Xiuwen Wang

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

Abstract 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.

Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non–Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial

Importance Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug’s efficacy in advanced non–small cell lung cancer (NSCLC). Objective To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment. Design, Setting, and Participants The ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle. Main Outcomes and Measures The primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety. Results In total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia. Conclusions and Relevance Among the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC. Trial Registration ClinicalTrials.gov identifier: NCT02388919