Efficacy of Tyrosine Kinase Inhibitors in Patients with Advanced or Metastatic Sarcomas After Prior Chemotherapy: A Meta-analysis

Overview

Journal Medicine (Baltimore)

Specialty General Medicine

Date 2024 Mar 15

PMID 38489731

Authors

Wenxia Li

Liwen Liu

Zhanpeng Liang

Huiqin Lai

Jiaming Wu

Huatang Zhang

Cantu Fang

Affiliations

Soon will be listed here.

Abstract

Background: Sarcoma is a heterogeneous malignancy arising from interstitial tissue. Anthracycline-based therapy is the first-line treatment recommended by guidelines for patients with locally advanced or metastatic unresectable sarcoma. Recently, targeted therapies, in particular tyrosine kinase inhibitors (TKIs), have made significant progress in the treatment of sarcoma, and their efficacy has been investigated in randomized controlled trials. The aim of this meta-analysis is to evaluate the efficacy of TKIs in patients with advanced or metastatic sarcoma who have previously received chemotherapy.

Methods: We completed a meta-analysis after conducting literature searches in PubMed, Embase, and Cochrane. The single-drug, placebo-controlled, randomized controlled clinical trials of TKIs in patients with advanced or progressive sarcoma who have previously received chemotherapy are available for inclusion in the study. The observation results were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The subgroup analysis was performed according to histological subtypes of sarcoma.

Results: This study included 6 studies, including 1033 patients. The ORR (OR: 7.99, 95% CI: 3.62-19.61, P < .00001), DCR (OR: 2.54, 95% CI: 1.27-5.08, P = .009), PFS (HR: 0.46, 95% CI: 0.34-0.62, P < .00001), and OS (HR: 0.80, 95% CI: 0.67-0.96, P = .02) of patients treated with TKIs were better than those in the placebo group.

Conclusions: In patients with advanced sarcoma, TKIs have been shown to have advantages in terms of ORR, DCR and PFS and OS. Multi-targeted TKIs may be considered as one of the second-line treatment options for sarcoma patients who have received prior chemotherapy.

References

Brodowicz T, Liegl-Atzwanger B, Penel N, Mir O, Blay J, Kashofer K . Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study. Cancers (Basel). 2020; 12(12). PMC: 7763753. DOI: 10.3390/cancers12123746. View

Martin-Broto J, Hindi N, Grignani G, Martinez-Trufero J, Redondo A, Valverde C . Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. J Immunother Cancer. 2020; 8(2). PMC: 7674086. DOI: 10.1136/jitc-2020-001561. View

Taylor B, Barretina J, Maki R, Antonescu C, Singer S, Ladanyi M . Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011; 11(8):541-57. PMC: 3361898. DOI: 10.1038/nrc3087. View

Hamberg P, Verweij J, Sleijfer S . (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist. 2010; 15(6):539-47. PMC: 3227994. DOI: 10.1634/theoncologist.2009-0274. View

Kumar R, Knick V, Rudolph S, Johnson J, Crosby R, Crouthamel M . Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007; 6(7):2012-21. DOI: 10.1158/1535-7163.MCT-07-0193. View

van der Graaf W, Blay J, Chawla S, Kim D, Bui-Nguyen B, Casali P . Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012; 379(9829):1879-86. DOI: 10.1016/S0140-6736(12)60651-5. View

Lee S, Chang M, Baek K, Han B, Lim T, Lee J . High-dose ifosfamide as second- or third-line chemotherapy in refractory bone and soft tissue sarcoma patients. Oncology. 2011; 80(3-4):257-61. DOI: 10.1159/000328795. View

Saerens M, Brusselaers N, Rottey S, Decruyenaere A, Creytens D, Lapeire L . Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis. Eur J Cancer. 2021; 152:165-182. DOI: 10.1016/j.ejca.2021.04.034. View

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

10.

Chen H, Shen J, Choy E, Hornicek F, Duan Z . Targeting protein kinases to reverse multidrug resistance in sarcoma. Cancer Treat Rev. 2016; 43:8-18. PMC: 4735639. DOI: 10.1016/j.ctrv.2015.11.011. View

11.

Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis J . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700. PMC: 2714672. DOI: 10.1136/bmj.b2700. View

12.

Joensuu H, Eriksson M, Hall K, Reichardt A, Hartmann J, Pink D . Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. J Clin Oncol. 2015; 34(3):244-50. DOI: 10.1200/JCO.2015.62.9170. View

13.

Wilky B, Trucco M, Subhawong T, Florou V, Park W, Kwon D . Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol. 2019; 20(6):837-848. DOI: 10.1016/S1470-2045(19)30153-6. View

14.

Karavasilis V, Seddon B, Ashley S, Al-Muderis O, Fisher C, Judson I . Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: retrospective analysis and identification of prognostic factors in 488 patients. Cancer. 2008; 112(7):1585-91. DOI: 10.1002/cncr.23332. View

15.

Tawbi H, Burgess M, Bolejack V, Van Tine B, Schuetze S, Hu J . Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017; 18(11):1493-1501. PMC: 7939029. DOI: 10.1016/S1470-2045(17)30624-1. View

16.

Paul M, Mukhopadhyay A . Tyrosine kinase - Role and significance in Cancer. Int J Med Sci. 2005; 1(2):101-115. PMC: 1074718. DOI: 10.7150/ijms.1.101. View

17.

Ugurel S, Mentzel T, Utikal J, Helmbold P, Mohr P, Pfohler C . Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up. Clin Cancer Res. 2013; 20(2):499-510. DOI: 10.1158/1078-0432.CCR-13-1411. View

18.

Schmoll H, Lindner L, Reichardt P, Heissner K, Kopp H, Kessler T . Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma: Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020; 7(2):255-262. PMC: 7758834. DOI: 10.1001/jamaoncol.2020.6564. View

19.

Duffaud F, Italiano A, Bompas E, Rios M, Penel N, Mir O . Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: Results of a non-comparative, randomised, double-blind, placebo controlled, multicentre phase II study. Eur J Cancer. 2021; 150:108-118. DOI: 10.1016/j.ejca.2021.03.039. View

20.

Strauss S, Frezza A, Abecassis N, Bajpai J, Bauer S, Biagini R . Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(12):1520-1536. DOI: 10.1016/j.annonc.2021.08.1995. View