Smoothened inhibitors provide new options for BCC treatment

Zurich, Switzerland - Since the dawn of smoothened inhibitors, patients with locally advanced and metastatic basal cell carcinoma (BCC) now have a new and effective treatment alternative beyond the traditional and less optimal treatment approaches such as surgery and radiotherapy.

“Before the era of the smoothened inhibitors, treatment options for patients with both locally advanced or metastatic BCC were very poor,” says Jil Dreier, M.D., department of dermatology, University Hospital Zurich, Switzerland. “Smoothened inhibitors offer a new promising treatment option and herald a new age for this patient population.”

Continued research has established that BCC is driven by an activated hedgehog pathway and smoothened inhibitors are being developed and used to specifically target and block the hedgehog signaling cascades involved in the development of BCC as well as a host of other diseases. Dr. Dreier and colleagues of professor Reinhard Dummer’s research team and professor Rainer Kustfeld (Vienna), recently performed a literature review study looking at the current drugs that target one or several of the hedgehog signaling cascades, which might be successfully used in BCC with special focus on possible candidates for combination therapy with hedgehog inhibitors.

Trials under way

Recently approved by the Food and Drug Administration (FDA) for the treatment of locally advanced and metastatic BCC, vismodegib (Erivedge, Genentech) is a smoothened inhibitor that is proving to be a good treatment option for patients who previously may have had to undergo multiple surgeries and/or radiation therapy in order to control the progression of the disease.

Currently undergoing a phase 2 clinical trial, LDE225 (sonidegib, Novartis) is one of the experimental smoothened inhibitors in the pipeline that could have an advantage over vismodegib, as interim results indicate that the novel drug may have a dose-toxicity relationship, which could possibly result in a decrease in side effects.

“In general, both vismodegib and sonidegib show similar adverse events such as muscle toxicity, dysgeusia and alopecia,” Dr. Dreier says. “However, it is too early to say which of these drugs will fair better in the long run in terms of AEs (adverse events), and head-to-head randomized clinical trials would need to be performed to address this question.”

Smoothened inhibitors have been shown to achieve an impressive tumor response in patents with locally advanced and metastatic BCC, witnessed in the positive FDA clinical trial results with vismodegib and the more recent trial results with sonidegib, Dr. Dreier says. Vismodegib is relatively well tolerated but has side effects that can negatively impact the quality of life of patients and sometimes lead to the discontinuation of treatment.

Careful clinical evaluation of vismodegib identified a high affinity, reversible binding to the plasma protein alpha-1-acid glycoprotein and to albumin in addition to solubility-limited absorption and slow metabolic elimination properties, which may explain the drugs nonlinear pharmacokinetic profile, according to Dr. Dreier. This in part led to the establishment of the drug’s current 150 mg/day dosing regimen.

Next: Dose regimens

Dose regimens

In a phase 1 dose-escalation clinical trial with sonidegib, the pharmacokinetic profile of the drug was found to be dose-proportional, allowing for the first time the identification of dose-limiting toxicities of smoothened inhibitors. Based on the results of the study, a randomized, double-blind phase 2 clinical trial was launched comparing 200 mg/day versus 800 mg/day dose regimens, the interim results of which will be announced at the upcoming 2014 ASCO meeting.

The number of lasting complete remissions achieved in the two study arms might reflect the cure rate, Dr. Dreier says, and may provide information whether a high-dose therapy is more efficient than a low-therapy dose. Because of the pharmacokinetic profile of sonidegib, further information from the phase 2 trial may soon become available regarding the dose correlation to adverse events such as muscle toxicity.

“Sonidegib shows a clear dose-toxicity relationship, which allows us to address the question whether there is a dose-dependency of regression rate, cure rate and progression-free survival,” Dr. Dreier says. “In addition, if treatment with sonidegib is found to be effective at a lower dose and with less AEs, this would of course be of significant benefit to the patient and might also lead to a higher compliance, as many patients stop treatment due to the adverse events of the drug.”

Disclosures: Dr. Dreier reports no relevant financial interests.