Anlotinib for Previously Treated Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ALTER1102): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

Background: Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced ESCC who are refractory to chemotherapy. Methods: This randomized, placebo-controlled, double-blind phase 2 trial was conducted across 13 hospitals in China. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive either oral anlotinib 12 mg or placebo on days 1-14 (the treatment was repeated every 21 days). The primary endpoint was PFS. This study is registered with ClinicalTrials.gov (NCT02649361). Findings: One hundred and sixty-five patients were randomly assigned to the anlotinib (n=110) or the placebo (n=55) arm. The median treatment duration was 2·6 months (range 0·5-20·9) in the anlotinib group and 1·2 months (range 0·5-10·8) in the placebo group. Median PFS was 3·02 months (95% CI 2·63-3·65) in the anlotinib group and 1·41 months (95% CI 1·38-1·41) in the placebo group (hazard ratio 0·46 [95% CI 0·32-0·66]; p<0·001). The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (six [6%] patients) and hyponatremia (four [4%] patients) in the anlotinib group and decreased appetite (two [4%] patients) in the placebo group. Three (3%) deaths in the anlotinib group were considered as related to study drug, while there were no treatment-related deaths in the placebo group. Interpretation: The use of anlotinib in previously treated, recurrent or metastatic ESCC patients significantly improved progression-free survival and disease control rate compared with placebo. Our findings suggest that anti-angiogenesis might be an important therapeutic target in advanced ESCC. Trial Registration Number: This study is registered with ClinicalTrials.gov (NCT02649361). Funding: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: The ethics committee at each study hospital approved the study protocol and all amendments, and the trial was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients before enrollment.