Journal Article

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

Benhadji, Karim A, Kozloff, Mark, Lahn, Michael M F, Garcia-Carbonero, Rocio, Gueorguieva, Ivelina, Tabernero, Josep, Pezet, Denis, Cleverly, Ann, Smith, Claire, Macarulla, Teresa, Melisi, Davide, Fuchs, Martin, Oettle, Helmut, Blunt, Al, Estrem, Shawn T, Deplanque, Gael, Trojan, Jorg

2018

Overview

BackgroundGalunisertib 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.MethodsThis 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.ResultsDose-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.ConclusionsGalunisertib–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.

• Publisher: Nature Publishing Group
• Subject: Adenocarcinoma / Bayesian analysis / Biomarkers / Chemotherapy / Clinical trials / Enzyme inhibitors / Gemcitabine / Inflammation / Macrophage inflammatory protein / Macrophage inflammatory protein 1 / Metastases / Monoclonal antibodies / Pancreatic cancer / Patients / Protein-serine/threonine kinase / Targeted cancer therapy / Toxicity / Transforming growth factor-b / α-Interferon / γ-Interferon