A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Abstract

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.

Keywords: ACOX1; PDAC; genetic biomarker; pain; pancreatic cancer; tyrosine–kinase inhibitor.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.

(A) Overall survival analysis in patients with advanced PDAC and treated with placebo plus gemcitabine (standard-of-care) according to subgroups defined via pharmacogenomic data (i.e. the ‘ACOX1’ subgroup versus its complement ‘non ACOX1’ subgroup); corresponding HR was 0.46 [95% CI (0.26; 0.82), P = 0.007]. (B) Overall survival analysis in patients with advanced PDAC and treated with placebo plus gemcitabine according to subgroups defined via a baseline variable (i.e. the ‘pain’ subgroup versus the ‘no pain’ subgroup); corresponding HR was 0.30 [95% CI (0.18; 0.48), P < 0.001]. These data demonstrate the prognostic value of ACOX1 overexpression in blood and baseline pain intensity, thereby revealing two patient subgroups with remarkably poor survival and a critical unmet medical need. Median follow-up of 26 months; univariate model.