Efficacy and toxicity of stereotactic radiotherapy combined with third-generation EGFR-TKIs and immunotherapy in patients with brain metastases from non-small cell lung cancer

OBJECTIVE: Stereotactic radiotherapy (SRT) is fast gaining attention as a preferred treatment alternative for patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). In this study, we examined the efficacy and safety of combining SRT with immunotherapy (IT) and targeted therapy (TT), either separately or concurrently with the aim to formulate an optimal therapeutic regimen for patients with NSCLC BM. METHODS: The combination therapy were comprised of IT and TT agents. For the SRT-combined TT agents group, TT was limited to third-generation EGFR-TKIs. The administration of these drugs within 30 days before or after SRT was defined as combination therapy. The primary endpoint was 1-year progression-free survival (PFS), which was evaluated by a blinded independent review committee and categorized into local recurrence at the radiation site and the emergence of new distant intracranial metastases. Secondary endpoints included confirmed intracranial objective response rate (IORR) and intracranial disease control rate in the overall population. Post-treatment grading was performed according to CTCAE, and the levels of radiation necrosis were differentiated. RESULTS: The 266 patients with NSCLC BM were categorized into the following four groups based on their treatment methods: SRT alone, SRT combined with IT, SRT combined with third-generation EGFR-TKIs, and SRT combined with both IT and TT. For the local radiation range, the 1‑year PFS of these four groups were 77.89% (P = 0.239), 88.75% (P = 0.266), 88.01% (P = 0.210), and 91.97% (P = 0.057), respectively. For new intracranial metastases outside of the radiotherapy site, the corresponding values were 63.96% (P = 0.039), 74.17% (P = 0.258), 88.70% (P = 0.024), and 87.81% (P = 0.015), respectively. By the end of the study period, the IORR increased from 32% with SRT alone to 46% in the IT group, 58% in the TT group, and 61% in the SRT combined with both the IT and TT groups. However, the group that received SRT in combination with IT and TT exhibited a higher occurrence rate of grade 3 adverse events, and a statistically significant difference was observed in grade 3 radiation necrosis. CONCLUSION: For NSCLC BM, IT, TT, or both together with SRT increased the distant intracranial tumor control. Nonetheless, combining SRT with both IT and TT increased the occurrence rate of acute adverse events. Thus, while SRT provided good local control independently, the incidence of symptomatic RN was low.