Standard targeted therapy implementation for driver alterations newly identified by comprehensive genomic profiling in clinically driver-negative advanced NSCLC.

BACKGROUND: Comprehensive genomic profiling (CGP) can identify oncogenic drivers missed by routine molecular testing in advanced or recurrent non-small cell lung cancer (NSCLC). However, the availability of standard targeted therapy, treatment implementation, and survival relevance of these CGP-identified new drivers remain unclear. METHODS: Using the nationwide Center for Cancer Genomics and Advanced Therapeutics database, we analyzed patients with advanced or recurrent NSCLC without clinically known driver alterations before CGP. CGP-identified new drivers were classified as actionable or non-actionable according to standard targeted therapy availability in Japan. We evaluated prevalence, treatment implementation, and overall survival (OS) from CGP registration. RESULTS: Among 2,296 patients, 855 had CGP-identified new drivers, of whom 495 (57.9%) had actionable alterations. Matched targeted therapy was administered to 191 patients with actionable alterations (38.6%) and to 84.5% of those with documented post-CGP systemic therapy. Median OS was longest in patients with actionable CGP-identified new drivers, followed by driver-negative patients and those with non-actionable CGP-identified new drivers (18.9, 11.4, and 10.2 months, respectively; log-rank P < 0.001). In multivariable analysis, actionable CGP-identified new drivers were associated with longer OS than driver-negative status (adjusted hazard ratio, 0.71; 95% confidence interval, 0.59-0.84; P < 0.001), whereas non-actionable new drivers were not. Sensitivity analyses using time-specific drug-availability definitions yielded consistent findings. CONCLUSIONS: CGP identified new drivers with available standard targeted therapy in patients with advanced or recurrent NSCLC. The clinical relevance of CGP-identified new driver detection appears linked to standard targeted therapy availability and translation of actionable findings into matched therapy.