Comprehensive Genomic Profiling Beyond Driver Testing in Non‐Squamous Non‐Small Cell Lung Cancer With Known Drivers

ABSTRACT In advanced non‐squamous non‐small cell lung cancer (non‐sq NSCLC), companion diagnostic testing (CDx) identifies actionable driver alterations and guides initial targeted therapy. However, disease progression inevitably occurs through acquired resistance, including activation of bypass signaling pathways. Although comprehensive genomic profiling (CGP) can identify emerging resistance alterations, its clinical utility in patients with known actionable driver alterations remains unclear. We retrospectively analyzed 227 patients who underwent CGP between June 2019 and August 2025. Patients with actionable driver alterations identified by CDx before CGP formed the known driver group. We also analyzed the nationwide C‐CAT registry to assess registry‐recorded therapeutic implementation. Among 227 patients, 74 (32.6%) had known actionable driver alterations. CGP identified additional clinically relevant genomic findings, including ESCAT Tier I–III or V alterations, in 34 patients (45.9%), comparable to that in patients without known actionable driver alterations (77/153, 50.3%). In the EGFR ‐mutated ( EGFR m) subgroup, CGP frequently identified alterations consistent with potential bypass resistance mechanisms, including MET amplification, RET fusions, and BRAF V600E mutations. Overall, 10 patients (13.5%) received CGP‐guided therapy based on additional findings, all within the EGFR m subgroup, whereas no patients with non‐ EGFR driver alterations did. In the C‐CAT registry, CGP‐associated therapy was documented in 21 of 381 (5.5%) in the EGFR m subgroup, 6 of 155 (3.9%) in the non‐ EGFR driver subgroup, and 195 of 2132 (9.1%) without registry‐defined driver alterations. These findings indicate that CGP provides molecular re‐evaluation during disease progression, particularly by identifying alterations consistent with potentially actionable resistance or bypass mechanisms in EGFR m NSCLC.