FDA Grants Approval to Vemurafenib for Erdheim-Chester Disease

Approval is based on an open-label, multicentre, single-arm, multiple cohort clinical trial in patients aged 16 years of age and older

On 6 November 2017, the US Food and Drug Administration (FDA) granted regular approval to vemurafenib (ZELBORAF, Hoffmann-La Roche Inc.) for the treatment of patients with Erdheim-Chester Disease (ECD) with BRAF V600 mutation.

Approval was based on an open-label, multicentre, single-arm, multiple cohort clinical trial in patients aged 16 years of age and older. The trial included 22 patients with BRAF V600 mutation- positive ECD. The best overall response rate, as assessed by the investigator using RECIST v1.1, was 54.5% (n=12) (95% CI: 32.2, 75.6). Eleven partial responses (50%) and 1 complete response (4.5%) were observed. The median duration of follow- up was 26.6 months (range: 3.0 to 44.3 months). The median time to response was 11 months (95% CI: 3.7, 14.6). The median response duration was not estimable.

In the trial, the most commonly reported adverse reactions (>50%) in patients with BRAF V600 ECD were arthralgia, maculo-papular rash, alopecia, fatigue, prolonged QT on electrocardiogram, and skin papilloma. The most common (≥ 10%) grade ≥ 3 adverse reactions were squamous cell carcinoma of the skin, hypertension, maculo-papular rash, and arthralgia. The incidence of adverse reactions resulting in permanent discontinuation was 32%.

The recommended dose of vemurafenib is 960 mg orally twice daily taken approximately 12 hours apart with or without a meal.

Full prescribing information is available here.  

FDA granted this application priority review. Breakthrough Therapy and Orphan Drug designations for this indication were also granted.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

About Erdheim-Chester Disease

It is a rare disease characterised by abnormal multiplication of histiocytes or tissue macrophages. Onset is typically in middle age. The ECD is associated with high mortality rates.

The first case of ECD was reported by the American pathologist William Chester in 1930, during his visit to the Austrian pathologist Jakob Erdheim.

The disease involves an infiltration of lipid-laden macrophages, multinucleated giant cells, an inflammatory infiltrate of lymphocytes and histiocytes in the bone marrow, and a generalised sclerosis of the long bones. Long bone involvement is almost universal in ECD patients and is bilateral and symmetrical in nature. More than 50% of cases have extraskeletal involvement.

Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees and ankles. The pain is often described as mild but permanent, and juxtaarticular in nature.

Radiologic osteosclerosis and histology are the main diagnostic features. Histologically, ECD differs from Langerhans cell histiocytosis.

Approximately half patients with ECD harbour point mutations of the BRAF gene at codon 600.