Sekwencjonowanie nowej generacji wolnego DNA (cfDNA) z krwi obwodowej może poprawić diagnostykę chorych na zaawansowanego niedrobnokomórkowego raka płuca, a także stać się metodą szybszą i tańszą od obecnych standardów – Natasha B. Leighl, IASLC 2020 Lung Cancer Hot Topic: Liquid Biopsy Virtual Conference (Abstract VP01.22).

Background: Next-generation sequencing (NGS) of cell-free DNA (cfDNA) obtained from blood samples may improve diagnostic testing in patients with advanced NSCLC, with faster turnaround time (TAT) and potential cost savings compared to standard tissue profiling. We examined the clinical utility and treatment outcomes with liquid biopsy in patients with advanced NSCLC from the perspective of the Canadian public healthcare system.

Methods: Patients with advanced non-squamous NSCLC at 6 cancer centres across Canada (BC, Alberta, Ontario, Quebec) were recruited (NCT03576937). Cohort 1 (N=150) included treatment naïve patients with measurable disease and ≤10 pack year smoking history. Cohort 2 (N=60) included patients with known oncogenic drivers that progressed on tyrosine kinase inhibitors (TKIs). Patients progressing on EGFR kinase inhibitors were required to have documented absence of EGFR T790M or to have failed prior osimertinib. Consenting patients had a peripheral blood draw and cfDNA NGS analysis using Guardant360TM (G360, Guardant Health), a validated assay that detects alterations in 74 cancer- associated genes, prior to starting initial treatment (Cohort 1) or next line of therapy (Cohort 2). Standard of care tissue profiling was performed per institutional standards. Pre-specified study endpoints include the number of actionable genomic alterations identified through G360 (EGFR, ALK, BRAF, ERBB2, KRAS G12C, MET amplification/exon 14 skipping, RET, ROS1, NTRK1), result TAT, time-to-treatment initiation, objective response rate, progression-free survival and patient-reported quality of life (EQ-5D).

Results: Between February 2019 and July 15, 2020, 148 patients (98 female, 51 male) were accrued to Cohort 1 and 60 (40 female, 20 male) to Cohort 2 with G360 results. After excluding variants of unknown significance and synonymous alterations, 117 patients in Cohort 1 (79%) had ≥1 alteration detected by G360 (301 alterations detected in 35 genes). Of these, 281 alterations were considered actionable with FDA-approved drugs and/or available clinical trials. Actionable targets included EGFR (31.7%), ERBB2 (3.2%), MET (3.2%), ALK (1.4%), KRAS G12C (1.1%), and ROS1 (0.4%), total 41%. Additional clinically relevant alterations included TP53 (27.8%), KRAS non-G12C (3.9%), PIK3CA (3.9%) and BRAF nonV600E (1.1%). In Cohort 2, 53 patients (85%) had ≥1 alteration detected, with a total of 165 alterations in 28 genes including EGFR (45.8%, 5 were C797S), ALK (fusions 3.3%; mutations 2.0%), BRAF (V600E 0.7%; other 3.3%), MET (amplification 2.0%; exon 14 0.7%), FGFR3 (0.7%) and RET (0.7%) as well as non-driver mutations. Twenty-six patients (13.5% in Cohort 1; 10% in Cohort 2) had no alterations detected by G360. In samples with alterations detected, the median number of alterations per patient was 3 (range 1-17). The median time to reporting of G360 was 7 days (range 5-27). Time to treatment initiation, turnaround time and differences between actionable results in liquid versus tissue biopsy will be presented.

Conclusion: Over 87% of advanced NSCLC patients had detectable cfDNA results, and 115 had actionable mutations identified by G360. Liquid biopsy is an important and timely method of molecular diagnosis in newly diagnosed patients with advanced NSCLC and in the setting of targeted therapy resistance.