As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne ® Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.

Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion‐positive (‐fp) solid tumours and ROS1‐fp non‐small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non‐invasive in vitro next‐generation sequencing (NGS)‐based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK‐fp or ROS1‐fp tumours and assessed the genomic landscape pre‐ and post‐entrectinib treatment. Among evaluable pre‐treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA+ F1L CDx+ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx+ and F1L CDx− samples in ROS1‐fp (5.6 vs. 17.3 months) but not NTRK‐fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue‐based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.

e13685 Background: As the availability of precision therapies expand, a well-validated blood-based comprehensive genomic profiling (CGP) assay has the potential to provide considerable value as a complement to tissue-based testing to ensure that potentially life-extending therapies are administered to the patients most likely to benefit. Comprehensive clinical and analytical validity data for blood-based assays are crucial to enabling physicians to understand the true performance of available testing options. Methods: The FoundationOne Liquid CDx assay is a blood-based CGP assay that has been validated for a Premarket Approval (PMA) submission to the Food and Drug Administration (FDA). Validation studies included > 9,000 tests and > 30,000 unique variants across > 300 genes and > 50 cancer types, allowing for a comprehensive assessment of performance. Results: The results of these extensive studies demonstrate a 95% limit of detection (LoD) of 0.40% variant allele fraction (VAF) for select short variants (subs and indels), 0.37% VAF for select rearrangements, 21.7% tumor fraction (TF) for select copy number amplifications, and 30.4% TF for copy number losses. LoD for complex biomarkers such as microsatellite instability (MSI) and blood tumor mutational burden (bTMB) were also determined. The limit of blank (LoB) was shown to be the ideal value of zero. Reproducibility of variant calling was determined to be 99.59% with two-sided exact CI of (99.58%, 99.60%). In comparison with an orthogonal method, an overall PPA (95% CI) of 96.3% (94.8, 97.4%) and NPA (95% CI) of > 99.9% (99.9%, 100.0%) was observed. Critically, clinical validity and concordance with tissue-based CGP results across multiple tumor types were also evaluated. Conclusions: The results of these studies demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations (short variants, rearrangements, and copy number alterations), as well as complex biomarkers, such as MSI, bTMB, and tumor fraction. These data demonstrate that the assay can identify genomic variants that may inform therapeutic decisions for cancer patients with any solid tumor using a single blood sample. Additionally, clinical validation results establish FoundationOne Liquid CDx as an additional tool for physicians in the therapeutic management of cancer patients.

No abstract

No abstract