Optimal timing of thoracic radiotherapy with osimertinib in unresectable EGFR-mutant non-small cell lung cancer

Abstract

Osimertinib is standard first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, the optimal timing of combined thoracic radiotherapy (TRT) remains unclear. The aim of the present study was to investigate the relationship between the interval from osimertinib treatment to TRT interval and the survival outcomes, defining an optimal therapeutic window for unresectable EGFR-mutant NSCLC. Data from 175 patients with stage IIIB/IV EGFR-mutant NSCLC receiving first-line osimertinib and consolidation TRT were retrospectively analyzed. Cox regression and restricted cubic spline (RCS) models, inverse probability of treatment weighting, and left-truncated and landmark analyses were performed. At a median follow-up time of 25.3 months, each 1-day delay in the osimertinib-to-TRT interval was identified as an independent adverse prognostic factor for locoregional progression-free survival [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.01–1.02; P<0.001], progression-free survival (HR, 1.01; 95% CI, 1.01–1.02; P<0.001), and overall survival (HR, 1.02; 95% CI, 1.01–1.02; P<0.001). The RCS model revealed a significant non-linear J-shaped association (non-linear P<0.05), with risk peaking between 40 and 102 days. All sensitivity analyses, including inverse probability of treatment weighting, left-truncated immortal time bias adjustment, 3/6/12-month landmark analyses, and osimertinib response adjustment, yielded consistent effect estimates. These findings indicate that the interval between osimertinib and TRT initiation is an independent prognostic factor for EGFR-mutant NSCLC, with a non-linear J-shaped association with survival. TRT initiation within 40 days of osimertinib commencement confers optimal benefit, providing evidence-based guidance for clinical treatment decision-making.