Evaluating Tumor Burden as a Predictive Biomarker for Epidermal Growth Factor Receptor Targeted Kinase Inhibitor Therapy in Advanced Non–Small Cell Lung Cancer

PURPOSE As treatment options for advanced non–small cell lung cancer (NSCLC) evolve, biomarkers are needed to guide therapy selection while balancing efficacy and toxicity. Although tumor burden is a promising candidate, its prognostic role in guiding epidermal growth factor receptor (EGFR)-targeted kinase inhibitor (TKI) therapies remains understudied in real-world settings. METHODS We identified patients with de novo stage IV EGFR -mutant NSCLC treated with first-line EGFR-TKI at Stanford Health Care (2000-2021). Tumor burden metrics were manually annotated from 592 baseline radiology reports, encompassing size, number, and location (1,807 lesions). Multivariable Cox regression evaluated associations between tumor burden metric and overall survival (OS), adjusting for confounders, in the overall cohort and an osimertinib subgroup. A weighted composite tumor burden score was constructed using statistically significant metrics to stratify risk. RESULTS Of 312 patients, bone metastasis (hazard ratio (HR) adjusted , 1.64 [95% CI, 1.23 to 2.19]) and the number of metastatic organs (HR adjusted , 1.21 [95% CI, 1.10 to 1.32]) were independently associated with worse OS and used to construct the composite score. Patients with low tumor burden (composite-score ≤ median 1.06) experienced better OS than those with high tumor burden, with a 3-year OS of 59.8% versus 41.5% ( P = .001). Consistent findings were observed in the osimertinib subgroup, with a 3-year OS of 62.2% versus 44.6% ( P = .03) for low versus high tumor burden. CONCLUSION Tumor burden may serve as a prognostic biomarker in advanced NSCLC receiving EGFR-TKIs. These findings raise the hypothesis that durable survival in low-burden patients may be achievable with monotherapy, potentially sparing unnecessary toxicity from combination regimens. This warrants prospective validation comparing monotherapy versus combination strategies.