Zelboraf (vemurafenib) - 2 indications

Scroll down for more information on each indication:

• for the treatment of unresectable or metastatic melanoma with BRAFV600E mutation; approved August of 2011
• for the treatment of patients with Erdheim-Chester Disease with BRAF V600 mutation; approved November of 2017

General Information

Zelboraf (vemurafenib) is a selective inhibitor of the activated BRAFV600E gene, a gene found in 70% of malignant melanomas and a significant percentage of other cancers.

Zelboraf is specifically indicated for:

• the treatment of unresectable or metastatic melanoma with BRAFV600E mutation, as detected by an FDA-approved test
• the treatment of patients with Erdheim-Chester Disease with BRAF V600 mutation

Zelboraf is supplied as a tablet for oral administration. The recommended dose is 960 mg (four 240 mg tablets) twice daily. The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Each dose can be taken with or without a meal. If a dose is missed, it can be taken up to four hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time.

Mechanism of Action

Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation.

Side Effects

Adverse events associated with the use of Zelboraf for melanoma may include, but are not limited to, the following:

• arthralgia
• rash
• alopecia
• fatigue
• photosensitivity reaction
• nausea
• pruritus
• skin papilloma

Adverse events associated with the use of Zelboraf for Erdheim-Chester Disease may include, but are not limited to, the following: 

• arthralgia
• rash maculo-papular
• alopecia
• fatigue
• electrocardiogram QT interval prolonged
• skin papilloma

Indication 1 - for the treatment of unresectable or metastatic melanoma with BRAFV600E mutation

approved August of 2011

Clinical Trial Results

The FDA approval of Zelboraf in treatment naïve subjects was based on an international, randomized, open-label trial in 675 subjects. The subjects received Zelboraf 960 mg by mouth twice daily or dacarbazine 1000 mg/m2 intravenously on Day 1 every three weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures were overall survival (OS) and investigator-assessed progression-free survival (PFS). The overall response rate was 48.4% in the Zelboraf arm compared to 5.5% in the dacarbazine arm. There were two complete responses (0.9%) and 104 partial responses (47.4%) in the Zelboraf arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm. The median progression free survival was 5.3 months in the Zelboraf arm versus 1.6 months in the dacarbazine arm. The FDA approval of Zelboraf in subjects who received prior systemic therapy was based on single-arm, multicenter, multinational trial in 132 subjects. The confirmed best overall response rate was 52%. There were three complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response was 6.5 months.

Indication 2 - for the treatment of patients with Erdheim-Chester Disease with BRAF V600 mutation

approved November of 2017

Clinical Trial Results

An open-label, multicenter, single-arm, multiple cohort study of Zelboraf (Trial 4) was conducted in patients ≥ 16 years of age with non-melanoma BRAF V600 mutation–positive diseases. 18 The trial included 22 patients with ECD. Fifteen patients (68.2%) had received prior systemic therapies. The median age was 58.5 years (range, 34 to 77 years). Fifty-five percent of patients were men. All 22 patients received a starting dose of 960 mg orally twice daily with or without food. For 8 patients, the dose was reduced to 720 mg twice daily. For the remaining 14 patients, the dose was ultimately reduced to 480 mg. The median duration of treatment following a dose reduction to 720 mg was 77 days (range, 4 to 1325) and to 480 mg was 236 days (range, 21 to 924). The efficacy was maintained in these patients based on the overall response rate. The efficacy of Zelboraf in ECD was based on best overall response rate maintained on two occasions at least four weeks apart, as assessed by the investigator using RECIST v 1.1. 54.5% of the patients were considered responders, with 4.5% complete response and 50% partial response.