BACKGROUND Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (−65% vs. −11%, P = 0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.)

EMLA and L.M.X.4 provide comparable levels of anesthesia after a single 30-minute application under occlusion prior to electrodesiccation of superficial skin lesions.

BACKGROUND Liposomal lidocaine 4% (L.M.X.4 cream, Ferndale Laboratories Inc., Ferndale, MI, USA) has been proposed as a more rapidly acting topical anesthetic than the eutectic mixture of lidocaine 2.5% and prilocaine 2.5% (EMLA cream, AstraZeneca LP, Wilmington, DE, USA) for venipuncture and laser procedures. However, their anesthetic efficacy has not been previously compared for electrosurgical destruction of superficial skin lesions.OBJECTIVE To test the hypothesis that L.M.X.4 and EMLA differ in anesthetic efficacy when applied under occlusion for 30 minutes prior to electrodesiccation of papules of dermatosis papulosa nigra.METHODS Forty adults were randomly assigned to treatment with either agent for 30 minutes under Tegaderm. The study drug was administered for an additional 30 minutes if the electrodesiccation of the first few papules was too painful.RESULTS One subject treated with EMLA versus none treated with L.M.X.4 experienced complete anesthesia after a single 30-minute application. Nineteen of 20 (95%) subjects treated with EMLA versus 18 of 20 (90%) subjects treated with L.M.X.4 required only a single application (p = .49). Pain scores after the initial 30-minute application (scale: 0 = none to 10 = very severe) were EMLA 3.3 Ϯ 2.2 (mean Ϯ SD) versus L.M.X. 4 2.9 Ϯ 2.0 (p = .46). CONCLUSION EMLA and L.M.X.4 provide comparable levels of anesthesia after a single 30minute application under occlusion prior to electrodesiccation of superficial skin lesions.

Purpose: GDC-0449 (Genentech) is a new hedgehog pathway inhibitor that has been shown in a Phase I trial to reduce locally advanced/metastatic BCCs. We tested the efficacy of GDC-0449 for BCC prevention in a randomized, double-blind, placebo-controlled trial in patients with Basal Cell Nevus Syndrome (BCNS). Methods: We enrolled 41 BCNS patients from 3 clinical centers from September 2009 to January 2011. Subjects were randomized 2:1 to receive once daily oral GDC-0449 (150 mg) or placebo. The primary endpoint was to assess the number of new surgically eligible BCCs per month after 3 months; secondary endpoints included assessment of the change in size of existing BCCs and safety/tolerability. Results: 36 subjects (24 GDC-0449, 12 placebo) have been enrolled for greater than 1 month. Upon review of results at the interim analysis, the DSMB ended the placebo arm of the trial due to statistically significant differences between the 2 groups. Subjects treated with GDC-0449 developed 0.07 new BCCs per month vs. 1.74 BCCs per month for those receiving placebo (p&lt;0.0001). The change from baseline in the aggregate size of existing BCCs was −24 cm vs. −3 cm for GDC-0449 and placebo, respectively (p=0.006). Some subjects achieved near complete remission with no BCC developing resistance. Common grade 1–2 adverse events (GDC-0449 vs. placebo) included taste loss (83% vs. 8%), muscle cramps (67% vs. 8%), and weight loss (50% vs. 8%). Two GDC-0449 subjects experienced grade 3–4 adverse events (muscle cramp, suicide attempt). Overall 20% of GDC-0449 subjects discontinued drug participation due to adverse events. BCC samples from 23 subjects treated with GDC-0449 or placebo were available for molecular analysis. The anti-BCC efficacy of GDC-0449 was associated with on-target reduction of the Hedgehog pathway as Gli1 mRNA levels were decreased by 200-fold (p&lt;0.001) after 1month in BCCs. Gli1 mRNA levels were not changed in BCCs from placebo subjects. GDC-0449 also decreased tumor proliferation (Ki67) but had no effect on apoptosis (CC3). Biopsies of lesions taken after 3 months of GDC-0449 showed histologic clearance in 7 out of 11 samples. Conclusion: GDC-0449 has anti-BCC efficacy in BCNS patients and may be a potential new drug for BCC prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-1. doi:10.1158/1538-7445.AM2011-LB-1