Vismodegib

Chlorinated methylsulfonylbenzamide derivative, an antitumor agent from the group of so-called smoothened receptor antagonists. Vismodegib binds to the membrane protein smoothened (see below hedgehog signalling pathway). This in turn induces an inhibition of transcription of genes involved in tumour growth. The effects of Vismodegib are based on the inhibition of the Hedgehog signaling pathway, which plays an essential role in regulating the specialization of cells.

Vismodegib is used for the treatment of patients with advanced basal cell carcinoma (see basal cell carcinoma below) for whom surgery or radiotherapy is no longer suitable. It is also used in (extremely rare) patients with metastatic basal cell carcinoma.

More than 13,000 patients with locally advanced basal cell carcinoma have already been treated worldwide.

In a larger study of 104 patients (71 with advanced basal cell carcinoma, 33 with metastatic basal cell carcinoma) 30% of the metastatic patients showed partial remission, 64% stable disease and 3% progression. In advanced basal cell carcinoma 43% (27/63) showed partial and complete (13/67) remission, 38% stable disease and 13% progression.

The global safety study(STEVIE) with > 1,000 patients confirmed continued tumor control. In this study 92.9% of patients (basis: 1,215 patients evaluated) benefited from the therapy in the long term (median 2 years).

Long-term analyses with data from 300 patients prove the effectiveness and safety of Vismodegib.

Intermittent therapy application (150mg Vismodegib orally over 12 weeks, followed by 3x 8 weeks of placebo and again 150mg Vismodegib daily for 8 weeks) reduced the average number of BCCs by 62.5% (Dréno B et al. 2017), making this form of therapy a real alternative.

The recommended dose is 150mg/day p.o. The capsules can be taken independently of meals. The half-life of Vismodegib is several days.

Undesirable effects

Muscle spasms, hair loss, taste disorders, weight loss, fatigue, nausea, diarrhoea, lack of appetite, constipation, joint pain and vomiting. Deaths (cardiac causes, shock, pulmonary embolism) associated with the therapy have been reported.

An increased risk of consecutive squamous cell carcinoma after therapy with vismodegib was not confirmed (Bhutani T et al. 2017).

Vismodegib is excreted largely unchanged. With an increase in gastric pH, reduced levels must be expected.

The hedgehog signalling pathway plays an essential role in embryogenesis. Vismodegib is obligatory embryotoxic and teratogenic and therefore must not be used in pregnant or childbearing women. For women of childbearing age, regular pregnancy tests must be performed before and during therapy. It should be noted that Vismodegib can be excreted via the sperm. Men must not have unprotected sexual intercourse with female partners while taking Vismodegib. This also applies up to 2 months after the last intake of the preparation.

Erivedge (Roche)

Vismodegib has been approved as a drug (Erivedge) since July 2013.

1. Basset-Seguin N et al (20159 Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol 16:729-/36.
2. Bhutani T et al (2017) Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinomawith
   vismodegib. J Am Acad Dermatol 77: 713-718.
3. Dreier J et al (2013) Basal cell carcinoma: a paradigm for targeted therapies. Expert Opinion Pharmacother 14:1307-1318
4. Dréno B et al (2017) Two intermittent vismodegib dosing regimens in patients with multiple basal cell carcinomas
   (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol 18:404-412.
5. Fecher LA et al (2013) Systemic therapy for inoperable and metastatic basal cell cancer. Curr Treat Options Oncol 14:237-248
6. Harms KL et al (2013) Harnessing hedgehog for the treatment of basal cell carcinoma. JAMA Dermatol 149:607-608
7. Iarrobino A et al (2013) Emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. J Am Acad Dermatol 69:e33-e34
8. Jäger M (2017) Therapy of a huge metastasized basal cell carcinoma. Act Dermatol 43: 457-458
9. McCusker M et al (2014) Metastatic basal cell carcinoma: prognosis dependent
   on anatomic site and spread of disease. Eur J Cancer 50:774-783
10. Poggi L et al (2013) Vismodegib for the treatment of basal cell skin cancer. At J Health Syst Pharm 70:1033-1038
11. Roche - Erivedge, contraception program.
12. Sekulic A et al (2012) Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366:2171-2179
13. Sekulic A et al (2013) Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway. Curr Opin Oncol 25:218-22