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Clinical Trial
. 2018 Nov;119(10):1208-1214.
doi: 10.1038/s41416-018-0246-z. Epub 2018 Oct 15.

Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer

Davide Melisi  1 , Rocio Garcia-Carbonero  2 , Teresa Macarulla  3 , Denis Pezet  4 , Gael Deplanque  5 , Martin Fuchs  6 , Jorg Trojan  7 , Helmut Oettle  8 , Mark Kozloff  9 , Ann Cleverly  10 , Claire Smith  11 , Shawn T Estrem  12 , Ivelina Gueorguieva  10 , Michael M F Lahn  13 , Al Blunt  14 , Karim A Benhadji  15 , Josep Tabernero  16
Affiliations
Clinical Trial

Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer

Davide Melisi et al. Br J Cancer. 2018 Nov.

Abstract

Background: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined.

Methods: This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.

Results: Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit.

Conclusions: Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.

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Conflict of interest statement

D.M. reports research funding from Shire, Incyte, and Celgene; a consulting role with Eli Lilly, Shire, Baxter and Incyte. G.D. reports research funding from Bavarian Nordici, Genentech, Janssen-Cilag, Roche, Sanofi, Eli Lilly, Exelixis, Sotio and Merck Serono; and travel fees from Roche, Amgen and Sanofi. M.F. reports a consulting role with Eli Lilly. J.T. reports a consulting role with Eli Lilly; speakers’ bureau from Bayer, Amgen and Merck Serono; and travel fees from Bayer. M.K. reports honorarium from Eli Lilly, Genentech, and Roche; a consulting role with Eli Lilly, Genentech, and Roche; and speakers’ bureau from Eli Lilly during the conduct of the study, Genentech, and Roche. A.C., C.S., S.T.E., I.G. and K.A.B. are all current employees and stockholders of Eli Lilly; M.M.F.L. is a former employee and stockholder of Eli Lilly and current employee of Incyte. A.B. is a current employee and stockholder of Advaxis, Inc. J.T. reports a consulting role with Eli Lilly, Amgen, Boehringer Ingelheim, Celgene, Chugai, Imclone, Merck, Merck Serono, Millenium, Novartis, Roche, Sanofi, Symphogen and Taiho. R.G.-C., T.M., D.P. and H.O. declare no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimates of survival by Bayesian vs. frequentist analysis, with 95% Hall–Wellner confidence bands and numbers at risk. overall survival by a Bayesian analysis, b frequentist analysis and c progression-free survival by frequentist analysis. Data for one patient was missing from the progression-free survival analysis. CI=confidence interval; GAL=galunisertib; GEM=gemcitabine; No.=number; PLC=placebo
Fig. 2
Fig. 2
Kaplan–Meier estimates of survival by potential predictive factor, with 95% Hall–Wellner confidence bands and numbers at risk. Overall survival by plasma level of a follicle-stimulating hormone, b interferon-gamma induced protein 10, c macrophage inflammatory protein-1 alpha, and d plasminogen activator inhibitor 1. CL=confidence limits; GAL=galunisertib; GEM=gemcitabine; No.=number; PLC=placebo
See this image and copyright information in PMC

References

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