Integrated reflex molecular analysis to preserve clinically actionable targets in lung cancer regardless of specimen quality and panel coverage.

e20759 Background: Comprehensive molecular profiling is essential for precision treatment of lung cancer. However, in routine clinical practice, specimen-related limitations and restricted reportable gene lists may compromise detection of clinically actionable targets. We evaluated the clinical utility of an integrated reflex molecular analysis strategy based on extended re-analysis of next-generation sequencing (NGS) data in a real-world setting. Methods: We retrospectively reviewed consecutive lung cancer cases tested with ODxTT DNA/RNA NGS between 2021 and 2024. As part of institutional reflex molecular testing practice, concurrent single-gene assays included EGFR and KRAS RT-PCR (DNA-based) and ROS1 RT-PCR (RNA-based). All molecular assays were reported independently. ODxTT NGS data were routinely reviewed within the standard analytical environment and, in selected cases, underwent additional integrated molecular re-analysis of the same sequencing data to address specimen- or workflow-related limitations and/or to assess clinically important targets not included in the standard ODxTT reportable gene list. Clinically actionable alterations were identified through integrated pathologist review of all molecular test results generated for each case. Results: Among 465 lung cancer cases analyzed, additional integrated molecular re-analysis was performed in 33 cases (7.1%). Clinically actionable alterations were identified in 22 of these cases (66.7%), compared with 187 of 432 cases (43.3%) that did not require re-analysis (p = 0.0108). EGFR alterations remained a major actionable target, identified in 42.4% of cases undergoing re-analysis. Importantly, actionable alterations identified through extended re-analysis included clinically important targets not included in the standard ODxTT reportable gene list, such as ALK fusion events and NTRK family fusions, demonstrating preservation of clinically relevant targets despite specimen-related or reporting limitations. Conclusions: In a real-world clinical setting, integrated reflex molecular analysis incorporating extended re-analysis of NGS data within the standard analytical environment preserves clinically actionable targets despite suboptimal specimen quality and limited panel reporting. These findings support a pathologist-led, integrated molecular testing strategy to maximize therapeutic opportunities for patients with lung cancer.