Impact of concurrent liquid and tissue NGS in advanced NSCLC: Real-world insights from an Indian single-centre study.

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Background: Tissue NGS guides treatment in advanced NSCLC but is often limited by inadequate samples and delayed results. Upfront plasma cfDNA NGS may improve detection of actionable alterations and shorten time to therapy. We compared real-world clinical utility of upfront cfDNA versus routine tissue testing in advanced NSCLC (aNSCLC). Methods: In this real-world, single-center study, patients with aNSCLC underwent concurrent comprehensive genomic profiling using Guardant360 plasma cfDNA assay and Guardant360 tissue NGS between July 2022 and February 2026. The primary endpoint was detection of guideline-recommended Tier 1 actionable alterations by plasma NGS. Secondary analyses included concordance with matched tissue results, incremental diagnostic yield and turnaround time. Results: Among 76 patients, 73 (96%) yielded an informative cfDNA-NGS result. In the 35 patients who underwent paired tissue and plasma testing, Tier 1 actionable alterations were identified in 22 patients (63%). Importantly, plasma cfDNA-NGS uncovered 4 additional Tier 1 variants beyond tissue testing alone, resulting in a 23% relative increase in actionable detection (18 vs 22 patients). Median turnaround time was nearly two-fold shorter with plasma testing compared to tissue NGS (6 vs 11 days), enabling more rapid therapeutic decision-making. Matched targeted therapy was delivered to 19 of 22 patients (86%) with identified Tier 1 alterations. At a median follow-up of 549 days, median progression-free survival in the matched-treatment cohort was not reached, with 68% of patients remaining progression-free at the last observed timepoint reflecting durable clinical benefit associated with genomically guided therapy. Conclusions: In this real-world cohort of patients with advanced NSCLC, cfDNA-NGS enhanced detection of clinically actionable alterations with high concordance to tissue-based testing. Plasma testing identified additional targetable variants and significantly reduced turnaround time, enabling earlier treatment initiation without waiting for tissue genotyping results. These findings support concurrent plasma and tissue genomic profiling as a complementary and pragmatic approach to optimize precision oncology care in NSCLC.