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
Abstract
To simultaneously compare the efficacy and safety of small-molecule Human Epidermal Growth Factor Receptor 2 (HER2)-targeting tyrosine kinase inhibitor (TKI)-containing regimens for metastatic HER2-positive 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 response (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 Pyrotinib/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 Tucatinib/Trastuzumab/Capecitabine combinations ranked first best and second best among small-molecule anti-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.
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4. Wu X, Baig A, Kasymjanova G, Kafi K, Holcroft C, Mekouar H, et al. Pattern of Local Recurrence and Distant Metastasis in Breast Cancer By Molecular Subtype. Cureus. 2016;8(12):e924-e24.
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6. Wang JXu B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther. 2019;4(1):34.
7. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469-87.
8. Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, et al. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2014;2014(6):CD006242.
9. Zagouri F, Sergentanis TN, Chrysikos D, Zografos CG, Filipits M, Bartsch R, et al. Pertuzumab in breast cancer: a systematic review. Clin Breast Cancer. 2013;13(5):315-24.
10. Peddi PFHurvitz SA. Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Ther Adv Med Oncol. 2014;6(5):202-9.
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12. Schroeder RL, Stevens CLSridhar J. Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Molecules (Basel, Switzerland). 2014;19(9):15196-212.
13. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-43.
14. Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, et al. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With >/= 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020;38(27):3138-49.
15. Bischoff J, Barinoff J, Mundhenke C, Bauerschlag DO, Costa S-D, Herr D, et al. A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA). Anti-Cancer Drugs. 2019;30(4):394-401.
16. Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609.
17. Xuhong JC, Qi XW, Zhang YJiang J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am J Cancer Res. 2019;9(10):2103-19.
18. Venur VALeone JP. Targeted Therapies for Brain Metastases from Breast Cancer. Int J Mol Sci. 2016;17(9):1543.
19. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-84.
20. Chaimani ASalanti G. Visualizing Assumptions and Results in Network Meta-analysis: The Network Graphs Package. The Stata Journal. 2015;15(4):905-50.
21. Tonin FS, Borba HH, Mendes AM, Wiens A, Fernandez-Llimos FPontarolo R. Description of network meta-analysis geometry: A metrics design study. PLOS ONE. 2019;14(2):e0212650.
22. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
23. Daly CH, Neupane B, Beyene J, Thabane L, Straus SEHamid JS. Empirical evaluation of SUCRA-based treatment ranks in network meta-analysis: quantifying robustness using Cohen’s kappa. BMJ Open. 2019;9(9):e024625.
24. Higgins JP, Jackson D, Barrett JK, Lu G, Ades AEWhite IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3(2):98-110.
25. White IR, Barrett JK, Jackson DHiggins JP. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods. 2012;3(2):111-25.
26. Dias S, Welton NJ, Caldwell DMAdes AE. Checking consistency in mixed treatment comparison meta-analysis. Statistics in Medicine. 2010;29(7‐8):932-44.
27. Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020) 2020 [Available from: www.training.cochrane.org/handbook.
28. Jansen JPNaci H. Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers. BMC Medicine. 2013;11(1):159.
29. Chaimani A, Higgins JPT, Mavridis D, Spyridonos PSalanti G. Graphical Tools for Network Meta-Analysis in STATA. PLOS ONE. 2013;8(10):e76654.
30. White IR. Network meta-analysis. The Stata Journal. 2015;15(4):951-85.
31. Riley RD, Jackson D, Salanti G, Burke DL, Price M, Kirkham J, et al. Multivariate and network meta-analysis of multiple outcomes and multiple treatments: rationale, concepts, and examples. BMJ. 2017;358:j3932.
32. Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, Lake DE, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014;32(35):3959-66.
33. Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol. 2008;26(18):2999-3005.
34. Gomez HL, Neciosup S, Tosello C, Mano M, Bines J, Ismael G, et al. A Phase II Randomized Study of Lapatinib Combined With Capecitabine, Vinorelbine, or Gemcitabine in Patients With HER2-Positive Metastatic Breast Cancer With Progression After a Taxane (Latin American Cooperative Oncology Group 0801 Study). Clin Breast Cancer. 2016;16(1):38-44.
35. Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011;105(3):613-20.
36. Rixe O, Franco SX, Yardley DA, Johnston SR, Martin M, Arun BK, et al. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother Pharmacol. 2009;64(6):1139-48.
37. Cortes J, Dieras V, Ro J, Barriere J, Bachelot T, Hurvitz S, et al. Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol. 2015;16(16):1700-10.
38. Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, et al. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018;36(8):741-48.
39. Haluska P, Bernath AM, Ballman KV, Dueck AC, Linden HM, Goetz MP, et al. Randomized phase II trial of capecitabine and lapatinib with or without cixutumumab in patients with HER2+ breast cancer previously treated with trastuzumab and an anthracycline and/or a taxane: NCCTG N0733 (Alliance). Journal of Clinical Oncology. 2014;32(15_suppl):632-32.
40. Johnston SR, Gomez H, Stemmer SM, Richie M, Durante M, Pandite L, et al. A randomized and open-label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer. Breast Cancer Res Treat. 2013;137(3):755-66.
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| Issue | Vol 8, No 1 (2025) | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v8i1.17990 | |
| Keywords | ||
| Breast Neoplasms HER2 Network Meta-Analysis Protein Kinase Inhibitors | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Pastaki Khoshbin A, Darbeheshti F, Doosti-Irani A, Keshavarz-Fathi M, Mansournia MA. 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. Immunol Genet J. 2025;8.
