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

Wilmott JS, Tawbi H, Engh JA, Amankulor NM, Shivalingam B, Banerjee H, Vergara IA, Lee H, Johansson PA, Ferguson PM, Saiag P, Robert C, Grob JJ, Butterfield LH, Scolyer RA, Kirkwood JM, Long GV, Davies MA. Clin Cancer Res. 2022 Dec 7:CCR-22-2581. doi: 10.1158/1078-0432.CCR-22-2581. Epub ahead of print. PMID: 36477181.


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.