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Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK). Liver toxicity updated by Dr Amanda Oakley, February 2014.
In August 2011, the US Food and Drug Administration (FDA) approved vemurafenib (Zelboraf®, Plexxikon/Roche) for the first-line treatment of both metastatic and unresectable (inoperable) melanoma. Vemurafenib was registered by MedSafe for use in New Zealand in February 2012 but is not currently funded by PHARMAC (June 2017). It can also be taken in combination with cobimetinib, a MEK inhibitor (June 2017).
Vemurafenib and vemurafenib with cobimetinib have demonstrated prolonged survival in advanced melanoma patients.
Vemurafenib is a threonine kinase inhibitor, one of a new class of medicines known as epidermal growth factor receptor (EGRF) inhibitors or targeted therapy.
Melanoma tumours that carry the BRAF V600 mutation can be identified by a companion diagnostic test developed by the pharmaceutical company Roche, USA, and approved by the FDA.
The test is called the cobas® 4800 BRAF V600 Mutation Test and must be performed on melanoma biopsy samples from all patients before starting treatment with vemurafenib.
The test has several advantages including:
The FDA approval of vemurafenib was based on results from two clinical studies (BRIM3 and BRIM2) in patients with BRAF V600E mutation-positive, inoperable or metastatic melanoma as determined by the cobas® BRAF Mutation Test.
BRIM3 (B-RAF Inhibitor in Melanoma phase 3) is a global, randomized, open-label, multicenter, advanced (phase III) study that compared 960mg of vemurafenib given orally twice daily with dacarbazine (standard of care) 1000 mg/m2 given IV on day 1, every 3 weeks in 675 patients with previously untreated BRAF V600E mutation-positive, unresectable (inoperable) or metastatic melanoma. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal.
Key results are tabulated below:
(No. of patients = 337)
(No. of patients = 338)
|Overall survival (OS)|
|Number of Deaths||78 (23%)||121 (36%)|
|Median OS (months)||Not reached||7.9|
|Estimated OS at 6 months (% patients)||84%||64%|
|Median Follow-up (months)||6.2||4.5|
|Progression-free survival (PFS)|
|Median PFS (months)||5.3||1.6|
|Complete tumour shrinkage (% patients)||1%||0|
|Partial tumour shrinkage (% patients)||47.4%||5.5%|
BRIM2 is a global, single-arm, multicentre, open-label early-phase (phase II) study that enrolled 132 patients with previously treated BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of the study was best overall response rate.
Data showed that:
There is only limited data about safety and efficacy of vemurafenib due to small patient numbers treated up to now. Treatment should be monitored including monthly liver function tests and as clinically indicated.
The following adverse reactions have been reported:
Most common adverse reactions (≥30% treated patients) reported are:
Management of symptomatic adverse drug reactions may require dose reduction, treatment interruption, or treatment discontinuation. Dose reductions resulting in a dose below 480 mg twice daily are not recommended.
Some of the cutaneous side effects of vemurafenib are similar to those described with other EGFR and protein kinase inhibitors, but SCC appears to be a specific problem. Concern has been expressed that they may also lead to more melanocytic lesions, including common moles and perhaps new primary melanoma. The reactions are dose-related and may settle down even with continued therapy. Cutaneous side effects include:
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