Abstract 449: Use of comprehensive cell-free circuating tumor DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed advanced non-small cell lung cancer (NSCLC) patients
Authors: Palmero Ramon , Taus Alvaro , Viteri Santiago , Majem Margarita , Carcereny Enric , Garde Javier , Felip Enriqueta , Gomez Lourdes , Malfettone Andrea , Sampayo Miguel , López Noemí , Nagy Rebecca , Jackson Matthew , Faull Iris , Dix Daniel , Karachaliou Niki , Rosell Rafael 
Published: August 2019

Abstract
Background: In advanced NSCLC pts, current guidelines recommend broad molecular profiling for the following genes EGFR, ALK, ROS1, RET, MET, ERBB2, BRAF and KRAS. Tissue may be used for genomic testing in newly diagnosed advanced NSCLC but comprehensive plasma-based genotyping is less invasive and may provide a quicker and more complete assessment. The present study was conducted to prospectively assess performance of cfDNA compared to standard of care (SOC) tissue-based genomic testing to identify guideline recommended alterations in NSCLC pts.
Methods: In this prospective, multicenter study, blood samples from treatment-naïve stage IIIB-IV NSCLC pts were tested using the Guardant360 next-generation sequencing (NGS) cfDNA panel and compared with SOC tissue testing. The primary objective was to demonstrate the non-inferiority of cfDNA vs tissue analysis for the detection of guideline-recommended biomarkers (not including KRAS) in NSCLC (NI margin = 10%). The rate of incomplete tissue genotyping was defined as the proportion of pts who were biomarker negative in tissue but incompletely genotyped for all 8 guideline-referenced biomarkers. Exploratory analyses included estimation of positive predictive value (PPV) of cfDNA against tissue genotyping and the biomarker discovery rate in tissue testing alone vs tissue plus cfDNA testing.
Results: 199 metastatic NSCLC pts were enrolled between August 2016-June 2017, and 185 were included in this interim analysis. The primary objective of non-inferiority was met, with 47 actionable mutations identified by cfDNA vs. 48 by tissue (p&lt;0.002). Tissue testing was incomplete in 117/185 (63.2%, 95%CI = 55.9%, 70.2%) of pts. The majority (70%) of biomarker negative pts had tissue genotyping for 2 or fewer of the recommended biomarkers (most commonly EGFR and ALK). The PPV of cfDNA for EGFR, ALK, and MET alterations was 96.6% (95%CI = 82.2%, 99.9%). The addition of cfDNA increased the biomarker detection rate by 35.4% (95%CI= 22.2, 50.1), including those who were negative (1), not assessed (13), or quantity not sufficient (QNS) (3) for the biomarker in tissue.
Conclusions: This prospective, multi-center study demonstrates that a comprehensive and highly sensitive cfDNA NGS assay is non-inferior to SOC tissue testing in the detection of guideline-recommended actionable genomic alterations in NSCLC. Moreover, the addition of cfDNA to testing algorithms at the time of diagnosis markedly improved the biomarker detection rate in tissue negative/non-assessable pts. The PPV of the cfDNA assay utilized was high, supporting the use of cfDNA in treatment selection. These results demonstrate the clinical utility of comprehensive cfDNA genotyping to identify all guideline-recommended biomarkers in newly diagnosed advanced NSCLC pts.
Citation Format: Ramon Palmero, Alvaro Taus, Santiago Viteri, Margarita Majem, Enric Carcereny, Javier Garde, Enriqueta Felip, Lourdes Gomez, Andrea Malfettone, Miguel Sampayo, Noemí López, Rebecca Nagy, Matthew Jackson, Iris Faull, Daniel Dix, Niki Karachaliou, Rafael Rosell. Use of comprehensive cell-free circuating tumor DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed advanced non-small cell lung cancer (NSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 449.