Clinical features associated with outcomes and biomarker analysis of dabrafenib plus trametinib treatment in patients with BRAF-mutant melanoma brain metastases


 Purpose: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunological changes associated with dabrafenib in MBMs and extracranial (ECM) metastases. Patients and Methods: Post-hoc analysis was performed for baseline features of patients (n=125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with ICRR, PFS, and overall survival (OS). Exploratory biomarker analysis was performed on biospecimens collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10-14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunological profiling for comparative analyses. Results: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR (39% versus 63%, OR 0.323, CI 0.105-0.996, P= 0.049) and shorter PFS (HR 1.93, CI 1.06-3.51, P=0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR 0.565, CI 0.321-0.996, P=0.048) and improved OS in patients with ECOG 0 (HR 0.44, CI 0.25-0.78, P=0.005). Conclusion: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.