Abstract 1310: Serial plasma comprehensive genomic profiling detects therapy resistance and guides management of metastatic non-small cell lung cancer.

Abstract Introduction: Although plasma comprehensive genomic profiling (pCGP) shows significant potential as a minimally invasive alternative to tissue genotyping in non-small cell lung cancer (NSCLC), its precise clinical utility remains insufficiently studied. To bridge this gap, we conducted a single-center retrospective study of 718 patients with NSCLC who had undergone pCGP in our institution from 2015 through 2022. Methods: Integrated clinical and genomic data were extracted from the Precision Medicine Analytics Platform as part of a standard workflow of the Johns Hopkins Lung Cancer Precision Medicine Center of Excellence. Fixed gene panel hybrid capture next-generation sequencing (Guardant 360, n = 572 samples and Guardant 360CDx, n = 246 samples) data were retrieved, followed by variant characterization and annotation by an ensemble approach. Results: Across 718 patients with 818 instances of pCGP, including 79 (11%) patients with serial pCGP, liquid biopsies uniquely informed management in 92 (13%) patients. This primarily occurred when tissue testing was not possible (44%), although pCGP also contributed to clinical decision-making as an adjunct to tissue testing, by improving turnaround time, and by detecting plasma-only mutations. In a subset analysis of first instance of pCGP obtained at the time of diagnosis (n = 427), patients with undetectable ctDNA had significantly prolonged overall survival (OS) (log rank p 0.0001), with similar results when patients were classified as ctDNA undetectable, 1-2 mutations, or 3 or more detected mutations (log rank p 0.0001). Importantly, receipt of genotype-matched therapy informed by pCGP was associated with a significant improvement in OS (log rank p 0.0001). Focusing on 214 patients with EGFR mutant (EGFRm) NSCLC, pCGP uniquely guided patient management in 28% of cases, benefiting both newly diagnosed patients and those on their second or third iteration of genotyping. Among patients progressing on EGFR tyrosine kinase inhibitors (TKI), 31 (22%) had actionable pCGP findings, of whom 18 (58%) were matched to targeted therapy. pCGP captured differential on-target and off-target resistance genomic alterations based on TKI line of therapy and type of TKI (first or second generation vs. third generation). Mutations in PIK3CA most commonly emerged after first-line therapy with third generation TKI, while mutations in the RAS pathway were more frequently detected after third-line therapy, highlighting differential activation of resistance pathways. Conclusions: Serial pCGP captures actionable genomic alterations and the emergence of drivers of therapy resistance, enabling longitudinal care and timely, effective interventions for patients with NSCLC. Citation Format: William Bowers, Michael Conroy, Jaime Wehr, Vivian V. Altiery De Jesus, Archana Balan, Susan Scott, Benjamin Levy, Kristen A. Marrone, Vincent K. Lam, Josephine Feliciano, Christine Hann, Aliyah Pabani, Jarushka Naidoo, Julie R. Brahmer, Patrick M. Forde, Joseph C. Murray, Valsamo (Elsa) Anagnostou. Serial plasma comprehensive genomic profiling detects therapy resistance and guides management of metastatic non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1310.