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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Han reported consulting for AstraZeneca and Roche Pharmaceutical Company as well as receiving speaking fees from AstraZeneca Pharmaceutical Company and Lilly Pharmaceutical Company. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

FAS indicates full analysis set. The data cutoff date was January 6, 2017.

Figure 2.. Kaplan-Meier Estimates of Overall and Progression-Free Survival

A, For the anlotinib group, the median overall survival (OS) was 9.6 months (95% CI, 8.2-10.6); for the placebo group, the median OS was 6.3 months (95% CI, 5.0-8.1). The hazard ratio (HR) was 0.68 (95% CI, 0.54-0.87; P = .002). B, For the anlotinib group, the median progression-free survival (PFS) was 5.4 months (95% CI, 4.4-5.6). For the placebo group, the median PFS was 1.4 months (95% CI, 1.1-1.5). The HR was 0.25 (95% CI, 0.19-0.31; P < .001).

Figure 3.. Subgroup Analysis of Overall and Progression-Free Survival

ECOG PS indicates Eastern Cooperative Oncology Group Performance Status (score range: 0-5, with the highest score indicating death); EGFR, endothelial growth factor receptor; HR, hazard rationm; and SCC, squamous cell carcinoma.