The U.S. Food and Drug Administration (FDA) hasapproved vismodegib (Erivedge?, Roche/Genentech), the first medicine for adults with a type of skin cancer, called advanced or metastatic basal cell carcinoma or BCC, that has spread to other parts of the body or that has come back after surgery or that their healthcare provider decides cannot be treated with surgery or radiation. The new drug is a first-in-class Hedgehog Pathway Inhibitor that helps shrink disfiguring or potentially life-threatening lesions in advanced skin cancer.

Vismodegib is the first FDA-approved medicine for people with advanced forms of the most common skin cancer. The new drug is designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is an underlying molecular driver of BCC. It is a capsule that is taken orally once-a-day.

Generally considered curable
Basal cell carcinoma is generally considered curable if the cancer is restricted to a small area of the skin. However, in rare cases, lesions can become disfiguring and invade surrounding tissue (locally advanced) or spread to other parts of the body (metastasize). In these cases of advanced BCC, the disease cannot be effectively treated with surgery or radiation. Advanced BCC often results in severe deformity or loss of function of affected organs.

Few treatment options
?Today?s approval provides a new treatment for people with advanced basal cell carcinoma who, until now, had no approved medicines to help shrink disfiguring or potentially life-threatening lesions,? said Hal Barron, M.D., Chief Medical Officer and Head, Global Product Development. ?We are pleased that in the last six months we have been able to provide two new medicines for different types of advanced skin cancer to people who previously had few or no treatment options.?

BCC and the Hedgehog pathway
BCC is the most common type of skin cancer in Europe [1], Australia [1,2] and the United States [3]. In advanced BCC, if the disease is left untreated or recurs in the same location after surgery or radiotherapy, it may advance further into surrounding areas such as sensory organs (ears, nose and eyes), bone, or other tissues. Depending on the location of the lesion, some cases of advanced BCC can be disfiguring, and treatment with surgery or radiation can lead to the loss of sensory organs and their functions such as eyesight or hearing.

Advertisement #3

Vismodegib inhibits the Hedgehog pathway, an important embryonic developmental pathway regulating proper growth and development in the early stages of life and becomes less active in adults. Reproductive toxicology studies in rats demonstrated that vismodegib exposure during organogensis results in embryo-fetal death at higher exposures and severe birth defects at exposures within the range achieved with the recommended human dose.

The Hedgehog signaling pathway plays an important role in Abnormal Hedgehog signaling is implicated in more than 90% of BCC cases.

Ongoing development
Roche and Genentech are also evaluating vismodegib in a Phase II trial in people with operable forms of BCC.

In Europe, Roche has also submitted a marketing authorisation application (MAA) for Erivedge in the European Union (EU). In order to provide people with advanced BCC who live outside of the United States access to Erivedge while Roche pursues marketing authorisation world-wide, the company is conducting a phase II safety study in the EU and other countries that is enrolling patients with advanced BCC.

Efficacy in advanced basal cell carcinoma The FDA approval of vismodegib is based on results from ERIVANCE BCC (SHH4476g), a pivotal international, single-arm, multicenter, two-cohort, open-label, phase II study that enrolled 104 patients with advanced BCC. Central pathologic review of archival or baseline tissue confirmed the diagnosis of basal cell carcinoma (BCC) in 96 patients: 33 patients with metastatic basal cell carcinoma (mBCC) and 63 patients with locally advanced basal cell carcinoma (laBCC).

The trial?s primary endpoint was objective response rate (ORR) assessed by an independent review facility. Tumor response criteria for laBCC included assessment of tumor size, the presence or absence of ulceration, and biopsy of local disease sites. The criteria for complete response in localized disease required tumor biopsy (ies) demonstrating no pathologic evidence of BCC. RECIST version 1.0 criteria were used to assess responses in the mBCC population.

The ORRs were 30.3% (95% CI: 15.6, 48.2) and 42.9% (95% CI: 30.5, 56.0) in patients with mBCC and laBCC, respectively. All responses in the mBCC cohort were partial responses. For the 63 evaluable patients with laBCC, 13 (20.6%) patients had complete responses and 14 (22.2%) had partial responses. The median response duration was 7.6 months (95% CI: 5.6, not estimable) and 7.6 months (95% CI: 5.6, 9.7) for patients with mBCC and laBCC, respectively.

Patients with locally advanced BCC had lesions that recurred after surgery, were not candidates for surgery (inoperable, or for whom surgery would result in substantial deformity), recurred after radiotherapy or were not candidates for radiotherapy (radiotherapy was contraindicated or inappropriate). Study participants received 150mg of vismodegib orally, once daily until disease progression or unacceptable toxicity.

Safety and side effects
The most common side effects of vismodegib are muscle spasms, hair loss, change in how things taste or loss of taste, weight loss, tiredness, nausea, diarrhoea, decreased appetite, constipation, vomitting and joint aches.Other side effects may include low levels of sodium in the blood, low potassium levels, and a higher than normal blood level of urea or other nitrogen containing compounds in the blood.

Pregnancy status
The FDA instructs healthcare professionals to verify pregnancy status prior to the initiation of vismodegib, counsel pregnant women on the potential risks to the embryo/fetus, and advise non-pregnant women to use highly effective contraception during treatment with vismodegib and for up to 7 months after the last dose. To avoid exposing an embryo/fetus to vismodegib that may be contained in semen, doctors are instructed to counsel male patients to use condoms with spermicide during treatment with vismodegib up till 2 months after the last dose.

Vismodegib will be available in the United States within one to two weeks of approval and will be distributed through specialty pharmacies (also see: “for more information”).

[1] N.R.Telfer, G.B.Colver and C.A.Morton. Guidelines for the management of basal cell carcinoma. The British Journal of Dermatology. 2008;158(7):35-48
[2] Gilbody JS, et al. What causes basal cell carcinoma to be the commonest cancer? Aust J Public Health.1994; 18(2):218-21
[3] Von Hoff et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl J Med. 2009;361:1164-1172

For more information:
– Ongoing clinical trials
– Distribution in the United States Erivedge Access Solutions or call or 1-888-249-4918
– For doctors and patients coverage and reimbursement support: Erivedge Access Solutions
– Patient assistance and information resources.

Also read:
Vismodegib Helps Shrink Tumors< /a>; Healing Lesions in Advanced Basal Cell Carcinoma. Onco’Zine – June 20, 2011.
– New Drug Application to FDA for
Vismodegib (RG3616/GDC-0449) for Rare Form of Advanced Skin Cancer. Onco’Zine – September 12, 2011
– FDA Grants Priority Review for Vismodegib in Advanced form of Skin Cancer.Onco’Zine – November 9, 2011

Advertisement #5