BackgroundBRAF V600 mutations occur in 40-50% of metastatic melanomas as the most common "oncogenetic driver" event. Currently, BRAF V600 mutation status is assessed on tumor tissue to identify patients eligible for treatment with a BRAF+/-MEK inhibitor. The goal of this study is to estimate the frequency of the BRAF V600 mutation in a new tumor tissue analysis triggered by a mutant plasma test result, for patients with BRAF wild-type status based on a prior tissue test. MethodsThis is a single arm, multicenter, open label, non-randomized Phase II clinical study in adult patients with unresectable/metastatic melanoma. Patients were tested for the presence of BRAF V600 mutation using the IdyllaTM diagnostic platform on plasma cfDNA. In patients with a prior tissue BRAF V600 wild-type result, a mutant BRAF V600 plasma result triggered a new tissue analysis. The study had a power of 90% to reject the null hypothesis of a 3% probability of identifying the BRAFV600 mutation in case the real probability is 10%. Results172 patients with known tissue test results were included (9.3% unresectable Stage IIIc and 90.7% Stage IV). The median time since diagnosis of metastatic melanoma was 19.3 (range: 0–268)) months. In 7 out of 118 patients (5.9%), previously determined as wild type BRAF V600 based on a tumor tissue test, a BRAF V600 mutation was found upon plasma cfDNA testing. In 5 of these 7 patients, presence of a BRAF V600 mutation could be confirmed in the tissue re-test. For 4.2% (5/118) the mutation could be shown in a re-test triggered by the mutant plasma cfDNA result. The one-sided test comparing this frequency with the a priori hypothesis of 3% was not significant (p=0.215). ConclusionsIn 4.2% of the patients a known BRAF V600 wild-type status could be converted in a positive mutant status by retesting tumor tissue triggered by detection of a BRAF V600 mutation in cfDNA. Some patients could therefore benefit from plasma testing at the time of therapeutic decision making, although their number was not significantly more than the a priori required 3%. Identifying a BRAFwt subpopulation with the highest chance of having a BRAF V600mut cfDNA test result at the time of treatment decision making deserves further study. Clinical trial identificationNCT02768207. Legal entity responsible for the studyRoche. FundingRoche. DisclosureP. Rutkowski: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy: Blueprint Medicines; Speaker Bureau / Expert testimony: Eli Lilly. B. Jacobs: Full / Part-time employment: Biocartis. G.G. Maertens: Full / Part-time employment: Biocartis. V. Gadeyne: Full / Part-time employment: Roche. S. Liebert: Full / Part-time employment: Roche. B. Neyns: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (institution): Merck Srono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (institution): Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.