Characterization and Clinical Utility of BRAF(V600) Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma

SIMPLE SUMMARY: The choice of cancer drug(s) for the treatment of advanced melanoma is based on the types of gene alterations that are present in the patient’s tumor(s). Sometimes, the tumor sample that is obtained from surgery may be degraded, and the test does not provide a reliable result, leading to the selection of the wrong treatment, and, consequently, poor outcomes for the patient. Surgery to obtain fresh tumor samples is inconvenient. In recent years, scientists have learned that fragments of genes from dying cells, including tumors, are constantly being released into the blood. This study shows that the presence of altered genes can be reliably determined using easy-to-obtain blood samples. The study also shows that, while there is a small rate of error with the commonly used tests based on the tumor tissue sample, retests using blood samples may be a less invasive and rapid alternative for identifying the BRAF mutation status and selecting the right treatment for these patients. ABSTRACT: Tissue-based tests for BRAF(V600) mutation-positive melanoma involve invasive biopsy procedures, and can lead to an erroneous diagnosis when the tumor samples degrade. Herein, we explored a minimally invasive, cell-free deoxyribonucleic acid (cfDNA)-based platform, to retest patients for BRAF(V600) mutations. This phase 2 study enrolled adult patients with unresectable/metastatic melanoma. A prescreening testing phase evaluated the concordance between a prior tissue-based BRAF(V600) mutation test result and a subsequent plasma cfDNA-based test result. A treatment phase evaluated the patients who were confirmed as BRAF(V600) mutation-positive, and were treated with cobimetinib plus vemurafenib. It was found that 35/54 patients (64.8%) with a mutant BRAF status by prior tissue test had a positive BRAF(V600) mutation with the cfDNA test. Further, 7/118 patients (5.9%) with a wild-type BRAF status had a positive BRAF(V600) mutation cfDNA test; tissue retests on archival samples confirmed BRAF(V600) mutation positivity in 5/7 patients (71.4%). One of these patients received BRAF pathway-targeted therapy (cobimetinib plus vemurafenib), and had progression-free survival commensurate with previous experience. In the overall cobimetinib plus vemurafenib-treated population, 29/36 patients (80.6%) had an objective response. The median progression-free survival was 13.6 months (95% confidence interval, 9.5–16.5). Cell-free DNA–based tests may be a fast and convenient option to identify BRAF mutation status in melanoma patients, and help inform treatment decisions.