Objective:‌ To evaluate the progression-free survival (PFS) benefit of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with stereotactic body radiotherapy (SBRT) to primary and/or metastatic lesions versus EGFR-TKI monotherapy in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC).

Methods: In this prospective, randomized, controlled phase II study, 76 treatment-naive patients with stage IV EGFR-mutant NSCLC were enrolled. Patients received first-line third-generation EGFR-TKIs (almonertinib, furmonertinib, or osimertinib) and were enrolled upon achieving stable disease or partial response. Eligible participants were randomly assigned (1:1) to either the control group (continued EGFR-TKI monotherapy) or the combination group (EGFR-TKI plus SBRT to primary and/or metastatic lesions). SBRT doses were: primary lesions, 46–65 Gy in 4–10 fractions; brain metastases, 12–35 Gy in 1–5 fractions; extracranial metastases, 21–60 Gy in 3–15 fractions. The primary endpoint was PFS. Secondary endpoints included overall survival (OS) and safety.

Results: Between August 1, 2019, and June 23, 2023, 76 patients were enrolled and randomized to receive EGFR-TKI plus SBRT (n=38) or EGFR-TKI alone (n=38), including 17 patients who underwent SBRT to primary lesions only, 18 patients to metastatic lesions only, and 3 patients to both primary and metastatic lesions in the combination group. The median follow-up was 33.0 months (IQR 12.6–56.0). PFS was significantly prolonged in the combination group compared to the monotherapy group: median PFS was 26.2 months versus 20.7 months (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.30–0.93; P=0.027). However, the secondary endpoint of overall survival was still immature for analysis. Safety analysis revealed predominantly grade 1-2 treatment-related adverse events (TRAEs). Grade 2 adverse events occurred in 58% of the EGFR-TKI plus SBRT group versus 42% in the EGFR-TKI alone group. No grade 3 or higher TRAEs were observed in either group.

Conclusions: For patients with advanced EGFR-mutant NSCLC responding to first-line third-generation EGFR-TKIs, the addition of SBRT to primary and/or metastatic lesions significantly delayed disease progression with a manageable safety profile. Although this study did not demonstrate a significant improvement in OS, the potential for an OS benefit in larger future studies or with longer follow-up cannot be excluded.