Efficacy and safety of vismodegib in advanced basal-cell carcinoma

Abstract

Background: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.

Methods: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.

Results: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.

Conclusions: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Figure 1. Maximum Tumor Shrinkage in the Two Cohorts

Panel A shows a waterfall plot of maximum tumor shrinkage (the sum of the longest diameters, as compared with baseline), according to the independent review before progression, in the group of 33 patients with metastatic basal-cell carcinoma. Each bar represents a patient; 3 had a best percentage change of 0 in the sum of the longest diameters, accounting for the gap in the bars. Three patients did not have measurements, and 1 could not be evaluated for assessment of best confirmed response; data from these 4 patients were excluded from this figure. Panel B shows a waterfall plot of maximum tumor shrinkage before progression, as assessed by independent review, in the 63 patients with locally advanced basal-cell carcinoma who were included in the efficacy analysis. For patients with target lesions that were assessed only by measuring the externally visible dimension, the maximum tumor shrinkage shown is based on the externally visible dimension. For patients who also underwent radiographic assessment, the waterfall plot shows the assessment approach yielding the greater percent reduction (either radiographic assessment or measurement of the externally visible dimension). Four patients did not have lesion measurements; data from these patients were not included in this figure. The asterisk denotes a patient with tumor shrinkage of less than 30% and a response assessed on the basis of the complete resolution of ulceration. In both panels, the dashed line represents a 30% decrease in the sum of the longest diameters.

Figure 2. Photographs of Lesions before and during Treatment in Two Patients with Locally Advanced Basal-Cell Carcinoma

Panel A shows locally advanced basal-cell carcinomas on the scalp and forehead of a 68-year-old woman; substantial deformity was anticipated from surgery. No prior surgeries other than biopsies were reported. Radiation therapy was considered to be contraindicated, owing to multiple coexisting conditions and a risk of damage to the brain. No residual basal-cell carcinoma was detected in biopsy specimens obtained at week 16. This patient was considered to have had a complete response, according to the independent review and the site investigator. Panel B shows three of five target lesions (on the right temple, back of the neck, and left temple and external auditory canal) in an 82-year-old man with locally advanced basal-cell carcinoma. The patient had undergone numerous surgical procedures. The lesions present at enrollment had recurred at least twice and were considered unlikely to be curatively resected or would have substantial anticipated morbidity or deformity from surgery. Radiation therapy was considered to be inappropriate, owing to the extensive disease. Although residual basal-cell carcinoma was detected on biopsy of the remaining ulceration on the left temple at week 24, biopsy specimens of other lesions showed no evidence of basal-cell carcinoma. This patient was considered to have had a partial response, according to the independent review and the site investigator.