Hedgehog inhibitors in the treatment of advanced basal cell carcinoma: risks and benefits

ABSTRACT

Introduction

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSC). Although surgery is the first-line therapy for BCC, some cases can progress to an advanced or, rarely, a metastatic state and targeted therapy are required. The main pathway involved in BCC tumorigenesis is the Hedgehog (Hh) signaling pathway and its inhibition is among the few treatment options available for patients with advanced BCCs. Recent advances in targeting this pathway have led to the development of two small-molecule oral Hh inhibitors, vismodegib and sonidegib

Areas covered

The aim of this article is to provide a complete overview on the use of HPI for the treatment of advanced BCCs describing the efficacy, the benefits, and risks related to these small molecules.

Expert opinion

To date, the class of Hh inhibitors has revolutionized the management of patients with advanced BCCs, even though they are usually related to a toxicity profile that may represent the major cause of treatment discontinuation; an accurate study of the Hh signaling pathway and the development of other small molecules could be useful to enlarge the armamentarium of treatment in order to assure patients a personalized approach to the choice of treatment.

KEYWORDS:

• Vismodegib
• sonidegib
• basal cell carcinoma
• hedgehog inhibitors
• adverse events

Article highlights

• Basal cell carcinoma (BCC) constitutes approximately 80% of non-melanoma skin cancers; although surgery is the first-line therapy for BCC, some cases can progress to an advanced or, rarely, a metastatic state and non-surgical approaches are required.

• The main pathway involved in BCC tumorigenesis is the Hedgehog (Hh) signaling pathway and its inhibition is among the few treatment options available for patients with advanced BCCs.

• Systemic treatment with Hh inhibitors such as vismodegib or sonidegib, has shown to effectively reduce tumor size, up to complete regression of BCCs, and to reduce tumor ulceration.

• To date, there are no head-to-head randomized controlled trials comparing vismodegib with sonidegib, only a joint expert opinion summarizing clinical and pharmacological profiles of the two drugs has been published.

• Patient education before starting treatment, a multidisciplinary approach and supportive cares should be considered in order to reduce side effects and to avoid treatment discontinuation.

• Five years hence, an accurate study of the Hh signaling pathway and the development of other small molecules targeting downstream could be useful to enlarge the armamentarium of treatment for advanced BCCs.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have been an investigator using vismodegib for clinical trials, both industry-sponsored and investigator-initiated. They are also a member of the Genentech speaker’s bureau for vismodegib and are involved in a steering committee regarding the use of patidegib for BCC. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.