Vemurafenib offered numerical improvement in disease-free survival in patients with resected melanoma, but the results did not reach statistical significance.
Vemurafenib offered numerical improvement in disease-free survival in a study of patients with completely resected stage IIC to IIIC BRAF V600 mutation–positive melanoma, but the results did not reach statistical significance. The benefit was bigger in those with stage IIC to IIIB disease, but this should be considered exploratory at this point.
“Despite full resection, patients with stage IIC to III melanoma remain at high risk for disease recurrence and death,” wrote study authors led by Michele Maio, MD, of University Hospital of Siena in Italy. “This situation warrants the use of adjuvant approaches to improve clinical outcomes.”
The BRIM8 trial was a phase III, double-blind, randomized study comparing adjuvant vemurafenib with placebo in patients with resected BRAF V600 mutation–positive melanoma. It consisted of two cohorts: cohort 1 included 314 patients with stage IIC to IIIB disease, and cohort 2 included 184 patients with stage IIIC disease. The two cohorts were followed for a median of 30.8 months and 33.5 months, respectively, and the results were published in Lancet Oncology.
The study incorporated hierarchical testing of disease-free survival (DFS) in cohort 2 before cohort 1, based on the assumption that an effect in higher-risk disease (cohort 2) would suggest the presence of an effect across the continuum of melanoma. Because of this design, the study did not yield positive results.
In cohort 2, the median DFS was 23.1 months with vemurafenib and 15.4 months with placebo, for a hazard ratio (HR) of 0.80 (95% CI, 0.54–1.18; P = .026). In cohort 1, the median DFS was not reached in the vemurafenib group, and it was 36.9 months in the placebo group, for an HR of 0.54 (95% CI, 0.37–0.78; P = .0010). Because the primary endpoint was not met in cohort 2, the authors wrote that the finding in cohort 1 cannot be considered significant.
In a prespecified exploratory pooled analysis of both cohorts, the median DFS was not estimable with vemurafenib and was 25.8 months with placebo, for an HR of 0.65 (95% CI, 0.50–0.85; P = .0013). Overall survival data remain immature, but the 2-year survival rate was 93.4% with vemurafenib and 86.8% with placebo in cohort 1. In cohort 2, those rates were 83.7% and 85.4%, respectively.
Most adverse events in the study were grade 1 or 2 and were manageable. Grade 3/4 adverse events occurred in 57% of vemurafenib patients and in 15% of placebo patients, with keratoacanthoma (10%), arthralgia (7%), squamous cell carcinoma (7%), and rash (6%) being the most commonly seen in vemurafenib patients. In total, 20% of vemurafenib patients and 2% of placebo patients discontinued treatment due to an adverse event.
The authors noted that though the study design rendered the DFS improvement nonsignificant, the benefit seen in the cohort 1 patients is greater than that reported in other trials of adjuvant interferon or ipilimumab. Still, this should only be considered exploratory at the present time.