In the BRIM-3 trial, Vemurafenib ( Zelboraf ) was associated with risk reduction versus Dacarbazine ( Deticene ) of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma.
An extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups, was presented.
Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1, and adequate haematological, hepatic, and renal function.
Patients were randomly assigned by interactive voice recognition system to receive either Vemurafenib ( 960 mg orally twice daily ) or Dacarbazine ( 1000 mg/m2 of body surface area intravenously every 3 weeks ).
Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population ( n=675 ), with data censored at crossover.
675 eligible patients were enrolled from 104 centres in 12 countries in the 2010 year. 337 patients were randomly assigned to receive Vemurafenib and 338 to receive Dacarbazine.
Median follow-up was 12.5 months on Vemurafenib and 9.5 months on Dacarbazine. 83 ( 25% ) of the 338 patients initially randomly assigned to Dacarbazine crossed over from Dacarbazine to Vemurafenib.
Median overall survival was significantly longer in the Vemurafenib group than in the Dacarbazine group ( 13.6 months vs 9.7 months; hazard ratio [ HR ] 0.70; p=0.0008 ), as was median progression-free survival ( 6.9 months vs 1.6 months; HR=0.38; p less than 0.0001 ).
For the 598 ( 91% ) patients with BRAFV600E disease, median overall survival in the Vemurafenib group was 13.3 months compared with 10.0 months in the Dacarbazine group ( HR=0.75; p=0.0085 ); median progression-free survival was 6.9 months and 1.6 months, respectively ( HR=0.39; p less than 0.0001 ).
For the 57 ( 9% ) patients with BRAFV600K disease, median overall survival in the Vemurafenib group was 14.5 months, compared with 7.6 months in the Dacarbazine group ( HR=0.43; p=0.024 ); median progression-free survival was 5.9 months and 1.7 months, respectively ( HR=0.30; p less than 0.0001 ).
The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma ( 19% ) and keratoacanthomas ( 10% ), rash ( 9% ), and abnormal liver function tests ( 11% ) in the Vemurafenib group and neutropenia ( 9% ) in the Dacarbazine group.
Eight ( 2% ) patients in the Vemurafenib group and seven ( 2% ) in the Dacarbazine group had grade 5 events.
In conclusion, the inhibition of BRAF with Vemurafenib has improved survival in patients with the most common BRAFV600E mutation and in patients with the less common BRAFV600K mutation. ( Xagena )
McArthur GA et al, The Lancet Oncology 2014; 15: 323-332