Clinical research zeroes in on targeted therapies for skin cancers

Atlanta - Continued research has led to new and exciting noninvasive therapies for basal cell carcinoma (BCC), lentigo maligna and malignant melanoma, offering some patients an alternative to surgery and/radiation treatment approaches.

Topical 5 percent imiquimod was first approved by the Food and Drug Administration for the treatment of genital warts, actinic keratosis (AKs) and superficial BCC. It is now being used off-label for the treatment of lentigo maligna.

“Different from the other topical therapies currently available, imiquimod has a potent immunostimulatory activity making the topical an exciting treatment for lentigo maligna,” says Scott W. Fosko, M.D., professor and chairman, department of dermatology, Saint Louis University School of Medicine, St. Louis. “I have used imiquimod many times for this indication and my experiences so far have been very positive.”

According to Dr. Fosko, the use of topical imiquimod could be ideal in patients who do not want or are contraindicated for surgery, and/or are not amenable to radiation therapy. Though still under investigation for the treatment of lentigo maligna in ongoing clinical trials, Dr. Fosko says a 12-week total duration treatment with the topical can achieve a good response and appears to be the most effective protocol.

Targeting hedgehog pathway

Another relatively new therapeutic development is vismodegib (Erivedge, Genentech), an oral drug currently used for the treatment of metastatic or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery or for radiation.

According to Dr. Fosko, this is the first hedgehog signaling pathway-targeting agent to gain FDA approval for the treatment of BCC, representing another exciting treatment option for this indication.

The hedgehog pathway is known to be patho-genetically relevant in more than 90 percent of BCCs. vismodegib acts as a cyclopamine-competitive antagonist of the “smoothened” receptor, selectively inhibiting the signaling in the hedgehog pathway by targeting the smoothened protein. The inhibition of smoothened causes transcription factors GLI1 and GLI2 to remain inactive, which, in turn, prevent the expression of tumor mediating genes within the hedgehog pathway.

Dosed at 150 mg a day, vismodegib is FDA-approved for metastatic BCC or locally advanced BCC. According to Dr. Fosko, the drug is approved for us until disease progression or unacceptable toxicity develops. Though the oral agent appears to be useful in patients with very extensive BCC lesions, Dr. Fosko says it still remains unclear which BCCs will best respond to vismodegib. Not all tumors respond, and tumor regrowth can occur after the discontinuation of the drug.

“Cancer treatment research today is focusing more and more on targeted therapies. This is a very exciting time for all skin cancers,” Dr. Fosko says. “Though it is early in its use, vismodegib appears to be a promising therapy for those patients with metastatic BCC or locally advanced BCC, especially where other treatment choices such as more invasive surgery and/or radiation therapy may prove to be less than optimal in the individual patient.”

BRAF ^V600E mutation

Another targeted skin cancer therapy is vemurafenib (Zelboraf, Genentech), a relatively new oral therapy used for the treatment of unresectable or metastatic malignant melanoma with a specific mutation, BRAFV600E, a very specific mutation in the tumor’s DNA. Though found to be effective in this subset of patients, Dr. Fosko cautions that the response to the drug is not always long-lived and that tumors can recur.

Nonetheless, Dr. Fosko says the drug is yet another example of the importance of understanding the mutations that are associated with malignant melanoma, and finding a targeted therapy directed at a specific part of the tumor’s genome.

“I believe this is an exciting time for cutaneous oncology because we are expanding our therapeutics beyond traditional surgery, radiation, and the existing chemotherapy regimens with these new targeted treatment modalities, both topically and orally,” Dr. Fosko says. “Skin cancer continues to be an ever-growing problem and it is the most common malignancy experienced by our general population, by both young and old.

“I think the armamentarium is expanding with these new approaches, and there is more that can be done now and help develop a brighter future for a range of skin cancers, both melanoma and nonmelanoma.” DT

Disclosures: Dr. Fosko is a paid consultant, serves on the speakers bureau and conducts clinical research for Genentech. He also has an investigator-initiated study for imiquimod and lentigo maligna, with no external funding.