Clinical implications of plasma EGFR T790M and ctDNA shedding across metastatic sites in plasma- or tissue-confirmed EGFR-mutant non-small cell lung cancer treated with lazertinib: a prospective multicenter cohort study

Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve outcomes in EGFR T790M-positive non-small cell lung cancer (NSCLC), but the prognostic value of plasma-detected T790M remains uncertain. We evaluated the clinical significance of baseline plasma T790M in patients treated with lazertinib, accounting for metastatic distribution and coexisting genomic alterations. Methods: In this prospective multicenter cohort, we analyzed 117 patients with EGFR-mutant NSCLC who received lazertinib after T790M confirmation in tissue or plasma. Plasma EGFR mutations were profiled using next-generation sequencing before treatment. Progression-free survival (PFS) and overall survival (OS) were compared by plasma T790M status, metastatic sites, and co-alterations. Results: Of 117 patients, 92 were plasma T790M-positive and 25 were plasma T790M-negative. Plasma T790M positivity was associated with shorter PFS (10.0 vs. 23.0 months, P=0.03) and OS (20.0 months vs. not reached, P=0.006). All patients with liver or adrenal metastases were plasma T790M-positive, and involvement of either site predicted poorer outcomes than in patients without these metastases. Bone metastasis also portended a worse prognosis, irrespective of plasma T790M status. Among co-alterations, EGFR C797S or MYC alterations correlated with shorter PFS. Conclusions: Baseline plasma T790M, interpreted alongside metastatic distribution, provided prognostic information in EGFR-mutant NSCLC treated with lazertinib. Liver and adrenal metastases occurred exclusively in plasma T790M-positive patients and were associated with markedly worse outcomes, consistent with a ctDNA-shedding phenotype. Bone metastasis was an adverse prognostic factor independent of plasma T790M, underscoring the combined prognostic impact of molecular and metastatic features.