Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases

Authors

James S Wilmott
Hussein Tawbi
Johnathan A Engh
Nduka M Amankulor
Brindha Shivalingam
Hiya Banerjee
Ismael A Vergara
Hansol Lee
Peter A Johansson
Peter M Ferguson
Philippe Saiag
Caroline Robert
Jean-Jacques Grob
Lisa H Butterfield
Richard A Scolyer
John M Kirkwood
Georgina V Long
Michael A Davies

Publication Date

2-1-2023

Journal

Clinical Cancer Research

Abstract

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 immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM).

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 intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS).

UNLABELLED: Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses.

RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% 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; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005).

CONCLUSIONS: 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.

Keywords

Humans, Proto-Oncogene Proteins B-raf, Melanoma, Oximes, Pyridones, Brain Neoplasms, Biomarkers, Antineoplastic Combined Chemotherapy Protocols, Mutation, Skin Neoplasms, COMBI-MB, brain metastases, dabrafenib, trametinib, biomarker

Comments

Trial Registration: ClinicalTrials.gov Identifier: NCT01266967 and NCT01978236

Supplementary Materials

PMID: 36477181