Anlotinib as Third-Line or Later Therapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Real-World Efficacy and Safety Outcomes.

Anlotinib, a multi-targeted tyrosine kinase inhibitor, has demonstrated anti-angiogenic and immunomodulatory activity in several solid tumors; however, its efficacy and predictive biomarkers in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remain unclear. This retrospective, single-center study included 68 patients with histologically confirmed R/M HNSCC who received anlotinib as third-line or later therapy (following failure of at least two prior systemic lines; 12 mg once daily on days 1-14 every 21 days, with dose reductions to 10 or 8 mg as needed) between January 2021 and October 2023. Tumor response was evaluated according to RECIST v1.1 in patients with available radiologic follow-up. Survival outcomes were analyzed in the overall treated population. Archived tumor tissues were subjected to next-generation sequencing (NGS) and multiplex immunofluorescence (mIF) to exploratorily assess genomic alterations and immune microenvironment features. Among 68 treated patients, 14 achieved partial response, and 39 had stable disease, yielding an objective response rate (ORR) of 22.1% and a disease control rate (DCR) of 74.6% in treated patients. The median progression-free survival (PFS) and overall survival (OS) in the overall cohort were 6.3 and 8.4 months, respectively. Patients with oropharyngeal carcinoma and ECOG performance status 0-1 demonstrated improved outcomes. NGS analysis identified frequent alterations in TP53, PIK3CA, CDKN2A, PTEN, and FGF/FGFR pathways. PI3K pathway alterations were not associated with prolonged PFS. Tumors with PD-L1 CPS ≥ 1 and higher CD8⁺ T-cell infiltration exhibited an inflamed phenotype and were associated with improved response. Grade ≥3 adverse events occurred in 25.0% of patients, most commonly hypertension and hand-foot syndrome. Anlotinib demonstrated promising responses with manageable toxicity in a heavily pretreated R/M HNSCC population. Integration of genomic and immune microenvironment features may provide hypothesis-generating insights into patient selection.