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COMPLETED RESEARCH: CLINICAL/TRANSLATIONAL RESEARCH
Abstract #CT03

Correlation of BRAF Mutation Status in Circulating Tumor DNA with Tumor Biopsy and Clinical Outcomes in the COLUMBUS Study

JHOP - March 2021 Vol 11 Special Feature - HOPA Abstracts, Biomarkers, Clinical Trials, Targeted Therapies

Presenter: Caroline Robert, MD, Department of Medicine and Paris-Saclay University, Gustave Roussy

Co-Authors: Keith T. Flaherty, MD, Massachusetts General Hospital; Helen J. Gogas, MD, National and Kapodistrian University of Athens, Laikon Hospital; Ana Arance, MD, PhD, Hospital Clinic of Barcelona; Mario Mandalà, MD, Papa Giovanni XXIII Cancer Center Hospital; Gabriella Liszkay, MD, National Institute of Oncology; Claus Garbe, University Hospital Tuebingen; Dirk Schadendorf, University Hospital Essen; Ivana Krajsova, University Hospital Prague and Charles University First Medical Faculty; Ralf Gutzmer, Skin Cancer Center Hannover, Hannover Medical School; Jan Willem B. de Groot, MD, Isla Oncology Center; Caroline Dutriaux, MD, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André; Carmen Loquai, MD, University Medical Center Mainz; Allison Harney, PhD, Pfizer; Enko Kiprilov, MD, Pfizer; Michael D. Pickard, PhD, Pfizer; Jean Cantey-Kiser, PhD, PharPoint Research; Reinhard Dummer, MD, University Hospital Zürich Skin Cancer Center and University of Zürich; Paolo A. Ascierto, MD, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale

Background: Circulating tumor DNA (ctDNA) testing offers a less invasive alternative to tissue biopsy for identifying patients with advanced melanoma and BRAF mutation who are candidates for targeted therapy, and may have prognostic value.

Objectives: To assess the concordance between ctDNA and BRAF mutation in tumor tissue status, and the clinical relevance of ctDNA BRAF mutation status, using data from the COLUMBUS trial.

Methods: In the COLUMBUS study,1 part 1, a total of 577 patients with advanced or metastatic melanoma and BRAF V600 mutation who had not received treatment or whose disease progressed after first-line immunotherapy, were randomized in a 1:1:1 ratio to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily, or to vemurafenib 960 mg twice daily. A total of 613 plasma samples were collected during screening. BRAF V600E/K mutations in ctDNA were assessed using BEAMing technology, and concordance of BRAF status between baseline ctDNA and tissue biopsy was assessed. The associations of ctDNA BRAF V600E/K mutation status (yes/no) with baseline markers of poor prognosis and centrally confirmed overall response rates (ORRs) were analyzed. The data are as-is and the trial is ongoing.

Results: In total, 502 patients had results for ctDNA and for tissue BRAF V600E/K assessments. Of these patients, 317 (63%) had BRAF V600E/K mutations detected by ctDNA, and 420 (84%) had BRAF V600E/K mutations detected by tissue. The overall agreement (positive agreement; negative agreement) of ctDNA versus tumor tissue was 78% (75%; 96%) for BRAF V600E/K mutations, 81% (75%; 99%) for BRAF V600E mutations, and 97% (70%; 99%) for BRAF V600K mutations. BRAF V600E/K mutations detectable by ctDNA were associated with higher lactate dehydrogenase levels, more organs with disease, and greater tumor burden at baseline (unadjusted Wilcoxon 2-sample, P <.0001 for each). Within each treatment arm, no notable ORR differences were seen between ctDNA BRAF mutation status. For patients with ctDNA BRAF V600E/K mutations, the ORR was 69.3% (95% confidence interval [CI], 57.6-79.5) with encorafenib and binimetinib, 57.5% (95% CI, 45.9-68.5) with encorafenib, and 42.3% (95% CI, 31.2-54.0) with vemurafenib. For patients without ctDNA BRAF V600E/K mutation, the ORR was 53.3% (95% CI, 34.3-71.7) with encorafenib and binimetinib, 60.0% (95% CI, 38.7-78.9) with encorafenib, and 40.7% (95% CI, 22.4-61.2) with vemurafenib.

Conclusion: These findings confirm the reliability of ctDNA for detecting BRAF mutations; ctDNA may serve as an alternative test for detecting BRAF V600E/K mutations. The ctDNA BRAF mutations correlated with baseline markers of poor prognosis but not with the ORR.

  1. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19:603-615.
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