Lessons learned: This study suggests that trametinib has significant clinical activity in non-V600 BRAF mutation and BRAF fusion metastatic melanoma, albeit in a small cohort. All patients with metastatic melanoma should undergo sequencing of the BRAF gene to identify noncanonical BRAF mutations that may indicate benefit from treatment with trametinib.
Background: Non-V600 BRAF mutations and BRAF fusions in aggregate occur in approximately 5% of all melanomas. Inhibition of the mitogen-activated protein kinase (MAPK) pathway has been implicated as a possible treatment strategy for these patients.
Methods: In this open-label, multicenter, phase II study, patients with advanced melanoma harboring mutations in BRAF outside V600 (non-V600) or BRAF fusions received trametinib 2.0 mg daily. Patients were divided into cohorts based on the intrinsic catalytic activity of BRAF mutation (high, cohort A; low/unknown, cohort B). The primary endpoint was objective response rate (ORR) for patients in cohort A; secondary endpoints included ORR in cohort B, safety, and survival in both treatment arms.
Results: Among all patients, the ORR was 33% (three of nine patients), including 67% in cohort A and 17% in cohort B. Two patients had stable disease as best response, and six patients had some degree of tumor shrinkage. The median progression-free survival (PFS) was 7.3 months. Treatment-related adverse events occurred in all patients (100%); most (89%) were grade 1-2.
Conclusion: In contrast to recently described tumor-agnostic studies in a genetically similar population, trametinib had considerable activity in a small population of patients with melanoma harboring BRAF non-V600 mutations and fusions, providing rationale for sequencing in search of these genomic alterations.
Trial registration: ClinicalTrials.gov NCT02296112.
Keywords: BRAF; Fusion; MEK; Melanoma; Trametinib.
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