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TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer

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Abstract

Purpose

Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking.

Methods

In the Phase 1b/2 JBAJ study, 156 patients were randomized 2:1 to galunisertib + gemcitabine (N = 104) or placebo + gemcitabine (N = 52). Clinical outcome data were integrated with baseline markers and pharmacodynamic markers while patients were on treatment, including circulating proteins using a multi-analyte panel, T cell subset evaluation, and miRNA profiling.

Results

Baseline biomarkers associated with overall prognosis regardless of treatment included CA19-9 and TGF-β1. In addition, IP-10, FSH, MIP-1α, and PAI-1 were potential predictive proteins. Baseline proteins that were changed during treatment included amphiregulin, CA15-3, cathepsin D, P-selectin, RAGE, sortilin, COMP, eotaxin-2, N-BNP, osteopontin, and thrombospondin-4. Plasma miRNA with potential prognostic value included miR-21-5p, miR-301a-3p, miR-210-3p, and miR-141-3p, while those with potential predictive value included miR-424-5p, miR-483-3p, and miR-10b-5p.

Conclusions

Galunisertib + gemcitabine resulted in improvement of overall survival, and 4 proteins (IP-10, FSH, MIP-1α, PAI-1) were potentially predictive for this combination treatment. Future studies should also include baseline evaluation of miR-424-5p, miR-483-3p, and miR-10b-5p.

Trial registration

Clinicaltrials.gov NCT01373164.

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Acknowledgements

The study team thanks patients and families for their willingness to participate in this study. We also thank all site staff and investigators at the institutions, and the trial personnel at Eli Lilly and Company and Covance. Work in the unit of the corresponding author was supported by the Investigator Grant no. 19111 through the Associazione Italiana per la Ricerca sul Cancro, Italy. Writing assistance was provided by Ananya Biswas (Eli Lilly Services India Pvt. Ltd., India).

Funding

This study was funded by Eli Lilly and Company, Indianapolis, Indiana, USA (Grant Number 230-0061-07472).

Author information

Authors and Affiliations

  1. Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, Università degli studi di Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy

    Davide Melisi & Francesca Simionato

  2. University Hospital Doce de Octubre, Institute of Health Research Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain

    Rocio Garcia-Carbonero

  3. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Autonomous University of Barcelona, CIBERONC, Barcelona, Spain

    Teresa Macarulla & Josep Tabernero

  4. Digestive Surgery Service, CHU Clermont-Ferrand, University Clermont Auvergne, Clermont-Ferrand, France

    Denis Pezet

  5. Medical Oncology, Saint Joseph Hospital, Paris, France

    Gael Deplanque

  6. Hospital Bogenhausen, Municipal Hospital Munich GmbH, Munich, Germany

    Martin Fuchs

  7. Goethe University Medical Center, Frankfurt, Germany

    Jorg Trojan

  8. Ingalls Memorial Hospital, Harvey, IL, USA

    Mark Kozloff

  9. Eli Lilly and Company, Erl Wood, UK

    Ann Cleverly & Claire Smith

  10. BioStat Solutions, Inc, Frederick, MD, USA

    Shuaicheng Wang

  11. Eli Lilly and Company, Indianapolis, IN, USA

    Michael Man, Kyla E. Driscoll, Shawn T. Estrem, Michael M. F. Lahn & Karim A. Benhadji

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  1. Davide Melisi
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Corresponding author

Correspondence to Davide Melisi.

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Conflict of interest

Ann Cleverly, Ivelina Gueorguieva, Karim A. Benhadji, Shawn T. Estrem, Kyla Driscoll, and Michael Man are employees of Eli Lilly and Company, Indianapolis, Indiana, USA, and may hold company stock. Michael M. F. Lahn and Claire Smith are former employees of Eli Lilly and Company and hold company stock. Josep Tabernero has had an advisory role for Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, MSD, Merck Serono, Merrimack, Novartis, Peptomyc, Roche, Sanofi, Symphogen, and Taiho. Denis Pezet has had an advisory role for Sanofi, Novartis, and Roche.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Melisi, D., Garcia-Carbonero, R., Macarulla, T. et al. TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Cancer Chemother Pharmacol 83, 975–991 (2019). https://doi.org/10.1007/s00280-019-03807-4

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  • DOI: https://doi.org/10.1007/s00280-019-03807-4

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