Efficacy of Eribulin in Soft Tissue Sarcomas

Edward Phillips, Robin L Jones, Paul Huang, Antonia Digklia, Edward Phillips, Robin L Jones, Paul Huang, Antonia Digklia

Abstract

Soft tissue sarcomas are a highly heterogenous group of tumors with limited systemic therapy options. Eribulin, a synthetic analogue of halichondrin B, is a potent mitotic inhibitor. A phase 3 trial of previously treated advanced Liposarcoma and Leiomyosarcoma demonstrated superiority of eribulin to dacarbazine. Eribulin appears to be particularly effective for liposarcomas. It has also been shown to be a safe and effective treatment alternative to doxorubicin in patients where doxorubicin is contraindicated. From retrospective studies, eribulin has demonstrated efficacy in patients with angiosarcoma, pleomorphic sarcomas, synovial sarcomas, rhabdomyosarcomas, angiosarcomas, and myxofibrosarcomas. Future areas of development include liposomal eribulin, which may provide increased efficacy and lower toxicity, and delineation of biomarkers of response and resistance, allowing better selection of patients for treatment.

Keywords: STS; eribulin; eribulin and related compounds; leiomyosarcoma; liposarcoma; review; sarcoma.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Phillips, Jones, Huang and Digklia.

Figures

FIGURE 1
FIGURE 1
Mechanisms of action of eribulin: (A) normalizes the tumor vasculature; (B) inhibits microtubule growth without having any effect on microtubule shortening. Eribulin also sequesters tubulin, reducing the supply available to microtubules; and (C) reverses the mesenchymal to epithelial transition.

References

    1. Agoulnik S. I., Kawano S., Taylor N., Oestreicher J., Matsui J., Chow J., et al. (2014). Eribulin Mesylate Exerts Specific Gene Expression Changes in Pericytes and Shortens Pericyte-Driven Capillary Network In Vitro . Vasc. Cel 6 (1), 3. 10.1186/2045-824X-6-3
    1. Almond L. M., Gronchi A., Strauss D., Jafri M., Ford S., Desai A. (2018). Neoadjuvant and Adjuvant Strategies in Retroperitoneal Sarcoma. Eur. J. Surg. Oncol. 44 (5), 571–579. 10.1016/j.ejso.2018.02.001
    1. Asano M., Matsui J., Towle M. J., Wu J., McGonigle S., De Boisferon M. H., et al. (2018). Broad-spectrum Preclinical Antitumor Activity of Eribulin (Halaven®): Combination with Anticancer Agents of Differing Mechanisms. Anticancer Res. 38 (6), 3375–3385. 10.21873/anticanres.12604
    1. Cao J., Wang J., He C., Fang M. (2019). Angiosarcoma: a Review of Diagnosis and Current Treatment. Am. J. Cancer Res. 9 (11), 2303–2313.
    1. Carbone F., Pizzolorusso A., Di Lorenzo G., Di Marzo M., Cannella L., Barretta M. L., et al. (2021). Multidisciplinary Management of Retroperitoneal Sarcoma: Diagnosis, Prognostic Factors and Treatment. Cancers (Basel) 13 (16), 4016. 10.3390/cancers13164016
    1. Committee for Medicinal Products for Human Use, European Medicines Agency. (2016). Halaven Assessment Report. Available at: [Accessed February 27, 2022].
    1. Cortes J., O'Shaughnessy J., Loesch D., Blum J. L., Vahdat L. T., Petrakova K., et al. (2011). Eribulin Monotherapy versus Treatment of Physician's Choice in Patients with Metastatic Breast Cancer (EMBRACE): a Phase 3 Open-Label Randomised Study. Lancet 377 (9769), 914–923. 10.1016/S0140-6736(11)60070-6
    1. Cortes J., Schöffski P., Littlefield B. A. (2018). Multiple Modes of Action of Eribulin Mesylate: Emerging Data and Clinical Implications. Cancer Treat. Rev. 70, 190–198. 10.1016/j.ctrv.2018.08.008
    1. De Vita A., Miserocchi G., Recine F., Mercatali L., Pieri F., Medri L., et al. (2016). Activity of Eribulin in a Primary Culture of Well-Differentiated/Dedifferentiated Adipocytic Sarcoma. Molecules 21 (12), 1662. 10.3390/molecules21121662
    1. De Vita A., Recine F., Mercatali L., Miserocchi G., Spadazzi C., Liverani C., et al. (2017). Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents. Int. J. Mol. Sci. 18 (12), 2662. 10.3390/ijms18122662
    1. Demetri G. D., Schöffski P., Grignani G., Blay J. Y., Maki R. G., Van Tine B. A., et al. (2017). Activity of Eribulin in Patients with Advanced Liposarcoma Demonstrated in a Subgroup Analysis from a Randomized Phase III Study of Eribulin versus Dacarbazine. J. Clin. Oncol. 35 (30), 3433–3439. 10.1200/JCO.2016.71.6605
    1. Demetri G. D., von Mehren M., Jones R. L., Hensley M. L., Schuetze S. M., Staddon A., et al. (2016). Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma after Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J. Clin. Oncol. 34 (8), 786–793. 10.1200/JCO.2015.62.4734
    1. Dickson M. A., Schwartz G. K., Keohan M. L., D'Angelo S. P., Gounder M. M., Chi P., et al. (2016). Progression-Free Survival Among Patients with Well-Differentiated or Dedifferentiated Liposarcoma Treated with CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. JAMA Oncol. 2 (7), 937–940. 10.1001/jamaoncol.2016.0264
    1. Digklia A., Britschgi C., Metaxas Y., Kollár A., Krasniqi F., Stathis A.., et al. (2021). SAKK 57/16 Nab-Paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): Results from the Phase Ibpart of a Phase Ib/II Trial [Conference Presentation]. Vancouver: Connective Tissue Oncology Society. CTOS 2021, virtual meeting.
    1. Ducimetière F., Lurkin A., Ranchère-Vince D., Decouvelaere A. V., Péoc'h M., Istier L., et al. (2011). Incidence of Sarcoma Histotypes and Molecular Subtypes in a Prospective Epidemiological Study with central Pathology Review and Molecular Testing. PLoS One 6 (8), e20294. 10.1371/journal.pone.0020294
    1. Ducoulombier A., Cousin S., Kotecki N., Penel N. (2016). Gemcitabine-based Chemotherapy in Sarcomas: A Systematic Review of Published Trials. Crit. Rev. Oncol. Hematol. 98, 73–80. 10.1016/j.critrevonc.2015.10.020
    1. Eisai Global. Eisai's Anticancer Agent Halaven® Newly Approved in japan for Treatment of Soft Tissue Sarcoma (2016). Available at: [Accessed November 10, 2011].
    1. Emambux S., Italiano A. (2017). Clinical Efficacy of Eribulin Mesylate for the Treatment of Metastatic Soft Tissue Sarcoma. Expert Opin. Pharmacother. 18 (8), 819–824. 10.1080/14656566.2017.1326908
    1. Escudero J., Heredia-Soto V., Wang Y., Ruiz P., Gallego A., Pozo-Kreilinger J. J., et al. (2021). Eribulin Activity in Soft Tissue Sarcoma Monolayer and Three-Dimensional Cell Line Models: Could the Combination with Other Drugs Improve its Antitumoral Effect. Cancer Cel Int. [Preprint 21 (1), 646. 10.1186/s12935-021-02337-5
    1. Evans T. R. J., Dean E., Molife L. R., Lopez J., Ranson M., El-Khouly F., et al. (2019). Phase 1 Dose-Finding and Pharmacokinetic Study of Eribulin-Liposomal Formulation in Patients with Solid Tumours. Br. J. Cancer 120 (4), 379–386. 10.1038/s41416-019-0377-x
    1. Fanciullino R., Ciccolini J. (2009). Liposome-encapsulated Anticancer Drugs: Still Waiting for the Magic Bullet. Curr. Med. Chem. 16 (33), 4361–4371. 10.2174/092986709789712916
    1. Fujisawa Y., Fujimura T., Matsushita S., Yamamoto Y., Uchi H., Otsuka A., et al. (2020). The Efficacy of Eribulin Mesylate for Patients with Cutaneous Angiosarcoma Previously Treated with Taxane: a Multicentre Prospective Observational Study. Br. J. Dermatol. 183 (5), 831–839. 10.1111/bjd.19042
    1. Funahashi Y., Okamoto K., Adachi Y., Semba T., Uesugi M., Ozawa Y., et al. (2014). Eribulin Mesylate Reduces Tumor Microenvironment Abnormality by Vascular Remodeling in Preclinical Human Breast Cancer Models. Cancer Sci. 105 (10), 1334–1342. 10.1111/cas.12488
    1. Goel S., Mita A. C., Mita M., Rowinsky E. K., Chu Q. S., Wong N., et al. (2009). A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies. Clin. Cancer Res. 15 (12), 4207–4212. 10.1158/1078-0432.CCR-08-2429
    1. Goto W., Kashiwagi S., Asano Y., Takada K., Morisaki T., Fujita H., et al. (2018). Eribulin Promotes Antitumor Immune Responses in Patients with Locally Advanced or Metastatic Breast Cancer. Anticancer Res. 38 (5), 2929–2938. 10.21873/anticanres.12541
    1. Gris-Oliver A., Ibrahim Y. H., Rivas M. A., García-García C., Sánchez-Guixé M., Ruiz-Pace F., et al. (2021). PI3K Activation Promotes Resistance to Eribulin in HER2-Negative Breast Cancer. Br. J. Cancer 124 (9), 1581–1591. 10.1038/s41416-021-01293-1
    1. Hayasaka N., Takada K., Nakamura H., Arihara Y., Kawano Y., Osuga T., et al. (2019). Combination of Eribulin Plus AKT Inhibitor Evokes Synergistic Cytotoxicity in Soft Tissue Sarcoma Cells. Sci. Rep. 9 (1), 5759. 10.1038/s41598-019-42300-z
    1. Inagaki C., Shimoi T., Okuma H., Kitano A., Shimomura A., Noguchi E., et al. (2018). A Case of Heavily Pretreated Metastatic Cardiac Angiosarcoma Treated Successfully Using Eribulin. Anticancer Drugs 29 (1), 97–101. 10.1097/CAD.0000000000000558
    1. Iwamoto K., Fujisawa Y., Ishitsuka Y., Maruyama H., Nakamura Y., Okiyama N., et al. (2018). A Case of Cutaneous Angiosarcoma Successfully Treated with Eribulin. Eur. J. Dermatol. 28 (3), 410–412. 10.1684/ejd.2018.3278
    1. Kashiwagi S., Asano Y., Goto W., Takada K., Takahashi K., Noda S., et al. (2017b). Use of Tumor-Infiltrating Lymphocytes (TILs) to Predict the Treatment Response to Eribulin Chemotherapy in Breast Cancer. PLoS One 12 (2), e0170634. 10.1371/journal.pone.0170634
    1. Kashiwagi S., Fukushima W., Asano Y., Goto W., Takada K., Noda S., et al. (2017a). Identification of Predictive Markers of the Therapeutic Effect of Eribulin Chemotherapy for Locally Advanced or Metastatic Breast Cancer. BMC Cancer 17 (1), 604. 10.1186/s12885-017-3598-5
    1. Kawai A., Araki N., Naito Y., Ozaki T., Sugiura H., Yazawa Y., et al. (2017). Phase 2 Study of Eribulin in Patients with Previously Treated Advanced or Metastatic Soft Tissue Sarcoma. Jpn. J. Clin. Oncol. 47 (2), 137–144. 10.1093/jjco/hyw175
    1. Kim G. C., Ahn J. N., Kim J. E., Kim J. H., Jeon M. K., Rha S. Y., et al. (2021). Eribulin and Gemcitabine in Previously Treated Patients with Advanced Liposarcoma or Leiomyosarcoma: A Multicenter, Single-Arm, Phase 2-trial. J. Clin. Oncol. 39, 11516. 10.1200/JCO.2021.39.15_suppl.11516
    1. Kobayashi E., Naito Y., Asano N., Maejima A., Endo M., Takahashi S., et al. (2019). Interim Results of a Real-World Observational Study of Eribulin in Soft Tissue Sarcoma Including Rare Subtypes. Jpn. J. Clin. Oncol. 49 (10), 938–946. 10.1093/jjco/hyz096
    1. Kobayashi H., Okuma T., Oka H., Okajima K., Ishibashi Y., Zhang L., et al. (2019). Body Composition as a Predictor of Toxicity after Treatment with Eribulin for Advanced Soft Tissue Sarcoma. Int. J. Clin. Oncol. 24 (4), 437–444. 10.1007/s10147-018-1370-8
    1. McBride A., Butler S. K. (2012). Eribulin Mesylate: a Novel Halichondrin B Analogue for the Treatment of Metastatic Breast Cancer. Am. J. Health Syst. Pharm. 69 (9), 745–755. 10.2146/ajhp110237
    1. Morgan R. J., Synold T. W., Longmate J. A., Quinn D. I., Gandara D., Lenz H. J., et al. (2015). Pharmacodynamics (PD) and Pharmacokinetics (PK) of E7389 (Eribulin, Halichondrin B Analog) during a Phase I Trial in Patients with Advanced Solid Tumors: a California Cancer Consortium Trial. Cancer Chemother. Pharmacol. 76 (5), 897–907. 10.1007/s00280-015-2868-7
    1. Mukohara T., Nagai S., Mukai H., Namiki M., Minami H. (2012). Eribulin Mesylate in Patients with Refractory Cancers: a Phase I Study. Invest. New Drugs 30 (5), 1926–1933. 10.1007/s10637-011-9741-2
    1. Nakai S., Tamiya H., Imura Y., Nakai T., Yasuda N., Wakamatsu T., et al. (2020). Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and via Vascular Remodeling. Mol. Cancer Ther. 19 (3), 742–754. 10.1158/1535-7163.MCT-19-0358
    1. Nakamura T., Tsukushi S., Asanuma K., Katagiri H., Ikuta K., Nagano A., et al. (2019). The Clinical Outcome of Eribulin Treatment in Japanese Patients with Advanced Soft Tissue Sarcoma: a Tokai Musculoskeletal Oncology Consortium Study. Clin. Exp. Metastasis 36 (4), 343–350. 10.1007/s10585-019-09980-3
    1. Nathenson M., Choy E., Carr N., Hibbard H. D., Mazzola E., Catalano P. J., et al. (2020). Phase II Study of Eribulin and Pembrolizumab in Patients (Pts) with Metastatic Soft Tissue Sarcomas (STS): Report of LMS Cohort. J. Clin. Oncol. 38, 11559. 10.1200/JCO.2020.38.15_suppl.11559
    1. Nathenson M. J., Choy E., Mazzola E., Morgan J. A., Cote G., Hohos M., et al. (2021). Abstracts Connective Tissue Oncology Society 2021 Virtual Meeting. Vancouver: Connective Tissue Oncology Society. in press.
    1. National Cancer Institute. Drugs Approved for Soft Tissue Sarcoma (2020). Available at: [Accessed November 7, 2021].
    1. Robles A. J., Kurmasheva R. T., Bandyopadhyay A., Phelps D. A., Erickson S. W., Lai Z., et al. (2020). Evaluation of Eribulin Combined with Irinotecan for Treatment of Pediatric Cancer Xenografts. Clin. Cancer Res. 26 (12), 3012–3023. 10.1158/1078-0432.CCR-19-1822
    1. Sampson V. B., Vetter N. S., Zhang W., Patil P. U., Mason R. W., George E., et al. (2016). Integrating Mechanisms of Response and Resistance against the Tubulin Binding Agent Eribulin in Preclinical Models of Osteosarcoma. Oncotarget 7 (52), 86594–86607. 10.18632/oncotarget.13358
    1. Schöffski P., Chawla S., Maki R. G., Italiano A., Gelderblom H., Choy E., et al. (2016). Eribulin versus Dacarbazine in Previously Treated Patients with Advanced Liposarcoma or Leiomyosarcoma: a Randomised, Open-Label, Multicentre, Phase 3 Trial. Lancet 387 (10028), 1629–1637. 10.1016/S0140-6736(15)01283-0
    1. Schöffski P., Ray-Coquard I. L., Cioffi A., Bui N. B., Bauer S., Hartmann J. T.., et al. (2011). Activity of Eribulin Mesylate in Patients with Soft-Tissue Sarcoma: a Phase 2 Study in Four Independent Histological Subtypes. Lancet Oncol. 12 (11), 1045–1052. 10.1016/S1470-2045(11)70230-3
    1. Shetty N., Gupta S. (2014). Eribulin Drug Review. South. Asian J. Cancer 3 (1), 57–59. 10.4103/2278-330X.126527
    1. Smith J. A., Wilson L., Azarenko O., Zhu X., Lewis B. M., Littlefield B. A., et al. (2010). Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability. Biochemistry 49 (6), 1331–1337. 10.1021/bi901810u
    1. Tan A. R., Rubin E. H., Walton D. C., Shuster D. E., Wong Y. N., Fang F., et al. (2009). Phase I Study of Eribulin Mesylate Administered once Every 21 Days in Patients with Advanced Solid Tumors. Clin. Cancer Res. 15 (12), 4213–4219. 10.1158/1078-0432.CCR-09-0360
    1. Tap W. D., Wagner A. J., Schöffski P., Martin-Broto J., Krarup-Hansen A., Ganjoo K. N., et al. (2020). Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients with Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA 323 (13), 1266–1276. 10.1001/jama.2020.1707
    1. The U.S. Food and Drug Administration (2016). Available at: [Accessed November 15 2021].
    1. Tolaney S. M., Kalinsky K., Kaklamani V. G., D'Adamo D. R., Aktan G., Tsai M. L., et al. (2021). Eribulin Plus Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer (ENHANCE 1): A Phase Ib/II Study. Clin. Cancer Res. 27 (11), 3061–3068. 10.1158/1078-0432.CCR-20-4726
    1. Tsuchihashi K., Kusaba H., Yoshihiro T., Fujiwara T., Setsu N., Endo M., et al. (2020). Eribulin as a First-Line Treatment for Soft Tissue Sarcoma Patients with Contraindications for Doxorubicin. Sci. Rep. 10 (1), 20896. 10.1038/s41598-020-77898-y
    1. Ueda S., Saeki T., Takeuchi H., Shigekawa T., Yamane T., Kuji I., et al. (2016). In Vivo imaging of Eribulin-Induced Reoxygenation in Advanced Breast Cancer Patients: a Comparison to Bevacizumab. Br. J. Cancer 114 (11), 1212–1218. 10.1038/bjc.2016.122
    1. U. S. National Library of Medicine. Eribulin and Radiation Therapy in Treating Patients with Retroperitoneal Liposarcoma that Can Be Removed by Surgery (2021). Available at: [Accessed November 11, 2021]
    1. Vahdat L. T., Pruitt B., Fabian C. J., Rivera R. R., Smith D. A., Tan-Chiu E., et al. (2009). Phase II Study of Eribulin Mesylate, a Halichondrin B Analog, in Patients with Metastatic Breast Cancer Previously Treated with an Anthracycline and a Taxane. J. Clin. Oncol. 27 (18), 2954–2961. 10.1200/JCO.2008.17.7618
    1. van der Graaf W. T., Blay J. Y., Chawla S. P., Kim D. W., Bui-Nguyen B., Casali P. G., et al. (2012). Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE): a Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial. Lancet 379 (9829), 1879–1886. 10.1016/S0140-6736(12)60651-5
    1. Wada N., Uchi H., Furue M. (2018). Case of Angiosarcoma of the Scalp Successfully Controlled by Eribulin. J. Dermatol. 45 (1), 116–117. 10.1111/1346-8138.13775
    1. WHO Classification of Tumours Editorial Board (2020). WHO Classification of Tumours of Soft Tissue and Bone. 5th Ed. Lyon, France: IARC Press.
    1. Wiemer E. A. C., Wozniak A., Burger H., Smid M., Floris G., Nzokirantevye A., et al. (2017). Identification of microRNA Biomarkers for Response of Advanced Soft Tissue Sarcomas to Eribulin: Translational Results of the EORTC 62052 Trial. Eur. J. Cancer 75, 33–40. 10.1016/j.ejca.2016.12.018
    1. Wozniak A., Boeckx B., Modave E., Weaver A., Lambrechts D., Littlefield B. A., et al. (2021). Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma. Clin. Cancer Res. 27 (11), 3106–3115. 10.1158/1078-0432.CCR-20-4315
    1. Yoshida T., Ozawa Y., Kimura T., Sato Y., Kuznetsov G., Xu S., et al. (2014). Eribulin Mesilate Suppresses Experimental Metastasis of Breast Cancer Cells by Reversing Phenotype from Epithelial-Mesenchymal Transition (EMT) to Mesenchymal-Epithelial Transition (MET) States. Br. J. Cancer 110 (6), 1497–1505. 10.1038/bjc.2014.80
    1. Yu Y., Desjardins C., Saxton P., Lai G., Schuck E., Wong Y. N. (2013). Characterization of the Pharmacokinetics of a Liposomal Formulation of Eribulin Mesylate (E7389) in Mice. Int. J. Pharm. 443 (1-2), 9–16. 10.1016/j.ijpharm.2013.01.010

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