A, Patient 5 demonstrating a large periorbital basal cell carcinoma prior to treatment. B, Patient 5 eight months after treatment with intermittent vismodegib (1 week receiving and 1 week without receiving medication for 6 cycles, followed by 1 week with and 2 weeks without medication for 5 cycles).
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Becker LR, Aakhus AE, Reich HC, Lee PK. A Novel Alternate Dosing of Vismodegib for Treatment of Patients With Advanced Basal Cell Carcinomas. JAMA Dermatol. 2017;153(4):321–322. doi:10.1001/jamadermatol.2016.5058
Basal cell carcinoma (BCC) is the most common cutaneous malignancy with a favorable prognosis, as the estimated cure rate when treated early is around 95%.1 Despite this, BCC can progress locally or metastasize. Vismodegib has been shown to lead to significant improvement in patients with advanced BCC.2 Unfortunately, adverse effects (AE) have often led to drug discontinuation.2,3
Multiple-month drug holidays were introduced in patients with basal cell nevus syndrome with increased drug tolerability.4,5 To our knowledge, there has been no report regarding the use of weekly intermittent dosing of vismodegib. This study evaluates a novel alternate dosing regimen of vismodegib that has led to decreased toxicity and eliminates the need for a loading dose.
This retrospective study was approved by the institutional review board at the University of Minnesota. Informed consent was not required as all data were deidentified. We included patients seen in the Department of Dermatology at the University of Minnesota with confirmed BCC who were on an intermittent dosing regimen of vismodegib. Patient age, sex, BCC status, dosing schedule, length of treatment, treatment response, clinical photos, and AEs were compiled from the electronic medical record.
A total of 7 patients with advanced BCC, including 1 with confirmed basal cell nevus syndrome, were treated with intermittent dosing of vismodegib, with dosing regimens that ranged from 1 week receiving medication followed by 1 to 3 weeks without receiving medication (Table). All patients experienced improvement in their BCCs (Figure), and BCCs were resolved in 3 patients. Improvement was determined by clinical decreases in size and number of BCCs using clinical photos from previous visits. Those with resolution remained free of tumors at follow-up (range, 9-24 months). Adverse events were collected from the medical record and therefore were not standardized but rather reported by patients. Adverse events included 6 patients (85.7%) with mild fatigue, 4 (57.1%) with dysgeusia, 3 (42.9%) with arthralgia/arthritis, 3 (42.9%) with muscle spasms, 2 (28.6%) with alopecia, 1 (14.3%) with diarrhea, and 1 (14.3%) with constipation. If AEs persisted, the dose was decreased to as low as 1 week with and 3 weeks without medication. In one patient with a large BCC on the nose, the medication was discontinued once tumor size decreased, and Mohs micrographic surgery was performed. This dosing schedule was well tolerated, and AEs were mild or resolved with less medication, as no patients discontinued vismodegib owing to treatment-related AEs.
Vismodegib is an oral inhibitor of the Hedgehog signaling pathway.6 Increasing research in BCC pathogenesis has led to the discovery that stimulating mutations in the Hedgehog pathway account for most sporadic and basal cell nevus syndrome–associated BCCs.7
Adverse effects have limited treatment duration and tolerability. Alopecia, muscle spasms, dysgeusia, and weight loss occurred most frequently in all studies.3 Other AEs noted were fatigue, nausea, decreased appetite, diarrhea, and cough.3 In a 12-month follow-up study, it was found that all patients had treatment-emergent AEs, which led to discontinued treatment in 17.3% of patients.2 Although our patients demonstrated a variable profile to the larger ERIVANCE trial,2 the AEs in our study were not standardized and were patient reported. Our study had limitations. This was a retrospective medical record review and used a relatively small sample size and patient-reported AEs and assessed improvement based on clinical photos rather than measurement. Most importantly, none of our 7 patients terminated the medication owing to AEs.
To our knowledge, this is the first study to demonstrate efficacy with 1- to 3-week drug holidays. An intermittent dosing schedule of vismodegib should be considered when treatment-related AEs would cause discontinuation of treatment. Dosing regimens as low as 1 week with and 3 weeks without medication continued to demonstrate clinical improvement in patients with BCCs in this cohort. Pharmacokinetic and prospective randomized clinical trials are needed to determine the ideal intermittent regimen without causing resistance.
Corresponding Author: Peter K. Lee, MD, PhD, Department of Dermatology, University of Minnesota, 420 Delaware St SE, MMC 98/4-240 PWB, Minneapolis, MN 55455 (email@example.com).
Accepted for Publication: October 25, 2016.
Published Online: January 18, 2017. doi:10.1001/jamadermatol.2016.5058
Author Contributions: Drs Becker and Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Aakhus, Reich, Lee.
Acquisition, analysis, or interpretation of data: Becker, Reich, Lee.
Drafting of the manuscript: Becker, Lee.
Critical revision of the manuscript for important intellectual content: Aakhus, Reich, Lee.
Administrative, technical, or material support: All authors.
Study Supervision: Reich, Lee.
Conflict of Interest Disclosures: Drs Reich and Lee serve as investigators to Genentech. No other disclosures were reported.
Additional Contributions: We thank the patient for granting permission to publish this information.