Circulating tumor DNA analysis in patients with BRAF-mutated metastatic cutaneous melanoma treated with BRAF and MEK inhibitors: Analysis of the OPTIMEL study.
Authors: Harle Alexandre , Lhuillier Albane Marie , Sahki Nassim , Granel Brocard Florence , Schoeffler Amélie , Martin Hélène , Muller Philippe , Hervieu Alice , Rouyer Marie , Husson Marie , Bechet Denise , Lefebvre Magali , Scala Bertola Julien , Gambier Nicolas , Kolodziej Allan , Merlin Jean-Louis , Geoffrois Lionnel 
Published: July 2024

9541 Background: BRAF and MEK kinase inhibitors (KI) are indicated in combination for the treatment of adult patients with unresectable or metastatic melanoma (MM) harboring a BRAF V600 mutation. However, approximately half of the patients develop resistance to the treatment within a year. Circulating tumor DNA (ctDNA) has demonstrated its prognostic value for MM patients receiving specific treatment, offering potential assistance in patient follow-up. We present here the results of the prospective interventional study OPTIMEL (NCT03416933) that was conducted to investigate the relevance of ctDNA in predicting outcomes for MM patients undergoing BRAF and MEK inhibitors treatment. Methods: Thirty-five patients with histologically proven advanced cutaneous MM harboring BRAF mutations, either in a metastatic stage or cases ineligible for surgical intervention were enrolled in the study. All participants underwent treatment with BRAF and MEK inhibitors. Blood samples were systematically obtained on days 0, 15, 30, 90, 180, 270, and 365, or at the occurrence of disease progression. The assessment of mutations in the BRAF and NRAS genes in all plasma samples was conducted using the Idylla system (Biocartis, Mechelen, Belgium). Results: Out of the 35 patients initially enrolled in the study, 4 were excluded for not meeting the inclusion criteria, leaving 31 patients for the final analysis. At baseline, BRAF mutation was identified in 18 patients (58%), while it was not detected in 13 patients (42%). The presence of BRAF mutation at baseline was associated with a significantly lower progression-free survival (PFS) (HR = 3.42; CI95% [1.19;9.82]; p = 0.022). During the follow-up, BRAF mutation was detected in the plasma of 19 out of 31 patients. A BRAF variant allele frequency (vaf) below 2.3% was strongly linked to an objective response to treatment (p<0.001). The absence of BRAF variant detection during follow-up was significantly associated with better outcome (PFS 4.01 vs 12.0 months, HR = 28.5; CI95% [7.75;105.0]; p < 0.001). Moreover, PFS significantly deteriorated when BRAF vaf exceeded 4.5% (3.15 vs 12.0 months, HR = 112; CI95% [13.8;913.0]; p < 0.001). Lastly, the identification of NRAS mutation in plasma during follow-up was linked to treatment resistance and a worsened PFS (4.84 vs 10.9 months, HR = 11.6; CI95% [2.76;48.5]; p<0.001). Conclusions: This report presents the initial analysis of the OPTIMEL study. The variant allele frequency of BRAF mutations in circulating tumor DNA is indicative of the objective response to BRAF and MEK inhibitors, as well as PFS. These findings could potentially influence our approach to managing patients with MM harboring a BRAF mutation. Clinical trial information: NCT03416933 .