Vismodegib ‘life-changing’ for BCC patient populations

Orlando, Fla. - Vismodegib (Erivedge, Genentech) continues to demonstrate efficacy in treating patients with metastatic basal cell carcinoma (BCC) and locally advanced basal cell carcinoma (laBCC).

According to one dermatologist, the drug offers an excellent treatment alternative for this patient population that - until recently - had to undergo multiple surgeries and/or radiation therapy to control the progression of their sometimes-debilitating disease.

“Ever since receiving FDA (Food and Drug Administration) approval about two years ago, vismodegib has proven to be extremely useful in the treatment of metastatic BCC and locally advanced BCC. Prior to this drug, a lot of these patients would have needed major surgery resulting in significant morbidity, loss of function and possibly cranial nerve damage. In my opinion, vismodegib is a very welcome treatment option, and can be a life-changing drug for this patient population,” said George W. Monks, M.D., Tulsa Dermatology Clinic, Tulsa, Okla., who discussed the drug at the Orlando Dermatology Aesthetic and Clinical Conference.

How it works

Vismodegib is the first FDA-approved oral treatment for advanced BCC, Dr. Monks says, and it is also the first FDA-approved hedgehog pathway inhibitor. Patched (PTCH) is a membrane protein that blocks the translocation of smoothened (SMO), another membrane protein, to the cell surface. This translocation of SMO to the cell surface is required for intracellular signal transduction. In the presence of hedgehog ligand, PTCH inhibition of SMO is removed, and SMO is able to move to the cell membrane, resulting in intracellular signal transduction and expression of target genes.

Dysregulation of the hedgehog pathway - either through activation mutations in SMO or inactivating mutations in PTCH - can result in uncontrolled proliferation and tumorigenesis. Regardless of the exact mutation, the SMO receptor is activated, which is responsible for hedgehog pathway-mediated downstream BCC proliferation and survival signaling.

Metastatic BCC is extremely rare, Dr. Monks says, with rates ranging from 0.0028 to 0.55 percent of all BCCs. Advanced BCCs can be invasive and found in difficult-to-treat areas, such as next to cartilage or bone, or they can be recurrent. According to Dr. Monks, only a small subset of BCC patients can be classified as advanced.

“The term ‘locally advanced’ has long been used in oncology in their staging system for cancer but is a fairly new term in our dermatology lexicon,” he says. “The term really was introduced to our specialty when vismodegib was approved for the treatment of metastatic and laBCC. Many in our specialty are still unclear on what the true definition of a locally advanced basal cell carcinoma is.”

ERIVANCE trial

In the pivotal phase 2 ERIVANCE trial that led to the FDA approval of vismodegib, the definition of laBCC used the “S.E.L.E.C.T.” acronym:

Size: ≥ 10 mm in diameter;

Extent: locally invasive BCC extending into underlying tissue, cartilage, bone, or nerve;

Location: surgery or radiation would result in significant disfigurement or loss of function;

Expected morbidity or deformity if surgery or radiation were to be performed;

Curative resection unlikely or contraindication to surgery;

Two or more recurrences in the same location after ≥ 2 surgical procedures.

Physicians can employ this useful acronym as a guideline, Dr. Monks says, to help them more accurately assess their BCC patients and see whether vismodegib might be the appropriate treatment choice in a given patient. Vismodegib treatment is, however, associated with some adverse events including muscle spasms and cramps, alopecia, dysgeusia and ageusia, weight loss, fatigue and nausea.

“Prior to starting this drug, I think it is very important to educate patients in what the most common side effects are. They will be much more compliant with the drug if they know what to expect,” Dr. Monks says.

Side effects

Although the side effects associated with vismodegib are typically mild-to-moderate in severity, Dr. Monks says the trade-off of developing some of these symptoms compared to the multiple - and sometimes disfiguring - surgeries and/or radiation therapies and their associated morbidities is worth it.

“I’ve recommended vismodegib in select patients ever since its FDA approval, and in my experience, most patients tolerate the side effects relatively well. Many of them have had extreme tumor burden and have undergone hundreds of BCC surgeries resulting in significant surgical fatigue,” he says. “After starting them on vismodegib, the vast majority stopped developing tumor and cleared their existing tumors within several months, circumventing the need for surgery and/or radiation.”

The recommended dose for vismodegib is 150 mg/day. It remains unclear, however, how the use of the drug is going to play out in the long-term, for instance in patients with Gorlin syndrome (nevoid basal cell carcinoma syndrome), characterized by the development of multiple nonmelanoma skin cancers over a lifetime.

Considering combo therapies

According to Dr. Monks, an interesting corollary can be made when looking at the beginnings of the biologics for the treatment of psoriasis. At first, physicians were not clear on how to exactly use biologics for psoriasis, so the main goal was to get patients cleared, he says, and when they were clear, drug holidays were recommended.

Physicians soon learned, however, that a drug holiday was perhaps not in the best interest of the patient in that it was difficult to recapture the efficacy of the biologic once the drug was restarted, as opposed to keeping patients on the drug. This is something that still needs to be learned with vismodegib, Dr. Monks says, in terms of exactly how the drug should be ideally administered over time, particularly in challenging cases such as Gorlin syndrome.

A combination therapy for metastatic and locally advanced BCC would also be theoretically possible, according to Dr. Monks, using vismodegib and topical imiquimod. Although this would be an off-label use, each individual drug is indicated for the treatment of BCC. As patients on vismodegib have little to no localized skin reactions, a combination therapy with vismodegib and a topical immunomodulator such as imiquimod could be possible. Imiquimod treatment could be initiated after response to vismodegib is determined, Dr. Monks suggests, making for an interesting future clinical trial.

“I would put vismodegib in the same life-changing category as the biologics for psoriasis and isotretinoin for acne. It is an exciting time for medical dermatologists as we continue to see more biologics introduced for psoriasis and new drugs for the treatment of melanoma and nonmelanoma skin cancer,” Dr. Monks says.

Disclosures: Dr. Monks is a paid consultant for Genentech.