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Background: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant non‐small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR‐mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR‐TKIs in patients with EGFR‐mutant NSCLC with newly diagnosed brain metastases. Methods: We retrospectively analyzed the data of EGFR‐mutant NSCLC patients with CNS metastases who received EGFR‐TKIs as a first‐line therapy. Results: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR‐TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3–9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1–30.1). The overall response rate of the CNS was 37%. The median CNS progression‐free survival (PFS) was 13.2 months (95% CI: 10.0–16.2). Brain radiotherapy prior to EGFR‐TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS‐PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. Conclusion: EGFR‐TKI showed a favorable effect for EGFR‐mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS‐PFS were observed with upfront brain radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical significance of nivolumab plus ipilimumab in patients with recurrence after chemoradiotherapy followed by durvalumab remains unclear. We investigated the efficacy and safety of nivolumab plus ipilimumab in patients who relapsed after chemoradiotherapy followed by durvalumab. The 6- and 12-month PFS rates for nivolumab plus ipilimumab for relapse after durvalumab were 46.7% and 36.4%, indicating a long-tail plateau. Nivolumab plus ipilimumab was particularly effective in patients treated with durvalumab for 6 months or more. Therefore, nivolumab plus ipilimumab is a promising treatment option for patients who have relapsed after CCRT–durvalumab, with good tolerability. Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7–7.7) and 18.5 months (95% CI: 3.5–33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8–64.5) and 36.4% (95% CI: 19.0–53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT. [ABSTRACT FROM AUTHOR]