Efficacy and Safety of Small-Molecule Human Epidermal Growth Factor Receptor 2 (HER2)-Targeting Tyrosine Kinase Inhibitor-Containing Regimens for Metastatic HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis of Randomized Clinical

Amin Pastaki Khoshbin; Farzaneh Darbeheshti; Amin  Doosti-Irani; Mahsa Keshavarz-Fathi; Mohammad Ali Mansournia

doi:10.18502/igj.v8i1.17990

Amin Pastaki Khoshbin School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Farzaneh Darbeheshti Department of Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Amin Doosti-Irani Department of Epidemiology, School of Public Health and Research Center for Health Sciences, Hamadan University of Medical Sciences, Hamadan, Iran
Mahsa Keshavarz-Fathi School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Mohammad Ali Mansournia Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/igj.v8i1.17990

Keywords: Breast Neoplasms; HER2; Network Meta-Analysis; Protein Kinase Inhibitors

Abstract

To simultaneously compare the efficacy and safety of small-molecule Human Epidermal Growth Factor Re- ceptor 2 (HER2)-targeting tyrosine kinase inhibitor (TKI)-containing regimens for metastatic HER2-pos- itive breast neoplasm. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Web of Science, and Scopus databases were systematically searched to identify randomized clinical trials (RCT) that investigated the difference in overall survival (OS), progression-free survival (PFS), overall re- sponse (OR), recurrence in central nervous system/brain metastasis (RCNS), total and grade 3 or 4 adverse events (AE), diarrheal AEs, and cardiac AEs of small-molecule HER2-targeting TKI-containing regimens in women with metastatic HER2-positive breast carcinoma. The revised Cochrane risk-of-bias tool for randomized trials (RoB2) was used to evaluate the risk of bias in the included studies. When applicable, pooled network estimates were synthesized by frequentist random-effect network meta-analysis using Stata MP Software (version 14). Twenty-three studies comprising 7497 eligible patients were included. In all, 17 small-molecule anti-HER2 TKI (Lapatinib, Neratinib, Afatinib, Pyrotinib, and Tucatinib)-containing and 10 other regimens were compared. In terms of increasing OS, the Pyrotinib/Capecitabine combination ranked first best among small-molecule HER2-targeting TKI-containing regimens. In terms of PFS, the Py- rotinib/Capecitabine combination prolonged PFS in comparison with all other small-molecule anti-HER2 TKI-containing regimens in the network. In the corresponding network, Pyrotinib/Capecitabine and Tucati- nib/Trastuzumab/Capecitabine combinations ranked first best and second best among small-molecule an- ti-HER2 TKI-containing regimens. In terms of AE, the Tucatinib/Trastuzumab/Capecitabine combination ranked the highest for AE occurrence. Pyrotinib/Capecitabine and Tucatinib/Trastuzumab/Capecitabine combinations seemed to be the most efficacious small-molecule HER2-targeting TKI-containing regimens in metastatic HER2-positive breast cancer.