Hedgehog Pathway Inhibitor Therapy for Locally Advanced and Metastatic Basal Cell Carcinoma: A Systematic Review and Pooled Analysis of Interventional Studies

JAMA Dermatol. 2016 Jul 1;152(7):816-24. doi: 10.1001/jamadermatol.2016.0780.


Importance: Hedgehog pathway inhibitors (HPIs) were made available by US Food and Drug Administration approval in 2012 for vismodegib and 2015 for sonidegib. Both target the Smoothened molecule and are indicated for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC).

Objective: To evaluate clinical experience with HPIs, including efficacy and adverse effects.

Data sources: We conducted a systematic review in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EMBASE, using search terms "vismodegib," "sonidegib," "Erivedge," "Odomza," "basal cell carcinoma," and "BCC."

Study selection: We included clinical trials, retrospective medical record reviews, and prospective case series that used HPIs for the treatment of laBCC or mBCC in human subjects. Individual case reports and limited, retrospective case series were excluded from our review.

Data extraction and synthesis: Data were extracted independently by 2 reviewers on a predesigned, standardized form.

Main outcomes and measures: The following data were recorded: number of patients with laBCC or mBCC, dose and frequency of drug administration, median duration of treatment, clearance and recurrence rates, and adverse effects.

Results: Eleven vismodegib articles (published between 2009 and 2015) met criteria for inclusion, and 8 articles were able to be pooled for analysis. The 8 pooled articles included 744 total patients with 704 patients clinically evaluable. Sonidegib did not yield enough publications for a formal analysis. Objective response to vismodegib for laBCC had a weighted average of 64.7% (95% CI, 63.7%-65.6%); complete response averaged 31.1% (95% CI, 30.4%-31.8%). Objective response for mBCC was 33.6% (95% CI, 33.1%-34.2%); complete response averaged 3.9% (95% CI, 3.3%-4.4%). Median duration of therapy was 35.8 weeks (95% CI, 35.1-36.5 weeks).

Conclusions and relevance: In a systematic review of HPIs for laBCC and mBCC, vismodegib, but not sonidegib, had enough studies to warrant a pooled analysis. Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC. While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Anilides / adverse effects
  • Anilides / therapeutic use*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biphenyl Compounds / therapeutic use*
  • Carcinoma, Basal Cell / drug therapy*
  • Carcinoma, Basal Cell / secondary*
  • Hedgehog Proteins / antagonists & inhibitors
  • Humans
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology*
  • Smoothened Receptor / antagonists & inhibitors


  • Anilides
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Hedgehog Proteins
  • HhAntag691
  • Pyridines
  • Smoothened Receptor
  • sonidegib