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Background: The study is to evaluate the efficacy and safety of combined anlotinib and EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) who had gradual, oligo, or potential progression after previous EGFR-TKIs treatment., Methods: We conducted an open-label, single-arm, multicenter, phase II trial in China. Eligible patients were 18-75 years old with histologically or cytologically confirmed NSCLC who were EGFR mutation positive and showed gradual, oligo, or potential progression after EGFR-TKIs. Anlotinib (12 mg/day) was administered orally for 2 weeks and then off 1 week in a 3-week cycle. EGFR-TKIs were continue used. The primary endpoint was progression-free survival (PFS). The secondary endpoints included 6- and 12-month PFS rate, objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety., Results: From July 2019 to December 2022, 120 patients were enrolled. The median PFS (mPFS) was 9.1 months (95% CI 6.8-11.7). The PFS rates at 6 and 12 months was 68.5% and 38.8% respectively. For 86 patients with first-line 1st /2nd generation EGFR-TKIs, the mPFS was 9.2 months (95% CI 6.7-12.6). For 32 patients with first-line 3rd generation EGFR-TKIs, the mPFS was 10.3 months (95% CI 6.1-13.3). Overall ORR and DCR were 6.7% (95% CI 2.9-12.7) and 87.5% (95% CI 80.2-92.8), respectively. 52.5% of patients had grade 3 or higher treatment-emergent adverse events (TEAEs)., Conclusion: Anlotinib in combination with continuation of EGFR-TKIs prolonged the clinical benefit of EGFR-TKIs, demonstrating favorable survival outcomes and manageable toxicity in NSCLC treated with EGFR-TKIs and had specific progression modes, such as gradual progression., Trial Registration: NCT04007835., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the institutional review board (IRB) of each participating center. The IRB approval number in leading site Guangdong Lung Cancer Institute was 2018–375 H, and all patients provided written informed consent prior to participation. The study was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice requirements. Consent for publication: Not applicable. Competing interests: Yi-Long Wu declares advisory services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; speaker fees from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi; and grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Hengrui, and Roche outside the submitted work. The remaining authors declare no conflict of interest., (© 2024. The Author(s).)