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We aimed to explore the feasibility of combining anlotinib with WBRT based on the hypothesized vascular normalization window, and to investigate potential associations with intracranial tumor control, iPFS, and quality of life in patients with NSCLC brain metastases. This study was designed as a prospective, non-randomized, single-center cohort study. From Feb 8, 2024, to Sep 30, 2025, a total of 38 patients with NSCLC brain metastases diagnosed by the Department of Oncology, the Fifth Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, were prospectively recruited. Anlotinib was used as the intervention measure in this study. According to whether the patients received anlotinib or not, they were divided into the experimental group (anlotinib combined with WBRT) and the control group (sole WBRT), with 19 patients in each group. In the experimental group, the vascular normalization time window of anlotinib, which is 5 to 7 days, was precisely utilized. The specific medication regimen was to start taking 8\u00a0mg of anlotinib 5 days before the initiation of WBRT and continue the medication until the end of WBRT. In contrast, the control group received only WBRT. The primary and secondary endpoint indicators of the patients in both groups were followed up regularly. The primary endpoint indicators included the intracranial objective response rate (iORR) and iPFS, while the secondary endpoint indicators included the intracranial disease control rate (iDCR), quality of life, and adverse reactions. The Kaplan-Meier method was used to draw the survival curve.Meanwhile, the clinical characteristics of the patients in both groups, such as gender, age, primary tumor site, T stage, N stage, and the number of brain metastases, were collected. Univariate analysis was used to screen out the prognostic factors that might affect iPFS. Then, the factors with statistical differences (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.10) in the univariate analysis were taken as independent variables, and further Cox multivariate regression analysis was carried out to explore the independent prognostic factors affecting iPFS. The test standard P value was &lt; 0.05. From Feb 8, 2024, to Sep 30, 2025, a total of 38 patients diagnosed with brain metastases from NSCLC by the Oncology Department of the Fifth Affiliated Hospital of Chengdu University of Traditional Chinese Medicine were prospectively recruited and included in the statistical analysis. The median follow-up time was 15.2 months (95%\n                    <jats:italic>CI<\/jats:italic>\n                    : 9.02\u201321.37). The results showed that the experimental group had better iORR (57.90% vs. 15.79%,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.017) and iDCR (100% vs. 73.68%,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.046) compared to the control group, with statistically differences. Compared with the control group, the experimental group showed a advantage in iPFS (6.7 months vs. 4.27 months,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.038), and the median iPFS was extended by an additional 2.43 months. The results of subgroup analysis showed that the iPFS of patients with \u2265 3 brain metastases and patients with &lt; 3 brain metastases were 6.3 months and 6.7 months, respectively, and there was no significant difference between the two groups (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.723). The iPFS was longer in patients with less than 3 metastases than those with more than 3 metastases (11.73 months vs. 3.17 months,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.035). After WBRT, the iPFS of NSCLC patients with brain metastases who received anti-tumor therapy was improved compared with those who did not receive anti-tumor therapy (8.67 months vs. 3.80 months,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.040). In terms of quality of life, the experimental group showed better outcomes in functional status, symptom domains, and overall health compared to the control group over time. Regarding adverse reactions, the main ones included decreased appetite, fatigue, nausea and vomiting, hypertension, Myelosuppression, dizziness, headache, and abnormal liver function indicators. Grade \u2265 3 adverse reactions primarily included anemia, agranulocytosis, leukopenia, thrombocytopenia, cognitive impairment and abnormal liver function indicators, most of which were tolerable after symptomatic treatment. Univariate regression analysis of the overall population indicated that antitumor therapy after WBRT (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.078) and the number of organ metastases (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.038) were clinically relevant factors affecting iPFS. Further multivariate Cox regression analysis revealed that antitumor therapy after WBRT (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.047) and the number of organ metastases (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.028) were independent prognostic factors influencing iPFS. In this exploratory cohort, low-dose (8\u00a0mg) anlotinib administered 5\u20137 days prior to WBRT was associated with higher iORR, iDCR, and longer iPFS relative to WBRT alone in patients with NSCLC brain metastases. This combination regimen showed a manageable safety profile and trends toward improved quality of life. Subgroup analyses suggested that patients with &lt; 3 organ metastases or those receiving post-WBRT antitumor therapy tended to have prolonged iPFS. Multivariate Cox regression identified post-WBRT antitumor therapy and number of organ metastases as potential independent prognostic factors for iPFS in this cohort. These findings are hypothesis-generating and require validation in larger randomized controlled trials.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-52632-2","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T09:13:17Z","timestamp":1778663597000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anlotinib plus whole-brain radiotherapy for NSCLC brain metastases: a prospective, non-randomized, single-center cohort study"],"prefix":"10.1038","volume":"16","author":[{"given":"Shuai","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongying","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilin","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"issue":"3","key":"52632_CR1","first-page":"221","volume":"46","author":"ZRS Chen","year":"2024","unstructured":"Chen, Z. 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