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Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review

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A Correction to this article was published on 22 August 2022

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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.

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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.

Funding

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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Authors and Affiliations

  1. Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, UK

    Ashray Gunjur

  2. Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    Ashray Gunjur, Adithya Balasubramanian, Umbreen Hafeez, Siddharth Menon, Lawrence Cher, Sagun Parakh & Hui Kong Gan

  3. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia

    Adithya Balasubramanian

  4. Olivia Newton-John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    Umbreen Hafeez, Siddharth Menon, Sagun Parakh & Hui Kong Gan

  5. La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    Umbreen Hafeez, Siddharth Menon, Sagun Parakh & Hui Kong Gan

  6. Medical Student Education, University of Melbourne, Gratton St, Parkville, VIC, 3010, Australia

    Umbreen Hafeez

  7. Department of Medicine, University of Melbourne, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    Hui Kong Gan

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  1. Ashray Gunjur
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Contributions

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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Correspondence to Hui Kong Gan.

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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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