Efficacy and safety of osimertinib combined with anlotinib in EGFR-mutant non-squamous non-small cell lung cancer with gradual progression after first-line osimertinib therapy: a single-center retrospective cohort study

Abstract

Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has substantially improved clinical outcomes in patients with EGFR-mutant non-squamous non-small cell lung cancer (NSCLC). Nevertheless, acquired resistance inevitably develops, leading to disease progression in the majority of patients. Preclinical and clinical evidence suggests that anlotinib, a multi-targeted anti-angiogenic TKI, may overcome osimertinib resistance. This study aimed to evaluate the efficacy and safety of continued osimertinib in combination with anlotinib in patients with EGFR-mutant non-squamous NSCLC who developed gradual progression following first-line osimertinib therapy. Methods This retrospective study enrolled patients with unresectable stage III or IV EGFR-mutant non-squamous NSCLC who received first-line osimertinib therapy at The First Affiliated Hospital of University of Science and Technology of China between January 2021 and December 2024. Eligible patients developed gradual progression after first-line osimertinib therapy. Subsequently, patients received combination therapy with osimertinib (80 mg orally once daily) plus anlotinib (10 mg orally on days 1–14 of every 3-week cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included PFS rates at 6 and 12 months, objective response rate (ORR), disease control rate (DCR), overall survival (OS), OS rates at 12 and 24 months, and safety profile. Results A total of 52 patients were enrolled. The median age was 66 years. 40(76.9%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, 16 (30.8%) presented with brain metastases, 23 (44.2%) harbored exon 19 deletions, and 29 (55.8%) had L858R mutations. Molecular testing was performed in 12 patients after gradual progression. As of September 6, 2025, the median follow-up was 34.8 months, 48 PFS events were recorded and 22 patients died. The ORR was 7.7% (4/52), and the DCR was 86.5% (45/52). The median PFS (mPFS) was 9.9 months [95% confidence interval (CI): 4.2–12.1], with PFS rates of 61.5% at 6 months and 40.4% at 12 months. The median OS was not reached. OS rates were 86.3% at 12 months and 62.4% at 24 months. The exploratory multivariate COX analysis revealed that ECOG PS [hazard ratio (HR): 3.115, 95% CI: 1.111–7.706, P<0.001] and brain metastasis (HR: 2.242, 95% CI: 1.341–7.842, P=0.009) were associated with mPFS. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 9.6% (5/52) of patients. The most frequently observed AEs were diarrhea (42.3%, 22/52), hypertension (34.6%, 18/52), proteinuria (30.8%, 16/52), decreased appetite (28.8%, 15/52), and weight loss (28.8%, 15/52). Conclusions In this retrospective cohort focusing on the specific pattern of gradual progression following first-line osimertinib therapy, continued osimertinib combined with anlotinib demonstrated encouraging antitumor activity, which warrants further evaluation in prospective comparative studies.