Zelboraf (Roche)
240 mg film-coated tablets
Australian Medicines Handbook section 14.2

The prognosis for patients with metastatic melanoma is poor. Apart from the recently approved ipilimumab (Aust Prescr 2011;34:153-9), treatment options are limited. Vemurafenib offers another alternative for patients whose melanoma carries a specific mutation called BRAF V600. This is found in 40–60% of melanomas. The abnormal BRAF protein kinase stimulates cell proliferation and cell survival. Vemurafenib blocks BRAF and slows tumour growth.

The approval of vemurafenib for patients with unresectable or metastatic BRAF V600-positive melanoma is based on results from two trials (Table). These were a phase III trial comparing vemurafenib with dacarbazine in 672 previously untreated patients1 and a single-arm phase II trial in 132 previously treated patients.2 Overall, 92% of people in the trials had the BRAF V600E mutation. The remaining 8% mainly had the BRAF V600K mutation. Patients with untreated brain metastases were excluded from both trials.

In the phase III trial, more patients responded to vemurafenib than to dacarbazine and progression-free survival was longer (Table). After an interim analysis, it was recommended that patients receiving dacarbazine cross over to vemurafenib.1 Outcomes with vemurafenib were similar in the phase II trial.2 Median overall survival was calculated to be 13.2–15.9 months.1, 2 It is unclear if vemurafenib is effective against melanomas which have BRAF V600 non-E mutations.

Adverse events in the trials were common. In the comparative trial, 38% of patients taking vemurafenib had their dose modified or stopped because of an adverse event compared with only 16% of those receiving dacarbazine.1 Arthralgia, rash, alopecia, fatigue, nausea, pruritus and skin papilloma were frequently reported with vemurafenib. Photosensitivity reactions were also common and patients should be advised to avoid the sun and cover up or wear sunscreen outdoors. The dose may need to be reduced for severe cases. Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis and uveitis have also been reported.

Between 18% and 26% of patients in the trials developed cutaneous squamous cell carcinoma or keratoacanthoma.1,2 These occurred after a median of 7–8 weeks and some patients had more than one lesion. New primary melanomas were also reported. Both of these malignancies are not a contraindication to treatment and can usually be excised. Rare cases of non-cutaneous squamous cell carcinoma of the head and neck also occurred in the trials. It is important that patients are examined for new malignancies at baseline and during treatment.

Vemurafenib can prolong the QT interval so it is not recommended for patients with uncorrected electrolyte abnormalities, long QT syndrome or who are taking other drugs that prolong the QT interval. ECG and electrolytes should be measured at baseline and after a dose change.

Liver abnormalities have occurred with vemurafenib so liver enzymes and bilirubin should be monitored before and during treatment. Dose reduction or interruption may be necessary to manage elevations.

Following oral administration of vemurafenib, maximum plasma concentrations are reached after four hours. Most of the metabolites are recovered in the faeces and the elimination half-life is 57 hours. Vemurafenib is an inhibitor of P-glycoprotein and the cytochrome P450 (CYP) enzymes 1A2 and 2C9. It is also a substrate of CYP3A4 so there is a potential for many drug interactions.

Up to half of patients carrying the BRAF V600 mutation are expected to respond to vemurafenib with a median overall survival of up to 16 months. However, adverse reactions may limit treatment and monitoring for new malignancies is important.

Table 1 Efficacy of vemurafenib in patients with BRAF V600-positive metastatic melanoma
Clinical outcome Phase III trial1
(672 patients)
Phase II trial2
(132 patients)
vemurafenib dacarbazine vemurafenib
Response rate * 48% (2 complete responses, 104 partial responses) 5% (12 partial responses) 53% (8 complete responses, 62 partial responses)
Median progression-free survival 5.3 months 1.6 months 6.8 months
Survival rate at 6 months 84% 64% 77%
Median overall survival 13.2 months 9.6 months 15.9 months
* complete response – disappearance of all target lesions
partial response – at least 30% decrease in the sum of the diameters of target lesions

manufacturer provided the product information

The Transparency Score is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.