Hedgehog Activation. Click to enlarge.
Vismodegib, an orally administered drug that targets the Hedgehog (Hh) signaling pathway, has demonstrated positive overall response rates in patients with advanced basal cell carcinoma (BCC), according to pivotal trial data scheduled to be presented at a conference in France on Tuesday.
The results of the ERIVANCE phase II trial are expected to help form the basis of a new drug application to the FDA, according to Genentech, a member of the Roche Group, which is developing the drug. The molecule also is known as GDC-0449 and RG3616.
Vismodegib resulted in overall response rates for 43% of patients with locally advanced BCC and 30% of study participants with metastatic BCC, Genentech said in a press release. The company said the data would be discussed at the 7th European Association of Dermato-Oncology Congress in Nantes.
“We’re excited by the data,” said Charlotte Arnold, a spokeswoman for Genentech, adding that advanced BCC patients often are not candidates for surgery and do not have other approved options. “This would be first-in-class.”
In all, 104 participants were enrolled in the single-arm, open-label study, including 71 patients with locally advanced BCC whose lesions were either inoperable or who would have been deformed by surgery, and 33 patients whose disease had metastasized to either the lymph nodes, lungs, bones, or internal organs.
Patients received 150-mg, once-daily doses until their disease progressed or they could not tolerate the toxicities.
The median duration of progression-free survival for both groups of patients was 9.5 months. In addition, the clinical benefit rate, defined as the proportion of patients with a response and/or stable disease for >24 weeks, was 75%.
Ligand-dependent Hedgehog signaling. Click to enlarge.
Twenty-six patients, or 25% of the participants, experienced serious adverse events (AEs) during the trial, with 4 people exhibiting AEs related to vismodegib consisting of 1 case each of cholestasis, syncope, cardiac failure, and pulmonary embolism. Seven patients with pre-existing diseases or symptoms died during the study, but investigators do not attribute the fatalities to vismodegib.
The most common AEs included muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite, and diarrhea.
BCC accounts for approximately 80% of all diagnosed skin cancers and is considered curable if restricted to a small area of the skin, according to Genentech. However, patients with advanced forms of the disease have few treatment options.
“Our goal is to provide a medicine to people with this rare and disfiguring form of advanced skin cancer as soon as possible, and we are discussing these results with global regulatory authorities,” Hal Barron, MD, chief medical officer and head of Global Product Development for Genentech, said in a press release.
Genentech, which discovered the molecule, intends to submit a new drug application to the FDA this year while Roche is planning to discuss a regulatory submission with the European Medicines Agency. Curis, Inc collaborated with Genentech in preclinical studies.
Vismodegib works by interfering with the membrane protein Smoothened, which provides positive signals to the Hh pathway. At present, there are no FDA-approved drugs targeting Hh signaling, although the pathway is the focus of investigation in a variety of cancers.