Efficacy and safety of third-line treatment with anlotinib in patients with refractory advanced non-small-cell lung cancer (ALTER-0303): a randomised, double-blind, placebo-controlled phase 3 study

Background Anlotinib hydrochloride, an oral tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR, and c-kit, showed promising efficacy in a phase 2 study. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced non-small-cell lung cancer. Methods We did a randomised, double-blind, placebo-controlled phase 3 trial (ALTER-0303) at 31 sites. Eligible patients with stage 3B/4 non-small-cell lung cancer who progressed after at least two lines of previous therapies were randomly assigned (2:1) to receive anlotinib (12 mg once a day from day 1 to 14 of a 21-day cycle) or placebo until progression or intolerable toxicity. Enrolled patients harbouring EGFR or ALK mutations must have failed in previous match-targeted therapies. The primary endpoint was overall survival. This trial is registered with ClinicalTrials, number NCT02388919. Findings Between February, 2015, and August, 2016, we randomly assigned 437 patients. The baseline characteristics of the anlotinib group (n=294) and placebo group (n=143) were well balanced in age, gender, ECOG performance status, and gene status. With 292 overall survival events (67%), a significant improvement in overall survival was observed in the anlotinib group compared with the placebo group (hazard ratio 0·68, 95% CI 0·54–0·87 p=0·0018), according to investigator-assessed results (table). Interpretation The ALTER-0303 trial met its primary endpoint; anlotinib significantly improved overall survival in advanced non-small-cell lung cancer with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced non-small-cell lung cancer. Funding Chia-tai Tianqing Pharmaceutical Co Ltd.