Risk stratification of EGFR+ lung cancer diagnosed with panel-based next-generation sequencing

•EGFR variant, TP53 and brain status together predict survival in EGFR+ NSCLC (ENS).•Co-mutations beyond TP53 are rare and their clinical significance remains unclear.•The ENS is a practical and reproducible baseline risk stratification of EGFR+ NSCLC. Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1–2.3) and overall survival (OS HR 1.7–2.2), in combination defining patient subgroups with distinct outcome (EGFR+NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (