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Efficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009–2022)

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Abstract

Background

Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC.

Objective

In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies.

Methods

An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher’s exact test.

Results

A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2–81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib.

Conclusion

SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.

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Acknowledgements

P.L. received grants from the Lady Davis Institute for Medical Research, from the Jewish General Hospital Foundation, from the Jewish General Hospital Department of Medicine, from the Fonds de recherche du Québec – Santé (#312768 and #324151), and from the Marathon of Hope Cancer Centre Network – Terry Fox Research Institute for this work (#3253). This research was enabled in part by support provided by Calcul Québec (www.calculquebec.ca), Compute Ontario (www.computeontario.ca), WestGrid (www.westgrid.ca), and the Alliance (www.alliancecan.ca) (RRG #4318).

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Authors and Affiliations

  1. Faculty of Medicine, McGill University, Montreal, QC, Canada

    Alex Nguyen

  2. Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

    Pingxing Xie, Ivan V. Litvinov & Philippe Lefrançois

  3. Division of Dermatology, Department of Medicine, Jewish General Hospital, Montreal, QC, Canada

    Philippe Lefrançois

  4. Division of Dermatology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Cote-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada

    Philippe Lefrançois

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Correspondence to Philippe Lefrançois.

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Funding

This study was supported by research grants from the Lady Davis Institute for Medical Research, the Jewish General Hospital Foundation, the Jewish General Hospital Department of Medicine, the Fonds de recherche du Québec—Santé (#312768 and #324151), and the Marathon of Hope Cancer Centre Network—Terry Fox Research Institute (#3253). This research was enabled in part by support provided by Calcul Québec (www.calculquebec.ca), Compute Ontario (www.computeontario.ca), WestGrid (www.westgrid.ca), and the Digital Research Alliance of Canada (www.alliancecan.ca) (RRG #4318).

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Alex Nguyen, Pingxing Xie, Ivan V. Litvinov, and Philippe Lefrançois declare they have no conflicts of interest that may be relevant to the contents of this manuscript.

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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Conceptualization: PL. Methodology: PX and PL. Formal analysis: AN, PX, and PL. Investigation: AN. Resources: PL. Data curation: AN, PX, and PL. Writing—original draft preparation: AN. Writing—reviewing and editing: AN, PX, IVL, and PL. Supervision: IVL and PL. Funding acquisition: PL. All authors have read and agreed to the published version of this manuscript.

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Nguyen, A., Xie, P., Litvinov, I.V. et al. Efficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009–2022). Am J Clin Dermatol 24, 359–374 (2023). https://doi.org/10.1007/s40257-023-00763-x

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