Vemurafenib in Erdheim-Chester Disease


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On November 6, 2017, vemurafenib (Zelboraf) was granted regular approval for the treatment of patients with Erdheim-Chester disease and BRAF V600 mutation.1,2 Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis, characterized by the excessive production of histiocytes and the accumulation of histiocytes within multiple tissues and organs. The disease affects women and men, with an average age at onset of 53 years. Erdheim-Chester disease mostly affects long bones (arms and legs), but can involve the retro-orbital region, kidney, skin, brain, lung, heart, pituitary gland, and the retroperitoneum. The symptoms and course of the disease depend on the location and extent of the involvement of the internal organs (ie, the disease outside the bones). To learn more, visit the National Organization for Rare Disorders (rarediseases.org).

Supporting Efficacy Data

Approval was based on observation of durable responses in a multicenter single-arm trial,2 in which 22 adult patients received a starting dose of 960 mg twice daily; the dose was reduced to 720 mg twice daily in 8 patients and ultimately to 480 mg in the remaining 14 patients. Patients had a median age of 58.5 years (range = 34–74 years), 55% were male, and 68% had received prior systemic therapy.

Median duration of follow-up was 26.6 months. Objective response was observed in 12 patients (54.5%), including a complete response in 1 (4.5%). Median time to response was 11 months. Median duration of response was not reached. 

How It Works

Vemurafenib inhibits some mutated forms of BRAF serine threonine kinase, including BRAF V600E. The agent also inhibits other kinases in vitro, including CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene, including at V600E, result in constitutively activated BRAF proteins that can cause cell proliferation in the absence of growth factors normally required for proliferation.

How It Is Used

The recommended dose of vemurafenib is 960 mg orally every 12 hours, with treatment continuing until disease progression or unacceptable toxicity. 

NEW INDICATION FOR VEMURAFENIB

  • On November 6, 2017, vemurafenib (Zelboraf) was granted regular approval for the treatment of patients with Erdheim-Chester Disease and BRAF V600 mutation.
  • The recommended dose of vemurafenib is 960 mg orally every 12 hours, with treatment continuing until disease progression or unacceptable toxicity.

Vemurafenib should be permanently discontinued for grade 4 adverse reactions at first appearance (if clinically appropriate) or second appearance, for QTc prolongation > 500 ms with an increase by > 60 ms from pretreatment values, severe dermatologic reactions, and severe hypersensitivity reactions. Treatment should be withheld for intolerable grade 2 or higher grade adverse reactions and can be resumed at the following doses upon recovery to grade 0 or 1: 720 mg twice daily for the first appearance of intolerable grade 2 or grade 3 adverse reactions; and 480 mg twice daily for the second appearance of grade 2 (if intolerable) or grade 3 adverse reactions or the first appearance of a grade 4 adverse reaction (if clinically appropriate). 

The dose of vemurafenib should not be reduced to below 480 mg twice daily. No dose modifications are recommended in patients developing new primary cutaneous malignancies. 

Concomitant use with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin) should be avoided. If concomitant use cannot be avoided, the vemurafenib dose should be increased by 240 mg as tolerated. The prior vemurafenib dose may be resumed at 2 weeks after discontinuation of the strong CYP3A4 inducer. 

Safety Profile

The most common adverse events of any grade in the 22 patients with Erdheim-Chester disease were arthralgia (82%), maculopapular rash (59%), alopecia (55%), fatigue (55%), QT interval prolongation (55%), skin papilloma (55%), hyperkeratosis (50%), and diarrhea (50%). The most common grade ≥ 3 adverse events were squamous cell carcinoma of the skin (36%), hypertension (23%), maculopapular rash (18%), and arthralgia (14%). 

OF NOTE

Patients on vemurafenib must be monitored for dermatologic changes, new noncutaneous squamous cell carcinoma, other malignancies, ECG and electrolytes, liver function tests, uveitis, and renal function.

Adverse events led to discontinuation of treatment in 32% of patients. An elevation from baseline to grade 3 toxicity was observed for 9.1% of patients for alanine transaminase, 4.5% for alkaline phosphatase, and 0% for aspartate transaminase and bilirubin. 

Vemurafenib carries warnings/precautions for new primary cutaneous malignancies; new noncutaneous squamous cell carcinoma; other malignancies; tumor promotion in BRAF wild-type melanoma; serious hypersensitivity reactions, including anaphylaxis and drug reaction with eosinophilia and systemic symptoms; severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis; QT prolongation; hepatotoxicity; photosensitivity; serious ophthalmologic reactions; embryofetal toxicity; radiation sensitization and radiation recall; renal failure; and Dupuytren’s contracture and plantar fascial fibromatosis. Patients must have regular monitoring for dermatologic changes, new noncutaneous squamous cell carcinoma, other malignancies, electrocardiogram and electrolytes, liver function tests, uveitis, and renal function. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA granted approval to vemurafenib for Erdheim-Chester disease. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm583975.htm. Accessed November 21, 2017.

2. Zelboraf (vemurafenib) tablets prescribing information, Genentech, Inc, November 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s016lbl.pdf. Accessed November 21, 2017.

REPORT ADVERSE EVENTS

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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