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.
- 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.