A Review of Hedgehog Inhibitors Sonidegib and Vismodegib for Treatment of Advanced Basal Cell Carcinoma
February 2021 | Volume 20 | Issue 2 | Original Article | 156 | Copyright © February 2021
Published online January 21, 2021
Michael Migden MDa, Aaron S Farberg MDb, Reinhard Dummer MDc, Nicholas Squittieri MDd, C. William Hanke MDe
aDepartments of Dermatology and Head and Neck Surgery, The University of Texas–MD Anderson Cancer Center, Houston, TX
bSection of Dermatology, Baylor University Medical Center, Dallas, TX
cDepartment of Dermatology, University of Zürich, Skin Cancer Center, University Hospital, Zürich, Switzerland
dSun Pharmaceutical Industries, Inc., Princeton, NJ
eAscension Saint Vincent Hospital, Indianapolis, IN
Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between sonidegib and vismodegib is their respective pharmacokinetic profiles with sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of sonidegib and vismodegib based on published literature to date. J Drugs Dermatol.
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For the majority of basal cell carcinomas (BCCs), surgery is the standard of treatment with an excellent prognosis, as recommended by the American Academy of Dermatology and the European consensus-based interdisciplinary guidelines.1,2 When surgery is contraindicated or unlikely to be effective, as in cases of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic Hedgehog inhibitors (HHIs) are recommended.1-3
Two inhibitors of Smoothened, a Hedgehog pathway protein, are currently approved for treatment of advanced BCC. Sonidegib (Odomzo®; Sun Pharmaceutical Industries, Inc.; Cranbury, NJ) is approved in the US for the treatment of adults with laBCC that has recurred following surgery or radiation therapy, or for patients who are not candidates for surgery or radiation therapy.4 In the EU, Switzerland, and Australia, sonidegib is approved for the treatment of adults with laBCC who are not amenable to curative surgery or radiation therapy.5-7 Sonidegib is also indicated for mBCC in Switzerland and Australia.6,7 Vismodegib (Erivedge®; Genentech, Inc.; San Francisco, CA) is approved in the US for the treatment of adults with mBCC, or laBCC that has recurred after surgery, or for those who are not candidates for surgery or radiotherapy.8 In the EU, Switzerland, and Australia, it is indicated for adults with mBCC or laBCC inappropriate for surgery or radiotherapy.9,10 In the absence of head-to-head clinical studies, this review summarizes and juxtaposes published reports to date on the efficacy, safety, and pharmacokinetics (PK) of sonidegib and vismodegib.
METHODOLOGY OF MAJOR CLINICAL STUDIES
Pivotal Studies in Advanced Basal Cell Carcinoma
The pivotal studies evaluating efficacy and safety of sonidegib and vismodegib in advanced BCC were BOLT (Basal Cell Carcinoma Outcomes with LDE225 [sonidegib] Treatment) for sonidegib, and ERIVANCE-BCC for vismodegib (Table 1). BOLT was a phase 2, randomized, double-blind, multicenter, adaptive clinical study, while ERIVANCE was a phase 2, single-arm, 2-cohort clinical study.11,12
Eligible patients in BOLT were ≥18 years old with an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.