Abstract
Purpose
Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue.
Methods
We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests.
Results
A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0–33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models (‘multiple models’) had a significantly better median response rate than those tested using only one (‘single model’) or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027).
Conclusion
Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.
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Data availability
All data collected was publicly available at the time of the systematic review. The dataset generated during this review and used for subsequent analyses is included as a supplementary material. R code is available from the corresponding author on reasonable request.
Change history
22 August 2022
A Correction to this paper has been published: https://doi.org/10.1007/s11060-022-04119-z
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Acknowledgements
We would like to thank Ms. Shreya Hariharan for her assistance with the generation of figures, Dr Emily Jenkins for her assistance with data management, and Ms. Kerryn Westcott for her advice and feedback on the manuscript at various stages.
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Author AG is supported by the Cancer Research UK Clinical Research Training Fellowship Programme and a John Monash Scholarship. Author HKG is a recipient of a Victorian Government Centre of Research Excellence in Brain Cancer award through the Victorian Cancer Agency.
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AG, AB, SP, HKG: research, manuscript writing and revision. SM, UH, LC: review, contribution to discussion, editing of manuscript. HG: Overall supervision.
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Author AG has received speaker honorarium from company Bristol Myers Squibb.
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The original version of this article has been revised: The last two sentences in the Results section have been corrected and the missing Supplementary Figs. 1 and 2 have been added to the Supplementary Information.
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Gunjur, A., Balasubramanian, A., Hafeez, U. et al. Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review. J Neurooncol 159, 539–549 (2022). https://doi.org/10.1007/s11060-022-04092-7
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DOI: https://doi.org/10.1007/s11060-022-04092-7