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Cancer Chemother Pharmacol. 2019 May;83(5):975-991. doi: 10.1007/s00280-019-03807-4. Epub 2019 Mar 18.

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

Author information

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@univr.it.
2
University Hospital Doce de Octubre, Institute of Health Research Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain.
3
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Autonomous University of Barcelona, CIBERONC, Barcelona, Spain.
4
Digestive Surgery Service, CHU Clermont-Ferrand, University Clermont Auvergne, Clermont-Ferrand, France.
5
Medical Oncology, Saint Joseph Hospital, Paris, France.
6
Hospital Bogenhausen, Municipal Hospital Munich GmbH, Munich, Germany.
7
Goethe University Medical Center, Frankfurt, Germany.
8
Ingalls Memorial Hospital, Harvey, IL, USA.
9
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.
10
Eli Lilly and Company, Erl Wood, UK.
11
BioStat Solutions, Inc, Frederick, MD, USA.
12
Eli Lilly and Company, Indianapolis, IN, USA.

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.

KEYWORDS:

CA19-9; Galunisertib; Pancreatic cancer; TGF-β1

PMID:
30887178
DOI:
10.1007/s00280-019-03807-4

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