Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome

Abstract

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.).

Figure 1. Surgically Eligible Basal-Cell Carcinomas (SEBs) in 36 Patients Followed for More Than 2 Months, According to Study Group

Data are shown for each of the 25 patients receiving vismodegib and 11 patients receiving placebo; individual curves cannot always be distinguished. Panels A and B show the cumulative number of new SEBs during the study period; Panels C and D show the percent change from baseline in the sums of the longest diameters of SEBs.

Figure 2. Surgically Eligible Basal-Cell Carcinomas in Two Patients Receiving Vismodegib

Reduction in the baseline sizes of existing superficial (back) and nodular (face) carcinomas (top row) is evident in the two patients at 5 months (bottom row).

Figure 3. Kaplan–Meier Estimates of Freedom from the Most Common Grade 1 or 2 Adverse Events and Study-Drug Use, According to Study Group

Panels A, B, C, and D show freedom from each of the four most common adverse events in the study: hair loss, weight loss of more than 5%, muscle cramps, and taste disturbance (dysgeusia), respectively. Panel E shows the continued receipt of the assigned study drug (with stopping due to adverse events).

Figure 4. Results from Histologic and Molecular Studies

Panel A shows clinical resolution of a typical basal-cell carcinoma lesion between baseline and 6 months. Panel B (hematoxylin and eosin) shows a biopsy specimen from a basal-cell carcinoma lesion at 6 months, with no obvious groups of tumor cells visible microscopically in random histologic sections after review by a dermatopathologist. (Scar and inflammatory cells are visible near the epidermis.) Panel C shows the messenger-RNA (mRNA) expression of the hedgehog target gene glioma-associated oncogene homolog 1 (zinc finger protein) (GLI1) in basal-cell carcinomas at baseline and at 1 month, according to study group. Data for individual patients are shown; the horizontal line indicates the mean, and the I bar indicates the standard error. Panel D shows the percent change from baseline in the sum of the longest diameters of existing surgically eligible basal-cell carcinomas (SEBs) in each of the first four patients (of seven in total) who stopped vismodegib before the 18-month end point and had over 3 months of follow-up. Solid segments of each curve indicate months during vismodegib treatment; and dashed segments, months after vismodegib was stopped.