Hedgehog Inhibitor Therapy’s Use in Advanced Basal Cell Carcinoma – Does It Work?


A study published in Future Medicine finds consistent use of the treatment is difficult for patients to maintain in a real-world setting.

Emily Ruiz, MD, MPH, of the department of dermatology at Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts, and colleagues conducted the study.

The most common non-melanoma skin cancer is Basal cell carcinoma (BCC), with over 2 million Americans diagnosed yearly.1 While BCC usually only needs surgery as treatment, 1% of BCC patients develop locally advanced or metastatic BCC.1 This type requires systemic treatments such as chemotherapy and radiation, according to the authors. “Activation of the Hedgehog signaling pathway resulting from genetic mutations has been identified as a key contributor to BCC formation,” Ruiz and colleagues wrote. The hedgehog pathway is a regulated and highly conserved pathway that is essential in stem cell maintenance and embryogenesis.2 If parts of the hedgehog pathway are dysregulated, it can result in malignancy.2

The first hedgehog pathway inhibitors (HHI) were first approved in the United States in 2012 (vismodegib) and 2015 (sonedegib) for patients with advanced BCC.1 However, researchers reported that while HHIs work very well, they have high toxicity. In order to manage these effects, treatment may be interrupted for weeks or even months. They emphasized that for patients with advanced BCC, there is “no consensus recommendation on the optimal duration of use of HHI, and few studies have investigated patterns of HHI use among real-world patients.”1 Their study looked at advanced BCC patient discontinuation of HHI treatment and patterns of restarting the therapy in real-world settings.

Researchers performed a retrospective cohort study of 526 patients diagnosed with BCC using IBM MarketScan Commercial and Medicare Supplemental databases. Men made up over 65% of study participants, and the median age was 64 years. Over 75% of patients had advanced BCC located in their heads and necks. Researchers looked at enrollment and health insurance claims to identify patients who were newly using HHIs between January 2013 and June 2019. “Time to treatment discontinuation and reinitiation were estimated using Kaplan–Meier methods using a 60-day grace period,” researchers reported.

Initiation of HHI treatment was defined as prescriptions filled by patients using Medicare or commercial insurance. Patients were considered to have discontinued treatment if there was more than a 60-day gap in refilling the prescription and the supply had run out.

Ruiz and colleagues found that for patients’ “first episode of HHI use, the median treatment duration was 144 days (95% CI: 131–162).”1 They reported that over 60% of patients had stopped the drug after 6 months. After 12 months, the risk of discontinuing treatment was 88%.1

The authors reported a low rate of reinitiation, with only 19.7% of patients trying HHIs again after 12 months. Of the 360 patients who tried the therapy again, patients stopped treatment after a median of 118 days, researchers said.

Study results highlighted the difficulty for patients to consistently use HHIs in a real-world setting. “High rates of HHI discontinuation, short times to discontinuation, and low rates of reinitiation among patients with BCC may affect the effectiveness of these medications in real-world clinical practice. Future research should evaluate the introduction of new therapies to address this unmet need,” Ruiz and colleagues said.

Study authors reported several disclosures. The study was funded by Regeneron and Sanofi, and authors Ge, Chen, Wu, Fury, and Jalbert are shareholders and employees of that company. In addition, they reported Ruiz has been paid consulting fees from PellePharm, Sanofi, Regeneron, and Leo Pharmaceuticals. She also consults and is on the advisory board for Checkpoint Therapeutics.


  1. Ge W, Chen CI, Wu N, Fury MG, Ruiz E, Jalbert JJ. Hedgehog pathway inhibitor real-world treatment patterns in patients with basal cell carcinoma: a claims-based analysis. Future Oncol. 2022;18(23):2561-2572. doi:10.2217/fon-2022-0373
  2. Jamieson C, Martinelli G, Papayannidis C, Cortes JE. Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia. Blood Cancer Discov. 2020;1(2):134-145. Published 2020 Aug 11. doi:10.1158/2643-3230.BCD-20-0007
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