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Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study

British Journal of Cancer volume 129, pages 1940–1948 (2023)Cite this article

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Abstract

Background

The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort.

Methods

Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success.

Results

From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%–[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%–[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%).

Conclusion

Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

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Data availability

The datasets generated and analysed during the current study are not publicly available due to European regulation on data privacy (GDPR). The datasets are also now under licence with Bayer and thus submitted to restrictions. Data are, however, available from the authors upon reasonable request and with permission of Bayer, according to the conditions stated as follows: European regulatory framework: De-identified study data are considered as personal data within the meaning of Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016, known as “GDPR”. French regulatory framework: In addition to GDPR, the transfer of this data by Unicancer is a processing in itself that is subject to Chapter IX and XII of the updated Within the framework of this law, the data processing is permitted by Unicancer’s conformity to the MR-001 Code of conduct.

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Acknowledgements

We thank the patients and their families for their participation in the study. We thank all the UNICANCER sarcoma staff members involved in the trial management. The data management was conducted by UNICANCER, the analysis was done by Centre Léon Bérard. We thank the patient advocacy group InfoSarcomes. We thank the French National Cancer Institute for funding the labelled networks for the management of sarcoma (e.g., NetSarc, RRePS, RESOS, and InterSarc).

Funding

Bayer Healthcare SAS (Loos, France) supplied regorafenib and placebo tablets and provided funding to UNICANCER. The funder had no role in study design, data collection, monitoring, analysis, and interpretation or writing of the report. Once the trial has been designed, UNICANCER, as the Sponsor for the study, in collaboration with the French Sarcoma Group was responsible for all aspects of the trial. This study was not funded by NIH.

Author information

Authors and Affiliations

  1. APHM Hopital La Timone, Medical Oncology Unit, and Aix-Marseille University (AMU), Marseille, France

    Florence Duffaud

  2. Medical Oncology Department, Centre Léon Bérard, Lyon, France

    Jean-Yves Blay

  3. Medical Oncology Department, Gustave Roussy, Villejuif, France

    Axel Le Cesne

  4. Medical Oncology Department, Institut Universitaire de Cancérologie de Toulouse, Oncopole, Toulouse, France

    Christine Chevreau

  5. Medical Oncology Department, Centre Hospitalier Universitaire Cochin, APHP, Paris, France

    Pascaline Boudou-Rouquette

  6. Medical Oncology Department, CHU J Minjoz, Besançon, France

    Elsa Kalbacher

  7. Medical Oncology Department, Centre Oscar Lambret and Lille University Hospital, Lille, France

    Nicolas Penel

  8. Medical Oncology Unit, Centre Eugène Marquis, Rennes, France

    Christophe Perrin

  9. Medical Oncology Department, Institut Curie, Paris, France

    Valérie Laurence

  10. Medical Oncology Department, Centre René Gauduchau, Saint Herblain, France

    Emmanuelle Bompas

  11. Medical Oncology Department, Centre Antoine Lacassagne, Nice, France

    Esma Saada-Bouzid

  12. Medical Oncology Department, Centre François Baclesse, Caen, France

    Corinne Delcambre

  13. Medical Oncology Department, Institut Paoli-Calmettes, Marseille, France

    François Bertucci

  14. Medical Oncology Department, Centre Hospitalier Régional Universitaire Bretonneau, Tours, France

    Mathilde Cancel

  15. Department of Statistics, Centre Léon Bérard, Lyon, France

    Camille Schiffler & Sylvie Chabaud

  16. Unicancer, Paris, France

    Laure Monard

  17. APHM Hopital La Timone, Pathology Department, and Aix-Marseille University, Marseille, France

    Corinne Bouvier

  18. APHM Hopital La Timone, Radiology Department, and Aix-Marseille University Marseille, Marseille, France

    Vincent Vidal

  19. Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Villejuif, France

    Nathalie Gaspar

Authors
  1. Florence Duffaud
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Contributions

FD and SC designed and supervised the trial and wrote the article; FD, SC and CS analysed the data and contributed to the trial design. All other authors supervised clinical patient management, reviewed and approved the article.

Corresponding author

Correspondence to Florence Duffaud.

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Competing interests

FD received travel grants from Pharmamar, and Leo Pharma, attended advisory boards for Bayer, Lilly. CC attended advisory boards for Leo Pharma, JYB receives research support and honoraria from Eisei, Eli Lilly, MSD, BMS, GSK, Ignyta, Novartis, Pharmamar and Roche unrelated to this work. AL, AI, PB, EK, NP, CP, VL, EB, ESBB, FB, CS, VL, MC, CS,LM, VV, NG and SC declare no competing interests.

Ethics approval and consent to participate

The study was approved by an ethical and regulatory committee (French Ethical Committee, Comité de Protection des Personnes Sud Méditerrannée 1, approved on March 26, 2014). This study was performed in accordance wuth the Declaration of Helsinki. All patients provided written informed consent before enrolment, and one study amendment (protocol V6, June 29, 2016) expanded enrolment to include paediatric patients aged >10 years (although ultimately only one child was enrolled). The trial is registered in the European Clinical Trials Register database (EudraCT N°: 2013-003910-42) and at ClinicalTrials.gov (NCT02389244).

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Duffaud, F., Blay, JY., Le Cesne, A. et al. Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study. Br J Cancer 129, 1940–1948 (2023). https://doi.org/10.1038/s41416-023-02413-9

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