Update on Drugs and Drug News: March 2012

Ingenol mebutate gel (0.015%, 0.05%)
Picato®

Leo Pharma Inc.

The US FDA approved ingenol mebutate gel (derived from the Euphorbia peplus plant) in January 2012 for the topical treatment of actinic keratosis (AK). The 0.015% formulation is used once-daily on the face and scalp for 3 consecutive days, and the 0.05% gel is used once-daily on the trunk and extremities for 2 consecutive days. The treatment course may be completed in 2-3 days. In phase III studies, 60-68% of patients with AKs on the face and scalp experienced ≥75% reduction of existing lesions vs. 7-8% with placebo; in treating AKs of the trunk and extremities 44-55% showed ≥75% reduction vs. 7% for placebo. Ingenol mebutate-treated patients experienced 37-47% complete clearance of lesions on the face and scalp and 28-42% on the trunk and extremities. The most common adverse events were local skin reactions, such as erythema, flaking/scaling, crusting, and swelling. Potential ocular side effects following exposure include severe eye pain, eyelid edema, eyelid ptosis, and periorbital edema. For more information:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202833lbl.pdf

Vismodegib capsule
Erivedge™
Genentech
Roche Group
Curis, Inc.

The US FDA approved vismodegib, a hedgehog pathway inhibitor, in January 2012 for the treatment of adults with advanced basal cell carcinoma (BCC). The drug is administered orally once-daily and is indicated for patients with locally advanced BCC who are not candidates for surgery or radiation and for patients with metastatic BCC. Safety and efficacy were evaluated in an international, single-arm, multi-center study (ERIVANCE BCC) involving 96 patients with locally advanced or metastatic BCC. In patients treated with vismodegib, 30% with metastatic disease experienced a partial response and 43% with locally advanced BCC showed a complete or partial response; median duration of response was 7.6 months. The most common side effects from therapy included muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased appetite, constipation, vomiting, and loss of taste function in the tongue.

A recent article published in the The New England Journal of Medicine* reported that vemurafenib (Zelboraf™), a BRAF enzyme inhibitor developed for the treatment of late-stage melanoma (FDA-approved in August 2011), does not trigger the mutations that cause squamous cell carcinoma (SCC), as previously suspected. However, it was uncovered that the drug does accelerate the growth of SCCs in patients with RAS mutations, likely resulting from photodamage. Between 15-30% of vemurafenibtreated patients have developed these secondary cancers, which are common with BRAF inhibitor therapy. Vemurafenib induces apoptosis in melanoma cell lines by interrupting RAS-RAF-MEK-ERK signaling, which is a major factor in the growth and progression of human melanoma tumors. The researchers described that vemurafenib stimulated mitogen-activated protein kinase signaling increased the proliferation of cells with RAS mutations, thereby promoting the growth of cutaneous lesions with such oncogene mutations. Co-administration of an MEK inhibitor in lab mice resulted in a 91% reduction in tumor development. Accordingly, this study suggests that addition of an MEK inhibitor to vemurafenib therapy in patients with RAS mutations could inhibit the emergence of secondary tumors.
*Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15.