Serial Plasma Comprehensive Genomic Profiling Captures Therapy Resistance and Guides Management of Non-Small Cell Lung Cancer

Abstract Plasma comprehensive genomic profiling (pCGP) is implemented in the clinical care of NSCLC. Although less well-documented, serial pCGP may also guide management of oncogene-driven NSCLC after first progression. Here, we assessed the clinical value of serial pCGP, focusing on EGFR-mutant NSCLC. We conducted a retrospective study of 718 patients with NSCLC who underwent pCGP between 2015 and 2022. Clinical-genomic data were programmatically extracted from the data workflows of the Johns Hopkins Lung Cancer Precision Medicine Center of Excellence. After variant annotation and actionability characterization, we examined the prevalence and evolving co-mutation patterns across serial pCGP, focusing on genomic mechanisms of TKI-acquired resistance in EGFR-mutant NSCLC. 718 patients had 818 instances of pCGP, with 79 patients having longitudinal pCGP (range 2-5). pCGP uniquely informed management in 13% of patients (n=92), both at initial diagnosis and on serial genotyping. This occurred predominantly through identification of actionable mutations when tissue testing was unavailable. Among 214 patients with EGFR-mutant NSCLC, pCGP identified PI3K pathway alterations in 11% after first-line therapy. BRAF V600E (3%) and MET exon 14 skipping mutations (3%) emerged after 3rd-generation TKI therapy. After TKI progression, 31 patients (22%) with EGFR-mutant disease had actionable pCGP findings, of whom 18 (58%) were matched to targeted therapy. Serial pCGP can inform treatment decisions in patients with NSCLC. In those with EGFR-mutant disease, pCGP at progression identifies actionable drivers of therapy resistance, enabling therapeutic intervention.