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November 6, 2017 with PAP

On November 6, 2017, the Food and Drug Administration 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, multicenter, 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 1.1, 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, rash maculo papular, alopecia, fatigue, electrocardiogram QT prolonged, and skin papilloma. The most common (≥ 10%) Grade ³ 3 adverse reactions were squamous cell carcinoma of the skin, hypertension, rash maculo-papular, 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 at

FDA granted this application priority review. Breakthrough Therapy and Orphan Drug designations for this indication were also granted. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

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 by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist's Applications to Practice

Vemurafenib for Treatment of Patients with Erdheim-Chester Disease with BRAF V600 Mutation

Author: Kelsea Seago, PharmD
PGY-1 Pharmacy Resident
WVU Medicine
Morgantown, WV

What is the potential role for vemurafenib in the treatment of Erdheim-Chester disease?

  • Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by a BRAF V600 mutation in more than 50% of patients. ECD histiocytes are positive for CD68, CD163, and Factor XIIIa and negative for CD1a and Langerin. Long-bone osteosclerosis is almost ubiquitous among patients with ECD, and central nervous system (CNS) involvement occurs in 25%–50% of patients.1
  • Vemurafenib is a BRAF-specific kinase inhibitor. It became the first agent approved by the U.S. Food and Drug Administration (FDA) for patients with ECD with a BRAF V600 mutation. It was approved on November 6, 2017.2
  • Approval was based on an open-label multicenter single-arm multiple-cohort study that included 22 patients with BRAF V600 mutation-positive ECD treated with vemurafenib. A response rate of 54.5% (95% confidence interval [CI], 32.2–75.6) was observed, which included 1 complete response and 11 partial responses. The study had a median time to response of 11 months (95% CI: 3.7–14.6) and a median treatment duration of 14.2 months in ECD patients.2
  • Guidelines for the diagnosis and clinical management of ECD were published in 2014 and state that although experience was limited at the time, the responses reported with vemurafenib suggested that all ECD patients with a BRAF V600 mutation should be treated with a BRAF inhibitor.1
    • At the time of publication, few prospective studies and no randomized controlled trials for ECD had been completed. Interferon-alfa-2a and pegylated interferon-alpha were the therapies with the largest amount of supporting evidence. These therapies were listed alongside clinical trials and anakinra as first-line options for treatment of ECD. Second-line options listed in the guidelines include a clinical trial, cladribine, imatinib, and infliximab.
    • Treatment with interferon-alfa-2a or pegylated interferon-alpha did show survival benefit in a prospective nonrandomized observational cohort study of 53 ECD patients, but an optimal dose was not established. Adverse effects of these therapies include constitutional symptoms (fever, fatigue, flu-like symptoms, myalgias, and arthralgias), neuropsychiatric toxicities, gastrointestinal symptoms, alopecia, pruritis, transaminitis, and myelosuppression.
  • A phase 2 clinical trial evaluating combination therapy with dabrafenib, another BRAF V600 inhibitor, and trametinib, an inhibitor of MEK downstream of BRAF, was started in 2014 but is currently suspended.3

What role can the pharmacist play in the management of patients on vemurafenib?

  • The recommended initial dose of vemurafenib for ECD with BRAF V600 mutation is 960 mg orally every 12 hours with or without food. Dosing is the same for BRAF V600 mutation-positive melanoma, which is the other FDA-approved indication of vemurafenib. However, for several reasons treatment may need to be modified.2
    • Vemurafenib should be permanently discontinued in the presence of a grade 4 adverse reaction upon first appearance if clinically appropriate or upon second appearance. Therapy should also be discontinued if QTc is prolonged to >500 msec in addition to being increased >60 msec from pretreatment values.
    • Treatment should be withheld for intolerable grade 2 or greater adverse reactions and vemurafenib restarted at a lower dose upon recovery. After resolution of the first appearance of an intolerable grade 2 or grade 3 adverse reaction, vemurafenib should be resumed at 720 mg twice daily. If the occurrence is the second appearance of an intolerable grade 2 or grade 3 adverse reaction or is classified as grade 4 and dose adjustment would be clinically appropriate, vemurafenib should be resumed at 480 mg twice daily.
    • Concomitant use of strong CYP3A4 inducers should be avoided. If simultaneous use of vemurafenib and a strong CYP3A4 inducer cannot be avoided, vemurafenib should be increased by 240 mg as tolerated. Two weeks after the strong CYP3A4 inducer is discontinued, the dose of vemurafenib that was taken prior to the initiation of the inducer may be resumed.
  • Monitor for and counsel patients on the following adverse reactions related to vemurafenib treatment in patients with ECD: 2
    • Vemurafenib is associated with an increased risk of new primary cutaneous malignancy, including cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma.
      • In the approval trial, the incidence of cuSCC or keratoacanthomas or both was 40.9%, with a median time to first appearance of 12.1 weeks.
      • Dermatologic evaluations should be performed prior to the initiation of therapy with vemurafenib and every 2 months during the therapy. Dermatologic monitoring should continue for 6 months after discontinuation of treatment.
    • Mild to severe photosensitivity can occur with vemurafenib therapy. Patients should be counseled to avoid sun exposure and to wear protective clothing in addition to broad-spectrum sunscreen and lip balm (SPF >30) when outdoors.
    • Uveitis, blurry vision, and photophobia can occur in patients treated with vemurafenib and may be managed with steroid and mydriatic ophthalmic drops if necessary.
    • All grades of adverse reactions with an occurrence rate >50% in ECD patients: arthralgia (82%), maculopapular rash (59%), alopecia (55%), fatigue (55%), QTc prolongation (55%), and skin papilloma (55%). Similar adverse events were seen in patients with BRAF V600 mutation–positive melanoma but at different rates.
    • Adverse reactions of grade 3 or greater with an occurrence rate of 10% or higher: squamous cell carcinoma of the skin (36%), hypertension (23%), maculopapular rash (18%), and arthralgia (14%).
    • Clinically relevant adverse reactions with an occurrence rate of less than 20% in ECD patients: keratoacanthoma, Dupuytren’s contracture, and worsening liver laboratory abnormalities.
  • Check for drug interactions with vemurafenib and modify therapy as clinically appropriate.
    • In vitro studies suggest that vemurafenib is an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. Coadministration of vemurafenib increased the mean area under the curve (AUC) of caffeine (CYP1A2) by 2.6-fold as well as dextromethorphan (CYP2D6) and warfarin (CYP2C9) by 47% and 18%, respectively. The AUC of midazolam (CYP3A4) was decreased by 39% when coadministered with vemurafenib.
    • Concomitant use of strong CYP3A4 inducers, if absolutely unavoidable, may be managed with a dose increase, but the use of vemurafenib with strong CYP3A4 inhibitors should be avoided because of the potential for increased toxicity.
    • Avoid concomitant use with drugs metabolized by CYP1A2 that have a narrow therapeutic index (NTI). If such use is unavoidable, monitor closely for toxicities and consider using a reduced dose of the CYP1A2 substrate.
    • Vemurafenib is both a substrate and an inhibitor of P-glycoprotein (P-gp). Avoid concurrent use with P-gp substrates that have an NTI. If absolutely necessary to use vemurafenib with an NTI P-gp substrate, consider dose reduction of the P-gp substrate.
  • Vemurafenib crosses the placenta and can cause fetal harm. Women of childbearing age should be advised of the potential harm to a fetus and encouraged to use effective contraception while they are on therapy. Likewise, lactating women should not breastfeed until 2 weeks after the final dose of vemurafenib therapy.2
  • Patient assistance programs are available for patients who qualify. These include the Genentech Access to Care Foundation for patients who are underinsured or whose health plan won’t cover the medication and Genentech Therapy-Specific Co-pay Cards for patients with commercial insurance.5

Clinical Pearls

  • Vemurafenib (Zelboraf) is supplied as 240-mg tablets. Tablets should not be crushed or chewed.2
  • Do not reduce dose to below 480 mg twice daily.2
  • Therapy should be continued until the disease progresses or an unacceptable level of toxicity is reached.2
  • Hypersensitivity reactions, anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis can occur with treatment or upon reinitiation of vemurafenib. Severe reactions warrant discontinuation.2
  • Evaluate the QTc interval prior to and after vemurafenib initiation, as well as after dose modification.
  • Although CNS penetration is not fully known, case reports indicate that vemurafenib may potentially have activity for patients with CNS involvement.5,6
  • Electrolytes, including potassium, magnesium, and calcium, and the QTc interval should be evaluated after 15 days of treatment, monthly during the first 3 months of therapy, and then at least every 3 months thereafter.1


  1. Diamond EL, Dagna L, Hyman DM, et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood. 2014;124(4):483-492.
  2. Zelboraf (vemurafenib) [package insert]. South San Francisco, CA: Genentech, Inc.; November 2017.
  3. U.S. National Library of Medicine. Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease. Available at Accessed December 20, 2017.
  4. Genentech Access Solutions. Available at Accessed December 20, 2017.
  5. Schäfer N, Scheffler B, Stuplich M, et al. Vemurafenib for leptomeningeal melanomatosis. JCO. 2013;31(11):e173-e174.
  6. Rochet NM, Kottschade LA, Markovic SN. Vemurafenib for melanoma metastases to the brain. N Engl J Med. 2011;365:2439-2441.