Association of BRAF V600–Mutant ctDNA With Outcomes in Patients With Advanced Melanoma Receiving Dabrafenib or Dabrafenib/Trametinib

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In a study reported in The Lancet Oncology, Syeda et al found that higher BRAF V600–mutant cell-free circulating tumor DNA (ctDNA) levels prior to and during treatment with dabrafenib or dabrafenib/trametinib were associated with poorer outcomes among patients with advanced melanoma.

Study Details

In the study, analytically validated droplet digital polymerase chain reaction assays were used to measure BRAF V600–mutant ctDNA in pretreatment and on-treatment (week 4) plasma samples from patients enrolled in the COMBI-d and COMBI-MB clinical trials.

COMBI-d was a phase III trial comparing dabrafenib/trametinib vs dabrafenib in previously untreated patients with BRAF V600 mutation­–positive unresectable or metastatic melanoma. Patients in cohort A of the phase II COMBI-MB trial, which evaluated dabrafenib/trametinib in patients with BRAF V600 mutation–positive metastatic melanoma and brain metastases, had asymptomatic brain metastases and no previous local brain-directed therapy.   

“Pretreatment and on-treatment BRAF V600–mutant ctDNA measurements could serve as independent, predictive biomarkers of clinical outcome with targeted therapy.”
— Syeda et al

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Key Findings

In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%). In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients. ctDNA was detected in pretreatment samples from 320 (93%) COMBI-d and 34 (89%) COMBI-MB cohort patients.

In COMBI-d, elevated baseline ctDNA concentration assessed as a continuous variable was associated with poorer progression-free survival (hazard ratio [HR] = 1.08, P < .0001) and poorer overall survival (HR = 1.13, P < .0001) on univariate analysis. Elevated levels were associated with poorer overall survival independent of treatment group and baseline lactate dehydrogenase (LDH) concentrations on multivariate analysis (HR = 1.08, P = .0020).

In the COMBI-MB cohort, elevated baseline ctDNA concentrations as a continuous variable were associated with poorer progression-free survival (HR = 1.17, P = .0024) and overall survival (HR = 1.21, P = .0020).

A ctDNA cutoff point of ≥ 64 copies/mL stratified COMBI-d patients as high risk for poorer progression-free survival (HR = 1.74, P < .0001) and overall survival (HR = 2.23, P < .0001). The cutoff was validated in the COMBI-MB cohort for progression-free survival (HR = 3.20, P = .0047) and overall survival (HR = 2.94, P = .016). 

In COMBI-d, undetectable vs detectable ctDNA at week 4 was significantly associated with improved progression-free survival (HR = 1.99, P = .027) and overall survival (HR = 2.38, P = .0089) among patients with LDH above the upper limit of normal but not among patients with LDH at or below the upper limit of normal.

The investigators concluded, “Pretreatment and on-treatment BRAF V600mutant ctDNA measurements could serve as independent, predictive biomarkers of clinical outcome with targeted therapy.”

David Polsky, MD, of NYU Langone Health, New York, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Novartis. For full disclosures of the study authors, visit