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Published on: April 22, 2019
Efficacy and safety of vismodegib in advanced basal-cell carcinoma
Aleksandar Sekulic1, Michael R Migden, Anthony E Oro
1Mayo Clinic, Scottsdale, AZ 85259, USA. sekulic.aleksandar@mayo.edu
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.).
Insights
Vismodegib effectively treats advanced basal-cell carcinoma by inhibiting hedgehog signaling. This study shows significant tumor response rates in patients with locally advanced or metastatic disease.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- Hedgehog signaling pathway alterations are key in basal-cell carcinoma (BCC) development.
- Current treatments lack efficacy for advanced or metastatic BCC.
- Vismodegib, a hedgehog pathway inhibitor, demonstrated promise in a Phase 1 study.
Purpose of the Study:
- To evaluate the efficacy and safety of vismodegib in patients with advanced BCC.
- To determine the objective response rate of vismodegib in metastatic and locally advanced BCC cohorts.
Main Methods:
- A multicenter, international, nonrandomized study.
- 150 mg of oral vismodegib administered daily to patients with metastatic or locally advanced BCC.
- Primary endpoint: independently assessed objective response rate.
Main Results:
- 30% response rate in metastatic BCC (n=33) and 43% in locally advanced BCC (n=63).
- Complete responses observed in 21% of locally advanced BCC patients.
- Median duration of response was 7.6 months; common adverse events included muscle spasms, alopecia, and dysgeusia.
Conclusions:
- Vismodegib demonstrates significant tumor response in patients with locally advanced or metastatic basal-cell carcinoma.
- The drug offers a potential therapeutic option for advanced BCC where surgery is not feasible.
- Further investigation into long-term efficacy and safety is warranted.