Efficacy and safety of anlotinib as a third-line treatment of advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials

Abstract

Anlotinib is a novel multitarget tyrosine kinase inhibitor, which has been indicated to inhibit both tumor angiogenesis and signal transduction pathways associated with proliferation. The main proposed mechanism of anlotinib inhibiting tumor angiogenesis is that anlotinib inhibits the activation of VEGFR2, PDGFRβ and FGFR1, and downstream ERK signal transduction. The aim of the present study was to systematically evaluate the efficacy and safety of third-line treatment with anlotinib for advanced non-small cell lung cancer (NSCLC). To meet this aim, studies published up to February 2022 were searched in PubMed, Web of Science, the Cochrane Library and several Chinese databases. Only randomized controlled trials (RCTs) were included and a metaanalysis was performed using RevMan 5.3 software. A total of 18 RCTs were identified and included in the present study, comprising 1,658 patients. The anlotinib treatment group was indicated to be better than the control group at prolonging progression-free survival [hazard ratio (HR), 0.33; 95% confidence interval (95% CI), 0.28-0.37] and overall survival (HR, 0.70; 95% CI, 0.60-0.81). Anlotinib also provided a significant improvement in the disease control rate [risk ratio (RR), 1.51; 95% CI, 1.27-1.79], objective response rate (1.75, 95% CI, 1.51-2.03) and Karnofsky performance status (mean difference, 9.85; 95% CI, 6.26-13.43). Compared with the control group, the incidence of adverse events (AEs), such as hypertension and hemoptysis, was increased by anlotinib. Through subgroup analysis, it was determined that, compared with the placebo, the incidence of AEs was increased by anlotinib, although compared with other therapeutic drugs, no significant differences were observed. In conclusion, the findings of the present study suggested that the thirdline treatment of advanced NSCLC with anlotinib is more effective compared with other control measures and that the AEs are also controllable. However, given the limitations of the quantity and the quality of the included studies, further studies are required to gain a more complete understanding of the effects of anlotinib.

Keywords: advanced non-small cell lung cancer; anlotinib; meta-analysis; thirdline therapy.

Figure 1.

Flow diagram for the selection of studies. A total of 955 articles were initially retrieved and 532 articles were excluded as duplicate studies. The remaining studies were reviewed by reading titles and abstracts. Of these, 318 studies were excluded, 53 of which were reviews, 160 were non-RCTs and 105 were not research-related. After careful review of the full texts of the 105 articles remaining and excluding 87 studies (59 articles due to being on nonthird line medication, 4 articles due to being from the same study and 24 articles due to not specifying the outcomes), 18 articles were finally decided to be included. RCT, randomized controlled trial.

Figure 2.

Bias evaluation of included studies. Only two studies had low selection bias. Furthermore, 5 studies had low performance bias and 2 studies had high performance bias. Performance bias may generally be avoided by using standard treatment methods and blinding methods for patients and investigators. The detection bias of 4 studies was low and the detection bias of 2 studies was high. In general, detection bias may be avoided by using unified standard measurement methods and blinding of the investigators. A total of two studies had higher attrition bias, while the others had lower attrition bias. None of the studies had any reporting bias.

Figure 3.

PFS for third-line treatment of advanced non-small cell lung cancer in the anlotinib group and control group. Vertical solid black line: Invalid line; horizontal black solid line: The width of the line represents the 95% CI of each study. The red squares represent the weight of each study. The results indicated that there was a significant difference in PFS between the anlotinib group and the control group (hazard ratio=0.33, 95% CI: 0.28-0.37, P<0.00001). PFS, progression-free survival; SE, standard error; IV, inverse variance; df, degrees of freedom.

Figure 4.

OS for third-line treatment of advanced non-small cell lung cancer in the anlotinib group and control group. Vertical solid black line: Invalid line; horizontal black solid line: The width of the line represents the 95% CI of each study; the red square represents the weight of each study. The results indicated that there was a significant difference in OS when comparing between the anlotinib group and the control group (hazard ratio=0.70, 95% CI, 0.60-0.81; P<0.00001). SE, standard error; IV, inverse variance; df, degrees of freedom; OS, overall survival.

Figure 5.

Disease control rate for third-line treatment of advanced non-small cell lung cancer in the anlotinib group and control group. Vertical solid black line: Invalid line; horizontal black solid line: The width of the line represents the 95% CI of each study; the blue square represents the weight of each study. The results suggested that the RR value of the anlotinib group was significantly higher compared with that of the control group (RR=1.51, 95% CI, 1.27-1.79; P<0.00001). RR, risk ratio; M-H, Mantel-Haenszel; df, degrees of freedom.

Figure 6.

Objective response rate for third-line treatment of advanced non-small cell lung cancer in the anlotinib group and control group. Vertical solid black line: Invalid line; horizontal black solid line: The width of the line represents the 95% CI of each study; the blue square represents the weight of each study. The results indicated that the RR of the anlotinib group was significantly higher compared with that of the control group (RR=1.75, 95% CI, 1.51-2.03; P<0.00001). RR, risk ratio; M-H, Mantel-Haenszel; df, degrees of freedom.

Figure 7.

KPS for third-line treatment of advanced non-small cell lung cancer in anlotinib group and control group. Vertical solid black line: Invalid line; horizontal black solid line: The width of the line represents the 95% CI of each study; the green square represents the weight of each study. The results suggested that the KPS of the anlotinib group was significantly higher compared with that of the control group (MD=9.85, 95% CI, 6.26-13.43; P<0.001). MD, mean difference; SD, standard deviation; IV, inverse variance; df, degrees of freedom; KPS, Karnofsky performance status.

Figure 8.

Funnel chart to assess the bias of studies included with regard to the disease control rate. The blue dotted line indicates the combined effect quantity. Each study is represented by a circle. Ideally, all studies should be evenly distributed on both sides. As the dots were distributed left- and right-asymmetrically, the study is asymmetric and there may be bias. SE, standard error; RR, risk ratio.

Figure 9.

Funnel chart to assess the bias of studies included with regard to the objective response rate. The blue dotted line indicates the combined effect quantity. Each study is represented by a circle. Ideally, all studies should be evenly distributed on both sides. As the dots were distributed left- and right-asymmetrically, the study is asymmetric and there may be bias. SE, standard error; RR, risk ratio.