274 - Osimertinib Combined with Stereotactic Body Radiotherapy vs. Osimertinib Alone in Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase II Randomized Controlled Trial

Purpose/Objective(s): We hypothesized that adding stereotactic body radiotherapy (SBRT) to osimertinib improves progression-free survival (PFS) and overall survival (OS) compared with osimertinib monotherapy. This study aims to validate this hypothesis in synchronous oligometastatic EGFR-mutant non-small cell lung cancer (NSCLC).

Materials/Methods: In this prospective, randomized, controlled, phase 2 study, participants were recruited at one institution in Zhengzhou, China. Eligible patients were histologically confirmed to have Oligometastatic stage IV NSCLC with an EGFR-sensitive mutation (19del/L858R). Patients who had received third-line EGFR-TKI (osimertinib) treatment and achieved partial response or stable disease were enrolled after three months. Eligible participants were randomly assigned (1:1) to osimertinib plus SBRT or osimertinib monotherapy. In the combination-group, different tumor sites were irradiated at doses ranging from30-70Gy/3-10F. The primary endpoint was PFS and secondary endpoints was OS.Survival outcomes were assessed via Kaplan-Meier analysis and log-rank tests. This study was registered at Chinese Clinical Trial Registry, with the registration number of ChiCTR1900027030.

Results: Between November 1, 2019, and June 23, 2023, thirty-eight patients were assigned per arm. Follow-up data were censored on February 7, 2026. In the combination-group, 17 patients received SBRT to primary lesions only, 18 to metastatic lesions only and 3 to both primary and metastatic lesions. With a median follow-up of 53.3 months, the combination-group demonstrated significantly prolonged median PFS versus monotherapy (27.8 vs. 21.8 months; HR=0.41, 95%CI 0.25–0.68; P<0.0001). A trend toward improved OS was observed in the combination- group (48.0 vs. 37.2 months; HR=0.60, 95%CI 0.33–1.10; P=0.094). The 2-year and 4-year OS rates were 89.5% and 47.8% for the combination arm versus 84.2% and 31.4% for the monotherapy arm, respectively (P=0.094). Subgroup analysis revealed that SBRT to primary lesions yielded markedly superior PFS compared to metastatic lesions (48.5 vs. 19.3 months; HR=0.22, 95%CI 0.10–0.52; P<0.0001). TRAEs were predominantly grade 1-2, with a higher incidence in the combination-group (57.9% vs. 42.1%, P=0.169). The most common TRAEs were hematological toxicities, including leukopenia, neutropenia, and lymphopenia (all P<0.05). In the combination-group, grade 2 radiation esophagitis (n=5) and radiation pneumonitis (n=9) occurred but remained highly manageable.

Conclusion: Adding SBRT to osimertinib significantly prolongs PFS and shows a clinically meaningful OS benefit trend in advanced EGFR-mutant NSCLC. The substantial PFS advantage in the primary SBRT subgroup supports prioritizing primary tumor irradiation. Despite increased grade 1-2 toxicities and manageable radiation-induced events, the safety profile remains favorable, warranting further validation in larger, multi-center phase III trials.