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.