Systematic Review of Vismodegib Toxicity Profile in the Treatment of Advanced Basal Cell Carcinomas Compared to Other Systemic Therapies in Dermatology

June 2014 | Volume 13 | Issue 6 | Original Article | 729 | Copyright © 2014

Margit L.W. Juhász MSca and Ellen S. Marmur MDa,b

aDepartment of Dermatology, Mount Sinai Hospital, NY, NY
bConsultant for Genentech, Inc.

Abstract

Vismodegib is a first-in-class, hedgehog-signal inhibitor that is FDA-approved for use with advanced basal cell carcinomas (BCCs) that cannot be removed by either surgical resection or treated with radiation. Release of the drug was fast-tracked because of need for this type of drug, and its overall efficacy in clinical trial by producing either regression or even resolution of advanced BCCs. Compared to placebo, patients using vismodegib have arrested BCC progression, reduced size of BCC, and decreased recurrence of BCC. Unfortunately, vismodegib has notable adverse effects (especially those of alopecia, gastrointestinal, muscle spasms, and dysguesia) that make dermatologists reluctant to prescribe the drug and patients unwilling to undergo therapy. In this article, we tackle this dilemma by comparing the toxicity profile of vismodegib to the adverse effect profiles of other dermatologic chemotherapeutics, immunomodulators, retinoids, and biologics. Considering that many of these drugs carry their own risks and those drugs used to treat advanced melanoma have similar toxicity profiles to that of vismodegib, we hope dermatologists and patients alike will be more willing to try vismodegib as a treatment option for advanced BCCs in the future.

J Drugs Dermatol. 2014;13(6):729-733.

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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

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