Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C).

Abstract

9020 Background: Tumor-derived cfDNA in the blood is a potential alternative source to derive tumor mutation (mut) status and could be a useful biomarker of therapeutic response. Data from METRIC (NCT01245062), an open-label randomized Phase III study evaluating the efficacy and safety of T vs C, were used to assess: correlation between baseline tumor and cfDNA BRAF muts; correlation between baseline cfDNA levels and tumor burden (i.e., the sum of target lesion diameters); and efficacy based on baseline cfDNA BRAF mut status. Methods: BRAF mut status was established for 322 pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 305/322 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using BEAMing technology. Spearman correlation coefficients were used to determine the association between cfDNA fraction (mut DNA molecules > 0.01%) and baseline tumor burden. A Cox proportional hazards model was used to assess the association between cfDNA mut status and progression-free survival (PFS). Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 77%, and 96% respectively. V600E or V600K cfDNA mut fraction did not correlate with baseline tumor burden (R=0.38 and 0.23, respectively). Benefit of T vs C was observed regardless of cfDNA BRAF mut status (HR= 0.42, 0.41, 0.47 for V600E, V600K, and not detectable (cfDNA ND) subgroups). Interestingly, cfDNA ND pts had longer PFS vs cfDNA V600E/K pts, independent of treatment (HR=0.37 for cfDNA ND vs V600E/K, p=<0.0001). For T cfDNA ND median PFS was not reached (n=52), however the first quartile was 4.5 months; for V600E (n=127) and V600K (n=21) median PFS was 3.5 and 4.4 months, respectively. For C median PFS was 3.5, 1.4, and 1.5 months for cfDNA ND (n=28), V600E (n=69), and V600K (n=7), respectively. Similarly, higher response rates were seen in cfDNA ND pts vs cfDNA V600E/K pts across both treatment arms. Conclusions: Free circulating DNA can be used to detect BRAF V600 muts. cfDNA mut fraction was not linked to tumor burden. The absence of circulating BRAF mut DNA in BRAF V600 pts may be a marker of a better outcome. Clinical trial information: NCT01245062.