The Waiting Game: How NGS and Guideline-Concordant-Care Timing Shape Survival in Advanced NSCLC

Background: Next-generation sequencing (NGS) and the initiation of biomarker-driven first-line (1L) treatment on overall survival (OS) was evaluated in advanced/metastatic non-small-cell lung cancer (a/mNSCLC). By applying a time-dependent regression modeling approach accounting for fluidity of clinical care, this study aimed to capture the dynamic interplay between NGS testing, turnaround time (TaT), treatment decisions and timing of initiation, and outcomes more comprehensively than traditional static analyses. Methods: This study was a retrospective observational study using the US Flatiron Health EHR-derived de-identified database. Eligible adults had non-squamous a/mNSCLC and received blood-based (B-NGS) or tissue-based (T-NGS) NGS within 90 days of diagnosis (1 January 2018–30 June 2023). A time-dependent covariate captured the NGS TaT, presence of a targetable alteration, time to 1L initiation, and 1L regimen (targeted concordant vs. discordant). OS was measured from the NGS order date to death. Results: A total of 1806 patients underwent B-NGS and 2583 underwent T-NGS. Starting empiric discordant 1L therapy before NGS results was associated with higher mortality versus initiating targeted concordant therapy after biomarker identification: B-NGS hazard ratio (HR): 1.58 (95% CI, 1.10–2.26); T-NGS HR: 1.07 (0.82–1.39). Considering discordant 1L therapy irrespective of timing, mortality remained higher versus targeted concordant therapy: B-NGS HR: 1.35 (1.04–1.74); T-NGS HR: 1.24 (0.98–1.56). Conclusions: This study demonstrates that waiting for comprehensive molecular profiling results before starting 1L treatment enables the delivery of appropriate biomarker-driven therapy, which translates into improved patient outcomes. Delays in NGS result availability or treatment initiation were linked to worse survival, underscoring the need for streamlined diagnostic workflows and rapid testing modalities.