The detection of circulating tumor DNA (ctDNA) in patients with BRAFV600 mutation-positive unresectable or metastatic melanoma predicted outcomes to targeted therapy in a clinical validation study published in The Lancet Oncology.

Using analytically validated droplet digital polymerase chain reaction (PCR) assays, study researchers measured BRAFV600-mutant ctDNA in plasma samples obtained from adult clinical trial participants with BRAFV600 mutation-positive melanoma before study treatment and during study treatment.

Patients were from COMBI-d ( Identifier: NCT01584648), a phase 3 trial that enrolled 423 treatment-naive patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and randomly assigned them to receive either dabrafenib plus trametinib or dabrafenib plus placebo.

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A multivariate analysis that adjusted for treatment group and baseline lactate dehydrogenase concentration showed that patients with elevated levels of BRAFV600 mutation-positive ctDNA before treatment had worse overall survival (hazard ratio [HR]=1.08; 95% CI, 1.03-1.13; P=.0020).

An optimal ctDNA concentration of 64 copies/mL of plasma was identified and used to stratify patients as high or low risk. Patients deemed low risk had superior progression-free survival (HR=1.74; 95% CI, 1.37-2.21; P<.0001) and overall survival (HR=2.23; 95% CI, 1.73-2.87; P<.0001) compared with high-risk patients.

The findings were then validated in plasma samples from 38 patients enrolled in cohort A of the phase 2 COMBI-MB ( Identifier: NCT02039947) trial. Cohort A consisted of patients with BRAFV600 mutation-positive metastatic melanoma and brain metastases, and all patients received dabrafenib plus trametinib.

“The current study provides evidence of the clinical validity of droplet digital PCR-based detection of BRAFV600-mutant ctDNA and the association with clinical outcome and response to targeted therapy in patients with metastatic melanoma, showing usefulness of ctDNA as a predictive biomarker,” the study researchers wrote.

They explained, “The next step in biomarker development is to determine clinical utility from analysis of prospective studies.”


Syeda MM, Wiggins JM, Corless BC, et al. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. Published online February 12, 2021. doi:10.1016/S1470-2045(20)30726-9