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 MD,a Aaron S. Farberg MD,b Reinhard Dummer MD,c Nicholas Squittieri MD,d 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

xplain observed differences in efficacy and toxicity between these two HHIs.

Efficacy and Safety in Patients With Nevoid Basal Cell Carcinoma Syndrome
Patients with the hereditary disease nevoid basal cell carcinoma syndrome (NBCCS) tend to develop multiple BCCs from a young age.44 Since multiple surgeries can be costly and result in deformity and emotional distress, HHIs are investigated as a potential treatment option for this patient population.

A phase 2, double-blind, randomized, placebo-controlled exploratory study evaluated preliminary efficacy and safety of sonidegib in patients with NBCCS.45 Twelve weeks of treatment resulted in histological clearance of target BCCs in 4 of 7 patients, and clinical clearance in 3 of 7 patients treated with sonidegib 400 mg QD, vs 0 of 2 patients treated with placebo. The total number of BCCs in the sonidegib group decreased from 566 at baseline to 341 after 12 weeks of treatment and to 309 after 4 additional weeks of follow-up. AEs were reported in 7 of 8 patients treated with sonidegib, the most common AE being muscle spasms in 3 patients. Alopecia and CK elevation were reported in 2 patients each.45

Vismodegib efficacy and safety in patients with NBCCS was evaluated in a phase 2 double-blind, randomized, placebo-controlled study.46 Treatment over 36 months resulted in a mean rate of appearance of new surgically eligible BCCs per-patient-per-year of 2 in 26 patients treated with 150 mg QD vismodegib vs 34 in 15 patients treated with placebo. Most common AEs in patients treated with vismodegib were muscle spasms and alopecia in 100% of patients, and dysgeusia in 93% of patients.46

Resistance to Treatment
A subset of patients treated with sonidegib or vismodegib exhibit lack of response (primary resistance), or develop resistance after initial response to treatment (secondary resistance).47 In the BOLT 42-month analysis, the rate of PD in patients with laBCC was 9% in the 200 mg and 18% in the 800 mg sonidegib group.11 Patients in ERIVANCE exhibited a rate of PD of 6% in laBCC and 2% in mBCC at 39 months.12

An open-label, single-arm, proof-of-concept study examined the efficacy of sonidegib and buparlisib in 7 patients with advanced BCC that did not respond to previous treatments, including treatment with vismodegib.48 Treatment resulted in PR in 1, SD in 4, and PD in 2 patients. The study was terminated early due to toxicity.48

The efficacy of sonidegib in 9 patients with advanced BCC resistant to vismodegib was evaluated in an open-label, investigator-initiated study.49 Treatment for a median duration of 6 weeks resulted in SD in 3 and PD in 5 patients. Most common AEs included muscle spasms in 5, nausea in 4, and CK elevation in 2 patients.49


Although clinical studies of sonidegib and vismodegib have distinct methodologies, they demonstrate similarities in efficacy and the AEs commonly encountered, including muscle spasms, elevated CK, alopecia, and dysgeusia. Sonidegib and vismodegib demonstrate differences in their PK profiles, with a trend towards longer half-life for sonidegib and a tendency for vismodegib to bind plasma proteins. Management of BCCs in patients with NBCCS and patients who develop resistance to HHIs are topics of ongoing interest.


M. Migden has participated on advisory boards and received honoraria from Genentech; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals; and Sun Pharmaceutical Industries, Inc. A. Farberg has participated on advisory boards and received honoraria from Ortho- dermatologics; Sensus; and Sun Pharmaceutical Industries, Inc. R. Dummer has participated on advisory boards and consulted for Amgen; Bristol-Myers Squibb; Catalym; Merck Sharpe and Dohme; Novartis Pharmaceuticals Corporation; Pierre Fabre; Roche; Sanofi; Second Genome; Sun Pharmaceutical Industries, Inc.; and Takeda. N. Squittieri is an employee of Sun Pharmaceutical Industries, Inc. C. W. Hanke participated in advisory boards for Sun Pharmaceuticals, Inc.; and has received research grants for clinical trials from Sun Pharmaceuticals, Inc.

Author’s contributions: All authors met the International Council of Medical Journal Editors criteria and received neither honoraria nor payment for authorship.

Funding: Research was funded by Sun Pharmaceutical Industries, Inc. (Princeton, NJ).


Writing and editorial support for manuscript preparation were provided by Zehra Gundogan, VMD (AlphaBioCom, LLC, King of Prussia, PA).


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Michael Migden MD mrmigden@mdanderson.org