Rethinking Hedgehog Inhibitors in Advanced Basal Cell Carcinoma: Sonedegib in Practice

This video is sponsored by Sun Pharma. Its content is editorially independent of the sponsor. 

In this episode of Topical Conversations, Mark Lebwohl, MD, is joined by Shannon Trotter, DO, for a targeted discussion on the use of Hedgehog inhibitors (HHIs) in advanced basal cell carcinoma (BCC), with a particular focus on sonedegib. Together, they walk through patient selection, real-world use, side-effect management, and pharmacokinetic differences that meaningfully influence clinical decision-making. 

Which patients are best suited for sonedegib? 

Dr Trotter opens by noting that “locally advanced basal cell carcinoma” lacks a standardized definition, and appropriate candidates for sonedegib can vary widely. Two patient profiles emerge most clearly in practice. 

The first includes patients with large tumors in high-function or cosmetically sensitive areas, such as the eyelid, nose, or ear, who are poor candidates for surgery or radiation. In these cases, sonedegib may be used as primary therapy. The second includes patients with locally advanced disease who ultimately want definitive surgical management, where sonedegib can be used neoadjuvantly to reduce tumor burden. 

Dr Lebwohl agrees, adding that in his practice, the most common use of sonedegib is to shrink tumors that would otherwise require deforming surgery. He explains that his approach is to treat until side effects emerge, then reassess whether the tumor has become surgically manageable. 

Real-world experience and long-term use 

Dr Lebwohl shares a case of a patient who has been on sonedegib for more than two years without side effects, with complete clinical regression of the tumor. Given the expectation of recurrence if therapy were stopped and the patient’s continued tolerability, he has elected to continue treatment indefinitely. This case highlights the variability in patient response and the importance of individualized decision-making. 

Early HHI Experience and lingering hesitancy 

The discussion turns to why some dermatologists remain hesitant to use HHIs. Dr Lebwohl suggests that early experiences with vismodegib, the first HHI introduced into dermatology, shaped perceptions of the entire class. Muscle cramps, dysgeusia, and alopecia often occurred earlier and more severely with vismodegib, leading to discontinuation and long-lasting caution among clinicians. 

Both speakers emphasize that sonedegib offers a different tolerability profile, and that reluctance to use it may deprive patients of a valuable option that can significantly reduce surgical morbidity and improve functional and cosmetic outcomes. 

Setting expectations and managing side effects 

Dr Trotter stresses that side effects remain the rate-limiting factor for most patients on HHIs, making expectation-setting critical. She routinely counsels patients on the possibility of muscle cramps, taste changes, alopecia, fatigue, and gastrointestinal symptoms, and walks them through when these effects are most likely to occur. 

Early intervention is key. For muscle cramps, she often initiates L-carnitine before starting therapy, along with counseling on hydration, stretching, and activity. For taste alterations, practical strategies such as brushing teeth before meals are discussed. Alopecia is addressed proactively, with topical or oral minoxidil as an option. 

Dr Lebwohl echoes that muscle cramps are the most common reason for discontinuation in his practice. He places all patients on sonedegib on L-carnitine, starting at 1 g daily and increasing to 2 g if needed, noting that this can delay cramps for several months, which is often long enough to achieve meaningful tumor shrinkage. 

Pharmacokinetics and why they matter 

The conversation closes with a comparison of the pharmacokinetic profiles of sonedegib and vismodegib. Dr Trotter explains that sonedegib has a significantly higher volume of distribution in the skin relative to plasma, allowing greater drug concentration at the site of disease. This may contribute to its clinical efficacy in BCC. 

Differences in half-life and time to steady state further distinguish the agents. Vismodegib reaches steady state within weeks, which may explain earlier onset of adverse effects, whereas sonedegib reaches steady state over several months. The longer half-life of sonedegib also provides greater flexibility for dosing adjustments, though Dr Trotter notes she often finds fewer adjustments are needed. 

Drs Lebwohl and Trotter conclude that sonedegib is a well-understood, underutilized tool that can meaningfully expand treatment options for patients with advanced basal cell carcinoma when used thoughtfully and proactively. 

Key takeaways 

• Locally advanced BCC lacks a single definition, making individualized assessment essential
• Sonedegib can be used as primary therapy or neoadjuvantly to reduce surgical morbidity
• Early experience with vismodegib has influenced perceptions of HHIs, but sonedegib offers a distinct tolerability profile
• Proactive counseling and side-effect management improve adherence and outcomes
• Delayed onset of adverse effects is a key advantage of sonedegib
• Pharmacokinetic differences between HHIs have practical implications for efficacy and tolerability