Pan-tumor analytical validation and osimertinib clinical validation in EGFR mutant non-small cell lung cancer, supporting the first next generation sequencing liquid biopsy in vitro diagnostic.

Comprehensive genotyping is necessary to identify therapy options for patients with advanced cancer; however, many are not tested, partly due to tissue limitations. Next generation sequencing (NGS) liquid biopsies overcome limitations but clinical validity is not established and adoption, limited. Clinical bridging studies used pre-treatment plasma samples and data from FLAURA (NCT02296125; n=441) and AURA3 (NCT02151981; n=450) pivotal studies to demonstrate clinical validity of Guardant360 CDx (NGS LBx) to identify patients with advanced EGFR mutant NSCLC who may benefit from osimertinib. Primary endpoint was progression-free survival (PFS). Patients EGFR mutant by NGS LBx had significant PFS benefit with first-line osimertinib over standard of care (15.2 vs 9.6 months, HR 0.41, p<0.0001) and with later-line osimertinib over chemotherapy (8.3 vs 4.2 months, HR 0.34, p<0.0001). PFS benefit were similar to the original trial cohorts selected by tissue-based EGFR testing. Analytical validation included accuracy, precision, limit of detection (LOD), and specificity. Analytical validity was established for EGFR mutation detection and pan-tumor profiling. Panel-wide LOD was 0.1%-0.5%, with 98-100% per-sample specificity. Patients with EGFR mutant NSCLC by NGS LBx had improved PFS with osimertinib, confirming clinical validity. Analytical validity was established for guideline-recommended therapeutic targets across solid tumors. The resulting FDA-approval of NGS LBx demonstrates safety and effectiveness for its intended use and is expected to improve adherence to guideline-recommended targeted therapy use.

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