Genentech, a member of the Roche Group, has submitted a New Drug Application for vismodegib to the U.S. Food and Drug Administration (FDA) for the treatment of people with advanced basal cell carcinoma (BCC) for whom surgery is considered inappropriate.

According to the American Cancer Society, BCC accounts for approximately 80% of all diagnosed skin cancers. In the majority of cases, the disease is generally considered curable if the cancer is restricted to a small area of the skin. However, in a very small group of people, if the disease is left untreated or recurs after surgery, it becomes locally advanced, and the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues. In a small proportion of patients,estimated at less than one percent of those affected, BCC can metastasize, spreading to other parts of the body. Currently, there are limited treatment options for advanced BCC with no standard of care.

Hedgehog signaling
The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. In addition to BCC, mutations in the pathway that reactivate Hedgehog signaling are seen in several types of cancer.

Potential new treatment option
Vismodegib (RG3616/GDC-0449)is an investigational medicine designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is the underlying molecular driver of BCC. Roche and Genentech are also evaluating vismodegib in a Phase II trial in people with operable forms of BCC.

Vismodegib, discovered by Genentech and jointly validated by Genentech and Curis through a series of preclinical studies, is an investigational, oral, targeted medicine designed to selectively inhibit signaling in the Hedgehog pathway, which is implicated in more than 90% of basal cell carcinoma cases.

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“The pivotal study results that showed vismodegib substantially reduced tumor size or healed lesions for people with this rare skin cancer, which has no approved treatments,” said Hal Barron, M.D., chief medical officer and head, Global Product Development. “We look forward to continuing our discussions with the FDA about these data.”

The FDA submission is based on results from the pivotal ERIVANCE(ERIVANCE BCC/SHH4476g)study, an international, single-arm, multicenter, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including laBCC (71) and mBCC (33). The trial evaluated vismodegib in people with advanced BCC and showed that vismodegib substantially shrank tumors or healed visible lesions (overall response rate; ORR) in 43% of patients with locally advanced BCC (laBCC) and 30% of patients with metastatic BCC (mBCC), as assessed by independent review, the primary endpoint of the study.

laBCC patients had lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. mBCC was defined as BCC that had spread to other parts of the body, including the lymph nodes, lungs, bones and/or internal organs. Study participants received 150mg vismodegib orally, once daily until disease progression or intolerable toxicity.

The overall response rate as assessed by study investigators, a secondary endpoint, was 60% for laBCC and 46% for mBCC. The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.

The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious adverse events (SAEs) were observed in 26 patients (25%). Four patients (4%) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism). Fatal events were reported in seven patients (7%); none were considered by investigators to be related to vismodegib. In all cases, patients had other pre-existing diseases or symptoms that were related to their presumed cause of death.

For more information:
Genentech clinical trial call center: at 888-662-6728
Clinical trial: A Study Evaluating the Efficacy and Safety of GDC-0449 (Hedgehog Pathway Inhibitor) in Patients With Advanced Basal Cell Carcinoma.

Genentech is developing vismodegib under a collaboration agreement with Curis, Inc.

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