U.S. Food and Drug Administration Approval: Vismodegib for Recurrent, Locally Advanced, or Metastatic Basal Cell Carcinoma

Abstract

The data and regulatory considerations leading to the U.S. Food and Drug Administration (FDA) January 30, 2012 approval of Erivedge (vismodegib) capsules for the treatment of patients with recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) are described. The FDA's approval decision was based primarily on the results observed in a single-arm, parallel cohort, international trial of vismodegib, administered orally at 150 mg daily until disease progression, in patients with pathologically confirmed, recurrent, locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma (mBCC). An independent review committee confirmed an overall response rate (ORR) of 30.3% [95% confidence interval (CI): 15.6-48.2] in 33 patients with mBCC and an ORR of 42.9% (95% CI: 30.5-56.0) in 63 patients with laBCC; median response durations were 7.6 months and 7.6 months for patients with mBCC and laBCC, respectively. The most common adverse reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, cough, arthralgias, vomiting, headache, ageusia, insomnia, and upper respiratory tract infection. Animal toxicology studies confirmed that vismodegib is a potent teratogenic agent. Approval was based on durable objective tumor responses supported by knowledge of the pathologic role of Hedgehog signaling in BCC and acceptable toxicity in a population without effective alternative therapies.

A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

“…They found that IL-23 signaling promotes tumor growth and progression, and the development of tumoral IL-17 response, resulting in an additional aggravation of disease progression (60). Efforts to target pathogenic Hedgehog signaling have steadily progressed from the laboratory to the clinic, and the recent approval of vismodegib for patients with advanced basal cell carcinoma represents an important milestone (61)(62)(63)(64)(65)(66). However, in a recent phase II study, vismodegib did not add to the efficacy of standard first-line treatment for metastatic colorectal cancer (67).…”

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)

“…As detailed knowledge regarding the molecular pathogenesis of BCC has been elucidated, multiple targeted therapies have been developed to target aberrant HH signaling. Vismodegib, a small molecule agent that binds to and directly inhibits SMO was recently FDA approved for recurrent, locally advanced, or metastatic basal cell carcinoma [32]. Targeted therapy has also been attempted in NBCCS; for example, a phase II study examining the efficacy of vismodegib in NBCCS found a significant reduction in surgically eligible BCCs encountered in the treatment group (2 per patient) versus the control group (29 per patient).…”

Recent developments in brain tumor predisposing syndromes

“…The smoothened inhibitor vismodegib has recently been approved for treating BCC in patients with NBCCS [74]. Unfortunately, 20% of all treated tumors developed resistance within one year of treatment; and mutations in SUFU have been proposed as a mediator of this resistance mechanism [75].…”