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

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/m 2 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.

Transforming Growth Factor-β Signaling in Immunity and Cancer

“…The most extensively tested compound is Galunisertib (LY2157299), a small molecule that inhibits TGFBR1 kinase activity. Galunisertib in combination with gemcitabine has shown modest but significant therapeutic activity in a phase 2 clinical trial for pancreatic cancer (Melisi et al, 2018). Another phase 2 clinical trial demonstrated therapeutic responses in a subset of hepatocellular carcinoma patients treated with Galunisertib as monotherapy (Faivre et al, 2014).…”

Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling

“…Interestingly, patients who had decreased expression levels of specified blood biomarkers [e.g., alpha-fetoprotein (AFP), TGF-β1, and CDH1] had improved clinical outcomes, indicating that the effects of galunisertib might be more pronounced in patients with a poor prognosis due to elevated AFP at baseline (147). Similarly, galunisertib in combination with gemcitabine improved OS with minimal added toxicity in a phase II study on patients with locally advanced or metastatic pancreatic adenocarcinoma who were considered candidates for first-line chemotherapy with gemcitabine (146).…”

Permissive State of EMT: The Role of Immune Cell Compartment

“…TGF-β is the central inflammatory cytokine in TME and its role in mediating EMT in different types of cancer has been extensively studied and well-established (51)(52)(53)(54)(55)(56)(57). It is known that TGF-β can have a dual role in cancer progression: it can exert an anticancer role by suppressing tumor proliferation, inducing apoptosis and cell differentiation, but it can also facilitate cancer development and metastasis (58).…”