Lancet oncol: BRAFv600 mutant ctDNA can be used as an independent predictive biomarker for melanoma targeting treatment prognosis

Melanoma lacks blood biomarkers that effectively monitor and predict therapeutic effects.
Cell-free circulatory tumor DNA (ctDNA) is a promising biomarker; although various tests have been used, no large-scale studies have so far found a link between a series of changes in ctDNA and the prognostication of survival after treatment with BRAF, MEK, or BRAF plus MEK inhibitors.
study aims to assess whether baseline ctDNA volume and dynamics can predict survival prognostics.
this is a clinically validated study that performs PCR verification on CTDNA BRAFv600 mutations in plasma samples from patients aged 18 and older recruited in two clinical trials (COMBI-d and COMBI-MB).
biomarker analysis is the exploratory end point of the two trials.
study assessed the correlation between the number of copies of mutations and the end of efficacy.
COMBI-d trial was a double-blind randomized Phase 3 trial that compared darafinib and qumentinib vs. darafinib to placebo therapy for unrecected or metastasis melanomas that were positive for the initial treatment of BRAFv600 mutations.
COMBI-MB trial was an open-label, non-random Phase 2 trial that evaluated the use of darafinib and qumedinib for BRAFv600 mutation-positive metastasis melanoma and brain metastasis.
345 (82%) pre-treatment plasma samples and 224 (53%) plasma samples (4 weeks) were obtained in 423 patients in the COMBI-d trial.
38 (50%) pre-treatment and in-treatment plasma samples were obtained in 76 patients with intracranial and intracranial metastasis melanoma in the COMBI-MB trial A queue.
93% and 89%, respectively, of ctDNA samples from plasma samples before the COMBI-d trial and the COMBI-MB trial.
In the COMBI-d trial, when evaluated as a continuous variable, the increase in baseline BRAF v600 mutation-positive ctDNA concentration was associated with a poor overall survival prognostic (risk ratio of 1.13, 95% CI 1.09-1.19, p.lt;0.0001), and was not related to concentrations in the treatment group and baseline lactic acid dehydrogenase.
CTDNA cut-off point is set at 64 copies/ml of plasma, which classes patients in the COMBI-d trial into high-risk or low-risk stratizations with survival prognosis (progression-free survival HR 1.74, 95% CI 1.37-2.21, p.lt;0.0001; Total survival 2.23, 1.73-2.87, p.lt;0.0001) and verified in the COMBI-MB queue (3.20, 1.39-7.34, p=0.0047;2.94, 1.18-7.32, p-0.016).
in comBI-d trials, ctDNA was not detected at 4 weeks to be significantly associated with progression-free survival and total lifetime extension, especially in patients with elevated lactic acid dehydrogenase (HR 1.99, 95% CI 1.08-3.64, p=0.027; 2.38, 1.24-4.54, p=0.0089）。
, the detection of BRAFv600 mutation ctDNA before and after treatment can be used as an independent predictive biomarker for clinical prognosis of melanoma-targeted treatment.