Clinical Validity of FoundationOne Liquid CDx for Detection of BRAFV600E in Colorectal Cancer.

Purpose: The BRAF inhibitor encorafenib (Enco) plus the anti-EGFR antibody cetuximab (Cetux) improved overall survival, objective response rate, and progression-free survival in previously treated BRAFV600E-mutant metastatic colorectal cancer in BEACON, a phase III randomized trial, leading to regulatory approval for this indication. To support rapid, plasma-based testing for BRAFV600E identification, clinical validity of a ctDNA-based assay, FoundationOneLiquid CDx (F1LCDx), was assessed against the reference tumor-based clinical trial assay (CTA) in liquid biopsy-evaluable samples from BEACON and commercially obtained tissue-matched plasma samples.

Patients And Methods: Pretreatment tissue samples were collected in BEACON to confirm BRAF mutational status using the central single gene PCR assay. Concordance between the CTA and liquid biopsy tests was assessed, and clinical validity of liquid biopsy testing was examined using clinical outcomes from BEACON.

Results: Of the 523 evaluable patients, 433 with matched tissue and plasma samples had CTA and F1LCDx results available (BEACON, n = 328; commercial, n = 105). A strong concordance in detecting BRAFV600E was found between F1LCDx and CTA, with a positive percent agreement of 87.2% and negative percent agreement of 97.1%. Among 42 F1LCDx-/CTA+ samples, 41 (97.6%) had ctDNA tumor fraction <1%. Among samples with ctDNA tumor fraction >1%, the positive percent agreement was 99.4% and negative percent agreement was 86.7%. Clinical outcomes with Enco plus Cetux were similar between those identified as F1LCDx+/CTA+ and CTA+ overall.

Conclusions: This study supports using liquid biopsies as a clinically valid assay for identifying BRAFV600E alterations in patients with metastatic colorectal cancer, particularly when ctDNA tumor fraction was >1%.

Significance: In the phase III BEACON trial, which established Enco plus Cetux as a standard of care for previously treated BRAFV600E-mutant metastatic colorectal cancer, mutational status was confirmed through testing of tumor tissue. To support rapid, less invasive testing for BRAFV600E in plasma, this retrospective study assessed a ctDNA-based assay and found strong concordance between the liquid biopsy test and the tumor-based assay in detecting BRAFV600E.