o assess the BRAF mutation status of DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant BRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wild type sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospective sequencing analyses have shown that the test also detects the less common BRAF V600D mutations and V600K mutations with lower sensitivity. Of the specimens available from the non-clinical and clinical studies (n=920), that were mutation-positive by the cobas test and additionally analyzed by sequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing.
Clinical efficacy and safety
The efficacy of vemurafenib has been eva luated in 336 patients from a phase III clinical trial (NO25026) and 132 patients from a phase II clinical trial (NP 22657). All patients were required to have advanced melanoma with BRAF V600 mutations according to the cobas 4800 BRAF V600 Mutation Test.
Results from the Phase III study (NO25026) in previously untreated patients
An open-label, multicentre, international, randomised phase III study supports the use of vemurafenib in previously untreated patients with BRAF V600E mutation-positive unresectable or metastatic melanoma. Patients were randomised to treatment with vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 on day 1 every 3 weeks).
A total of 675 patients were randomised to vemurafenib (n=337) or dacarbazine (n=338). Most patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1c disease (65%). The co-primary efficacy endpoints of the study were overall survival (OS) and progression-free survival (PFS).
At the pre-specified interim analysis with a December 30, 2010 data cut-off, significant improvements in the co-primary endpoints of OS (p<0.0001) and PFS (p<0.0001) (unstratified log-rank test) were observed. Upon Data Safety Monitoring Board (DSMB) recommendation, those results were released in January 2011 and the study was modified to permit dacarbazine patients to cross over to receive vemurafenib. Post-hoc survival analyses were undertaken thereafter as described in table 5.
Table 5: Overall survival in previously untreated patients with BRAF V600 mutation-positive melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib)
Cut-off dates
Treatment
Number of deaths (%)
Hazard Ratio
(95% CI)
Number of cross-over patients (%)
December 30, 2010
dacarbazine
75 (22)
0.37 (0.26, 0.55)
0 (not applicable)
vemurafenib
43 (13)
March 31, 2011
dacarbazine
122 (36)
0.44 (0.33, 0.59) (g)
50 (15%)
vemurafenib
78 (23)
October 3, 2011
dacarbazine
175 (52)
0.62 (0.49, 0.77) (g)
81 (24%)
vemurafenib
159 (47)
February 1, 2012
dacarbazine
200 (59)
0.70 (0.57, 0.87) (g)
83 (25%)
vemurafenib
199 (59)
December 20, 2012
dacarbazine
236 (70)
0.78 (0.64, 0.94) (g)
84 (25%)
