<p>The 2 US Food and Drug Administration (FDA)–approved HHIs sonidegib and vismodegib offer a nonsurgical option for patients with inoperable or high-risk locally advanced basal cell carcinoma (laBCC). In this way, these agents have transformed the management of laBCC.</p>

PTCH1 typically acts like a brake in a car to prevent hedgehog pathway signaling and cell growth through SMO. In BCC, PTCH1 is commonly mutated and does not work properly, and the accelerator, SMO, keeps the hedgehog pathway stuck in the “on” position. This can cause increased transcription, cellular multiplication, and the development of BCC. Like PTCH1 preventing hedgehog pathway signaling and cell growth through SMO, HHIs also essentially act like a brake in a car for cancer conditions whereby PTCH is broken, stopping the cell from multiplying by binding to and inhibiting SMO.

<br>

The objective response rates of the HHIs vismodegib and sonidegib in clinical trials were 43% to 47%, and the complete response rates ranged from 3% to 21%. HHIs are generally tolerable, and most side effects are mild to moderate in severity. However, adverse events such as muscle spasms, which are one of the most common, can be very frustrating for patients.

<br>

There are no head-to-head studies comparing vismodegib and sonidegib, but, based on my experience, I feel that sonidegib has an equivalent efficacy to that of vismodegib, or maybe slightly better, and may have a better side-effect profile. Sonidegib also has the advantages of a very large volume of distribution and a much longer half-life than vismodegib.

<br>

Unfortunately, laBCC can develop resistance to HHIs, and patients can have disease progression on therapy. The question is what to do about it, and the answer is to support the patient in trying additional therapy. That often means switching to the other HHI. Even though a patient’s laBCC may be resistant to 1 HHI, it may not be resistant to the other. If the patient’s laBCC is resistant to both HHIs or the patient is intolerant of the treatment, you need to quickly consider cemiplimab, which is FDA approved for patients with laBCC previously treated with an HHI or for those in whom HHI therapy is not appropriate.

<br>

Often, patients become disheartened and do not seek additional treatment for their laBCC. We need to encourage patients to proceed with treatment and not to give up, because you never know unless you try. It is important to develop a personalized treatment plan using a collaborative decision-making process between the clinician and the patient. Understanding what the patient’s goals are and their clinical presentation allows us to identify treatment options that balance their quality of life with efficacy.

<br>

Ongoing studies are evaluating novel agents targeting the hedgehog pathway and research on the localized delivery of HHIs. I look forward to future molecules that use the hedgehog pathway but with, hopefully, improved efficacy and fewer side effects.