Efficacy thresholds for clinical trials with advanced or metastatic leiomyosarcoma patients: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group meta-analysis based on a literature review for soft-tissue sarcomas

Georgios Kantidakis, Saskia Litière, Anouk Neven, Marie Vinches, Ian Judson, Patrick Schöffski, Eva Wardelmann, Silvia Stacchiotti, Lorenzo D'Ambrosio, Sandrine Marréaud, Winette T.A. van der Graaf, Bernd Kasper, Marta Fiocco, Hans Gelderblom*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

Background: In 2002, the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group reported well-established values for conducting phase II trials for soft-tissue sarcomas. An update is provided for leiomyosarcoma (LMS). Materials and methods: Clinical trials with advanced or metastatic LMS were identified via literature review in PubMed (published 2003–2018, ≥10 adult LMS patients). End-points were 3- and 6-month progression-free survival rates (PFSR-3m and PFSR-6m). When estimates could not be derived from publications, data requests were sent out. Treatments were classified as recommended (R-T) or non-recommended (NR-T) according to the ESMO 2018 guidelines. A random effects meta-analysis was used to pool trial-specific estimates for first-line (1L) or pre-treated (2L+) patients separately. The ESMO Magnitude of Clinical Benefit Scale was used to guide the treatment effect to target in future trials. Results: From 47 studies identified, we obtained information on 7 1L and 16 2L+ trials for 1500 LMS patients. Overall, in 1L, PFSR-3m and PFSR-6m were 74% (95% confidence interval [CI] 64–82%) and 58% (95% CI 50–66%), respectively. For 2L+, PFSR-3m was 48% (95% CI 41–54%), and PFSR-6m was 28% (95% CI 22–34%). No difference was observed between R-T and NR-T for first or later lines. Under the alternative that the true benefit amounts to a hazard ratio of 0.65, a PFSR-6m ≥70% can be considered to suggest drug activity in 1L. For 2L+, a PFSR-3m ≥62% or PFSR-6m ≥44% would suggest drug activity. Specific results are also provided for uterine LMS. Conclusions: This work provides a new benchmark for designing phase II studies for advanced or metastatic LMS.

Original languageEnglish
Pages (from-to)253-268
Number of pages16
JournalEuropean Journal of Cancer
Volume154
DOIs
Publication statusPublished - 1 Sept 2021

Bibliographical note

Funding Information:
This work was supported by the European Organisation for Research and Treatment of Cancer – Soft Tissue and Bone Sarcoma Group (EORTC – STBSG). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Funding Information:
Georgios Kantidakis's work as a Fellow at EORTC Headquarters was supported by a grant from the EORTC Soft Tissue and Bone Sarcoma Group and Leiden University as well as from the EORTC Cancer Research Fund (ECRF). Marie Vinches's work as a Fellow at EORTC Headquarters was supported by a grant from Fonds Cancer (FOCA) from Belgium. This publication was supported by a donation from the Kom Op Tegen Kanker from Belgium. The authors would like to express our gratitude to all primary investigators who shared 3- and 6-month PFS estimates of their clinical trials with leiomyosarcoma patients for undertaking this research project, namely, Dr Beatrice Seddon (one study), Prof Armando Santoro (one study), Dr William D. Tap (one study), Prof Scott M. Schuetze (two studies), Dr Akira Kawai (one study), and Dr Amit M. Oza (one study). The authors thank NRG Oncology Statistics and Data Management Center (NRG SDMC) for the provision of data from the NRG/GOG 087K, 087L, 131H, 231C clinical trials related to uterine Leiomyosarcoma. This article was prepared using data from Dataset GOG-0250 from the NCTN Data Archive of the National Cancer Institute's (NCI's) National Clinical Trials Network (NCTN). Data were originally collected from clinical trial NCT01012297 ‘A Randomised Phase III Evaluation of Docetaxel (NSC #628503) and Gemcitabine (NSC #613327) Plus G-CSF With Bevacizumab (NSC #704865) Versus Docetaxel (NSC #628503) and Gemcitabine (NSC #613327) Plus G-CSF With Placebo in the Treatment of Recurrent or Advanced Leiomyosarcoma of the Uterus’. All analyses and conclusions in this article are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, or the NCI.

Funding Information:
P.S. has reported honoraria from Deciphera, Blueprint Medicines, Boehringer Ingelheim; consultancy or advisory role for Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital; consultancy or advisory role to the Institution for Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Advanced Medical; has received support for travel, accommodation, expenses from Boehringer Ingelheim, MSD, Ipsen; research funding to the Institution from CoBioRes NV , Eisai , G1 Therapeutics , Novartis , PharmaMar ; all outside the scope of the submitted work. S.S. has reported honoraria, consultancy or advisory role for Adaptimmune, Bayer, Daiichi-Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Immunedesign, Karyopharm, Maxivax, Novartis, PharmaMar; institutional financial interests with Advenchen , Amgen-Dompè , Bayer , Epizyme , Eli Lilly , Daiichi-Sankyo , Glaxo , Hutchinson MediPharma , Karyopharm , Novartis , Pfizer , PharmaMar , and Springworks ; all outside the scope of this article. L.D’.A. has reported advisory boards for PSI, GSK, and Eisai; performed editorial activity for Novartis; received travel support from PharmaMar, Eli Lilly, and Celgene; all outside the submitted article. W.G. has reported advisory role for Bayer, GSK, and Springworks; received research grant support to the Institute from Eli Lilly and Novartis ; all outside the submitted work. All remaining authors have declared no conflicts of interest.

Funding Information:
This work was supported by the European Organisation for Research and Treatment of Cancer ? Soft Tissue and Bone Sarcoma Group (EORTC ? STBSG). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.P.S. has reported honoraria from Deciphera, Blueprint Medicines, Boehringer Ingelheim; consultancy or advisory role for Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital; consultancy or advisory role to the Institution for Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Advanced Medical; has received support for travel, accommodation, expenses from Boehringer Ingelheim, MSD, Ipsen; research funding to the Institution from CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMar; all outside the scope of the submitted work. S.S. has reported honoraria, consultancy or advisory role for Adaptimmune, Bayer, Daiichi-Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Immunedesign, Karyopharm, Maxivax, Novartis, PharmaMar; institutional financial interests with Advenchen, Amgen-Domp?, Bayer, Epizyme, Eli Lilly, Daiichi-Sankyo, Glaxo, Hutchinson MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, and Springworks; all outside the scope of this article. L.D?.A. has reported advisory boards for PSI, GSK, and Eisai; performed editorial activity for Novartis; received travel support from PharmaMar, Eli Lilly, and Celgene; all outside the submitted article. W.G. has reported advisory role for Bayer, GSK, and Springworks; received research grant support to the Institute from Eli Lilly and Novartis; all outside the submitted work. All remaining authors have declared no conflicts of interest.

Publisher Copyright:
© 2021 The Author(s)

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