FDA-approved antifungal agent, as a potent Hedgehog pathway antagonist with antitumor activity. Kim and colleagues therefore evaluated the effects of itraconazole on the Hedgehog pathway and tumor growth in an open-label, exploratory phase II trial in 29 patients with nonadvanced BCC. In one cohort, 15 patients received itraconazole tablets twice daily for 1 month, after which tumor size was measured and biopsy samples were analyzed for the proliferation marker Ki-67 and expression of the Hedgehog pathway gene GLI1. In a second cohort, 4 patients received a lower dose for approximately twice as long before tumor size was measured. Itraconazole was generally well tolerated, with mild and reversible adverse effects. Compared with baseline levels, itraconazole reduced Ki-67 levels and GLI1 expression by 45% and reduced tumor size by an average of 24% in vismodegib-naïve tumors. Tumor reductions were comparable between the cohorts, suggesting that lower doses of itraconazole may also be effective. However, cell proliferation, GLI1 expression, and tumor size were unchanged in untreated patients as well as in patients who had previously received vismodegib, raising the possibility that acquired vismodegib resistance may reduce itraconazole efficacy even though itraconazole and vismodegib inhibit SMO by distinct mechanisms. Although larger, longer studies are required to assess the activity of itraconazole and to compare the efficacy and safety of itraconazole and vismodegib, these results suggest that off-label use of itraconazole may be safe and effective in nonadvanced BCC.

Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol 2014;32:745–51.

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