Optimal timing of stereotactic radiosurgery with first-line osimertinib in EGFR-mutant non-small cell lung cancer brain metastases: Immediate, early-consolidation and salvage strategies.

The optimal timing for integrating stereotactic radiosurgery (SRS) with first-line osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC) with brain metastases (BMs) is undefined. The present study compared outcomes of three distinct SRS timing strategies. In the present dual-center retrospective study, patients with EGFR-mutant NSCLC and 1-10 BMs receiving first-line osimertinib were categorized into immediate SRS (≤4 weeks; n=62), early-consolidation SRS (4-12 weeks; n=62) and salvage SRS (>12 weeks upon progression; n=62). The primary endpoint was intracranial progression-free survival (iPFS). With a median follow-up of 43.5 months, median iPFS demonstrated a significant gradient: 27.0 (immediate), 22.5 (early-consolidation) and 15.7 months (salvage; overall P<0.001). Compared with salvage SRS, immediate SRS reduced the risk of intracranial progression/mortality by 71% [hazard ratio (HR) =0.292; 95% confidence interval (CI), 0.191-0.448; P<0.001] and early-consolidation SRS by 60% (HR=0.398; 95% CI, 0.268-0.592; P<0.001). Immediate SRS also outperformed early-consolidation SRS (HR=0.569; 95% CI, 0.391-0.827; P=0.001). Overall survival and PFS demonstrated consistent benefits for earlier intervention. Grade ≥3 adverse events were similar between groups (P=0.824). Multivariable and propensity-score matched analyses confirmed the robustness of these findings. In conclusion, for EGFR-mutant NSCLC with BMs, upfront SRS integrated within the first 12 weeks of first-line osimertinib, particularly within 4 weeks, is associated with markedly superior intracranial control and survival compared with a salvage approach, without increasing severe toxicity.