The Future of Hedgehog Inhibitors in Advanced Basal Cell Carcinoma

Desiree Ratner, MD

Kevin Hughes, MD

Hedgehog inhibitors have revolutionized the treatment paradigm for patients with advanced basal cell carcinoma, says Desiree Ratner, MD.

“Previously, there were not any highly effective treatments for this small subgroup of patients, but now we have therapeutic options that really work,” says Ratner, who is director of the Comprehensive Skin Cancer Center at Mount Sinai Beth Israel.

“Before these agents, patients would just have larger surgeries with or without adjuvant radiation. You really can’t compare going on an agent that shrinks your tumor with having a large disfiguring surgery.”

Currently, there are 2 hedgehog inhibitors approved for patients either with locally advanced basal cell carcinoma that has recurred following surgery or radiation, or who are ineligible for these treatments.

This includes sonidegib (Odomzo), which was approved by the FDA in July 2015 based on the phase II BOLT study, in which sonidegib had an objective response rate of 58% (95% CI, 0.45-0.70), as well as vismodegib (Erivedge), which was approved in 2012.

While these agents have had a significant impact for patients with advanced basal cell carcinomas, they are not appropriate for all patients—and, they do come with toxicities.

In an interview withTargeted Oncology, Ratner explains what oncologists should know about hedgehog inhibitors in advanced basal cell carcinoma and what the future holds for these agents.

TARGETED ONCOLOGY:What is the current standard treatment for advanced basal cell carcinoma?

Ratner:

Right now, the hedgehog pathway inhibitors are used for patients with either advanced or metastatic basal cell carcinoma. Advanced basal cell carcinomas are loosely defined as carcinomas that either are not surgically resectable or are recurrent following radiation treatment. These are tumors that cannot be treated by the standard modalities.

TARGETED ONCOLOGY:How common is it for basal cell carcinoma to advance?

Ratner:

Most patients with basal cell carcinoma do not present at an advanced stage. There is a select population of people who have large neglected tumors that went untreated early on. Some people are in denial that they have something that requires attention.

There is another population of patients with recurrent tumors after being treated with surgery, radiation or a combination of both. Over time, they evolve into these more difficult and advanced tumors.

TARGETED ONCOLOGY:What toxicities associated with hedgehog inhibitors should oncologists be aware of?

Ratner:

There are 3 principal side effects. One is muscle spasms or muscle cramps, the second is taste disturbances where food either tastes bad or the patient is unable to taste food, and the third is hair loss.

Those side effects don’t always kick in immediately; it sometimes takes a couple of months for patients to start experiencing them. There are a number of less common side effects that have been reported, but those are really the main 3.

TARGETED ONCOLOGY:At what point should patients with advanced basal cell carcinoma receive hedgehog inhibitors?

Ratner:

Some patients receive hedgehog inhibition too early when they are still candidates for surgery or radiation. This happens because physicians have different opinions of what they consider to be unresectable. I am someone who tends to operate on very large basal cell carcinomas because I am comfortable doing it. Therefore, I have a different definition of unresectable than someone who thinks that a 2-centimeter basal cell is unresectable.

These treatments should be reserved for patients who have tumors that, if removed surgically, could cause substantial functional or cosmetic morbidity. Surgery should be the first option. You have the highest chance of curing the disease if you can remove it surgically.

The challenge with these drugs is that, if you put a patient on it and then stop it, the tumor can return. We have had patients who have been on these and that have developed squamous cell carcinomas within their basal cells. Some patients are resistant to the drug. These drugs are not totally benign, so they need to be reserved for the patients who really need them.

TARGETED ONCOLOGY:What ongoing research in this area are you particularly interested in?

Ratner:

It is still very early, but there are people who are starting to look at topical hedgehog pathway inhibitors. I have no sense yet of their efficacy, as it is still early and they are just beginning to go into trials. However, a drug that could topically treat basal cells would have a huge potential market.

TARGETED ONCOLOGY:Is there potential for combination therapies with hedgehog inhibitors and chemotherapy or radiation?

Ratner:

That is still fairly early. Right now, hedgehog inhibitors are primarily used for either those with advanced or metastatic basal cell carcinoma or patients who have Gorlin syndrome, which means patients have such a large burden of tumors that they require a slightly different form of management.

The other way in which hedgehog pathway inhibitors are being used is in the neoadjuvant setting. This is done to shrink tumors prior to surgery; however, I think that using them in combination with either chemotherapy or radiation is still very early.