Clinical utility of repeat next-generation sequencing in patients with driver-negative non-small cell lung cancer: A report from the LC-SCRUM-TRY screening platform.

8626 Background: While precision medicine targeting driver oncogenes has improved clinical outcome of non-small cell lung cancer (NSCLC), the clinical utility of repeat or late-line multiplex genomic profiling remains unclear for patients whose tumors were initially identified as driver-negative. We evaluated the clinical impact of genomic screening for treatment-resistant NSCLC within the nationwide framework (LC-SCRUM-TRY). Methods: Between September 2020 and November 2025, a total of 2,088 patients with NSCLC were enrolled into LC-SCRUM-TRY. Of these, this analysis focused on 840 patients who were diagnosed as driver-negative at the time of enrollment. Genomic profiling was performed using Oncomine Precision Assay (ThermoFisher Scientific) for tumor tissue sample, or liquid biopsy (Guardant360 Guardant Health or liquid OPA). We compared overall survival (OS) among three groups: (A) Driver-negative, (B) Driver-positive without targeted therapy, and (C) Driver-positive with subsequent corresponding targeted therapy. Results: Among the 840 patients, median age at enrollment was 68 years (range 34-86); the majority were male (70%), ever-smokers (79%), and had adenocarcinoma (74%), with good ECOG-PS of 0-1 (91%). Of these, 89% underwent tissue-based NGS using OPA, while 11% underwent liquid biopsy. Actionable driver alterations were identified in 186 patients (22%), without significant difference between tissue- and liquid-based NGS. The detected drivers included EGFR mutation (mut) (n = 60), HER2 mut (n = 33), KRAS G12C mut (n = 31), BRAF V600E mut (n = 7), MET exon 14 skipping (n = 17), RET fusion (fus) (n = 17), ALK fus (n = 9), ROS1 fus (n = 7), and NRG1 fus (n = 5). Of the 186 patients with detected drivers, 74 patients (40%) received subsequent matched targeted therapies (Group C), including 13 patients enrolled in clinical trials. The median OS was 36.2 months in Group A, 34.1 months in Group B, and 70.2 months in Group C, respectively. Patients who received matched targeted therapies (Group C) had significantly longer OS compared to Groups A and B (p < 0.0001). Conclusions: Multiplex genomic profiling effectively identified actionable driver oncogenes in 22% of NSCLC patients previously considered driver-negative. Access to matched targeted therapies based on these results more than doubled the median OS (70.2 vs. 34.1 months), highlighting the critical importance of a multiplex genomic re-screening approach in this population. Clinical trial information: UMIN000041957.