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

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.

Trial registration: ClinicalTrials.gov NCT01012297.

Keywords: Advanced or metastatic leiomyosarcoma; Benchmark; Efficacy; Meta-analysis; Study design.

Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 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.

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