INTRODUCTION
Vismodegib is a first-in-class FDA-approved oral drug for basal cell carcinomas (BCCs) deemed unsuitable for surgical resection or radiotherapy. Release of this drug was fast-tracked for January 2012 due to the drug’s ability to fulfill a previously empty therapeutic niche and its impressive efficacy in clinical trials.1 Clinical trials have shown vismodegib to be effective at producing regression and/or resolution of advanced BCC with a dose of 150 mg orally daily with an acceptable safety profile. Compared to placebo, patients on vismodegib showed no further progression of the current BCC, reduction in size of the current BCC (if not full regression), and decreased incidence of new BCC.2-5
However, even with its exciting successes when treating advanced BCC, vismodegib use by dermatologists is limited and these patients are often referred to an oncologist for treatment. The hesitancy of dermatologists to use vismodegib may be due to a reluctance to manage this drug’s side effect profile. To our knowledge, this is the first review comparing the adverse effect profile of vismodegib to other dermatologic chemotherapeutics, immunomodulators, retinoids, and biologics.
Mechanism of Action
Vismodegib is the first drug to target the hedgehog-signaling pathway in the context of cancer therapy.6,7 The hedgehog pathway is important for embryonic development, because it controls the “body plan†(both the anterior-posterior axis and appendage formation) through a series of feedback mechanisms 8. It is this pathway that malfunctions in BCC. More than 90% of BCCs carry a SMO (smoothened) gene (chr 7q32.3) mutation; mutations in the PTCH1 gene (chr 9q22.3), a tumour suppressor that inhibits the hedgehog pathway, cause Basal-Cell Nevus Syndrome (Gorlin Syndrome) 9. Vismodegib is a competitive antagonist (like cyclopamine) at the SMO G-coupled protein receptor. The inhibition of SMO does not allow the transcription factors GLI1 and GLI2 to activate, and thus inactivates downstream hedgehog signaling that would normally promote tumour growth.6-9
Phase I and II clinical trials show successful response rates ranging from 30% to 60% (depending on the metastatic state of the BCC).3-5 However, even with this treatment success rate, the alleged aggressive toxicity profile makes some of the dermatological community reluctant to prescribe and patients reluctant to receive vismodegib. Here we compare vismodegib with other classes of drugs that are more traditionally prescribed in dermatology. It is our hope to demonstrate that the vismodegib toxicity profile is on par with other dermatological drugs, therefore arguing that physicians and patients should consider vismodegib as a viable option to treat advanced BCCs.
Side Effects of Vismodegib
Vismodegib has a side effect profile that most commonly includes all grades of GI irritation (nausea, vomiting, diarrhea, constipation, pain etc.), muscle spasms, alopecia, taste disturbance, and weight
