BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

Clinical Development AB Science Paris

Clinical Development AB Science Paris; Department of Clinical Hematology Necker Hospital Paris; INSERM UMR 1163 Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications Paris; Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris; CNRS ERL 8254 Paris; Laboratory of Excellence GR Ex Paris; National Reference Center on Mastocytosis Paris

Clinical Development Acobiom Montpellier

Department of Biostatistics University of Texas School of Public Health Houston USA

Department of Clinical and Experimental Oncology Maria Skłodowska Curie Memorial Cancer Center and Institute of Oncology Gliwice Poland

Department of Gastroenterology Hôpital Beaujon Clichy France

Department of Medical Oncology Saint Joseph Hospital Paris

Department of Medical Oncology University Hospital Lille France

Department of Medical Oncology University Hospital of Besançon Besançon

Department of Oncology Palacký University Medical School and Teaching Hospital Olomouc Czech Republic

Metro Minnesota Community Clinical Oncology Program Park Nicollet Institute Minneapolis USA

Signaling Hematopoiesis and Mechanism of Oncogenesis Inserm U1068 CRCM Marseille; Institut Paoli Calmettes Marseille; Aix Marseille University UM 105 Marseille; CNRS UMR7258 CRCM Marseille; Clinical Development AB Science Paris

Southeastern Medical Oncology Center Goldsboro USA

See more in PubMed

Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 2008; 8: 82. PubMed PMC

Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369(18): 1691–1703. PubMed PMC

Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25(15): 1960–1966. PubMed

Humbert M, Castéran N, Letard S, et al. Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model. PLoS ONE 2010; 5: e9430. PubMed PMC

Mitry E, Hammel P, Deplanque G, et al. Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 2010; 66(2): 395–403. PubMed

Zelvyte I, Ohlsson B, Axelson J, Janciauskiene S. Diverse responses between human pancreatic cancer cell lines to native alpha 1-antitrypsin and its C-terminal fragment. Anticancer Res 2003; 23(3B): 2267–2273. PubMed

Winter JM, Tang LH, Klimstra DS, et al. A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers. PLoS One 2012; 7(7): e40157. PubMed PMC

Chang DZ, Ma Y, Ji B, et al. Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res 2011; 17(22): 7015–7023. PubMed PMC

Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol 2013; 4: 210. PubMed PMC

Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009; 4(9): e7258. PubMed PMC

Demir IE, Schorn S, Schremmer-Danninger E, et al. Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. PLoS One 2013; 8(3): e60529. PubMed PMC

Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 2009; 1796(1): 19–26. PubMed PMC

Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

Different clinical presentations of metachronous pulmonary metastases after resection of pancreatic ductal adenocarcinoma: Retrospective study and review of the literature

See more in PubMed

ClinicalTrials.gov
NCT00789633