A pivotal Phase II study with vismodegib (RG3616/GDC-0449, Roche / Genentech) showed positive results in people with advanced basal cell carcinoma (BCC) for whom surgery is considered inappropriate.

The full results of the study will be presented at the Seventh European Association of Dermato-Oncology (EADO) Congress taking place in Nantes, France (Abstract C014,14:50. CET).

Disfiguring and debilitating effects
Basal Cell Carcinoma (BCC) is a form of skin cancer that can cause disfiguring and debilitating effects and can ultimately be life-threatening.

According to the American Cancer Society, BCC accounts for approximately 80% of all diagnosed skin cancers. It is also the most common type of skin cancer in Europe [2], Australia [2, 3] and the USA. [4]. The annual global incidence is more than 2 million cases. [5] Currently, there are limited treatment options for advanced BCC with no current standard of care. 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, the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues (laBCC). In a small proportion of patients (estimated at less than 1% of those affected [6]), BCC can advance or spread to other parts of the body (mBCC). Advanced BCC can be difficult to treat with current treatments and can be life-threatening.

New treatment option
Vismodegib is an first-in-class investigational, oral medicine belonging to the 2-arylpyridine class, which was discovered by Genentech under a collaboration with Curis Inc. The drug is designed to target the underlying molecular driver of BCC.

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Hedgehog pathway
The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and then becomes less active in adults. However, mutations in the pathway that reactivate Hedgehog signaling are seen in several different types of cancer. Abnormal signaling in the Hedgehog pathway is implicated in the majority of BCC cases. Abnormal signalling in a cell growth pathway, known as the Hedgehog pathway, is implicated in more than 90% of BCC cases. Vismodegib is designed to selectively inhibit abnormal signaling in the Hedgehog pathway.[1]

Phase II study with vismodegib
The ERIVANCE BCC trial showed vismodegib substantially shrank tumours or healed visible lesions (overall response rate) 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. The most common drug related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhoea.

?Vismodegib is an example of our commitment to understanding and developing medicines that target the biologic cause of a particular disease,? said Hal Barron, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. ?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.?

Trial Design
The ERIVANCE BCC is an international, single-arm, multi-centre, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including laBCC (71) and mBCC (33). 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, lung, bones and/or internal organs. The 31 study sites were located in the US, Australia and Europe. Study participants received 150mg vismodegib orally, once daily until disease progression or intolerable toxicity.

The primary endpoint of the trial showed an overall response rate of 43% in the laBCC cohort, and 30% in mBCC, as assessed by independent review. Study investigators assessed the overall response rate for laBCC and mBCC at 60% and 46%, respectively (secondary endpoint). The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.

In addition, the clinical benefit rate (defined as patients who experienced response as well as those who experienced prolonged stable disease for more than 24 weeks) showed vismodegib shrank tumours or healed visible lesions, or prevented them from growing any further in 75% of patients, as assessed by independent review.

Adverse events
The most common adverse events included muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhoea. Serious adverse events (SAEs) were observed in 26 patients (25%), however of these only four (4%) patients had SAEs that were considered to be related to treatment with vismodegib. Fatal events were reported in seven patients (7%)and none of these events were considered by investigators to be related to treatment with vismodegib. In all cases, patients had other pre-existing diseases or symptoms that were related to their presumed cause of death.

Because of its relatively low toxicity and specificity for the Hh pathway, vismodegib has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments.[7]

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

For more information:
Abstract: CO14
Study Authors: Sekulic A, Migden MR, Oro AE, Dirix L, Lewis K, Hainsworth JD, et al
Abstract title: A pivotal study evaluating efficacy and safety of the hedgehog pathway inhibitor (HPI) vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma (BCC)

[1] Caro I and Low JA. Clin Cancer Res. 2010;16:3335-3339
[2] 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
[3] Gilbody JS, et al. What causes basal cell carcinoma to be the commonest cancer? Aust J Public Health.1994; 18(2):218-21
[4] Von Hoff et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl J Med. 2009;361:1164-1172
[5] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277?300
[6] Ting, et al. Metastatic Basal Cell Carcinoma: Report of Two Cases and Literature Review. J Cutan Med Surg. 2005;10-15
[7] De Smaele E, Ferretti E, Gulino A. Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs. 2010 Jun;11(6):707-18.

Clinical Trials
– A Study of GDC-0449 (Hedgehog Pathway Inhibitor) in Patients Treated With GDC-0449 in a Previous Genentech-Sponsored Phase I or II Cancer Study [NCT00959647]
– A Study Evaluating the Efficacy and Safety of GDC-0449 in Operable Basal Cell Carcinoma (BCC)[NCT01201915]

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