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.
- Klíčová slova
- ACOX1, PDAC, genetic biomarker, pain, pancreatic cancer, tyrosine–kinase inhibitor,
- MeSH
- analýza podle původního léčebného záměru MeSH
- benzamidy MeSH
- časové faktory MeSH
- deoxycytidin škodlivé účinky analogy a deriváty terapeutické užití MeSH
- dospělí MeSH
- duktální karcinom slinivky břišní farmakoterapie enzymologie genetika mortalita patologie MeSH
- farmakogenetika MeSH
- gemcitabin MeSH
- individualizovaná medicína MeSH
- inhibitory proteinkinas škodlivé účinky terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory slinivky břišní farmakoterapie enzymologie genetika mortalita patologie MeSH
- oxidoreduktasy genetika MeSH
- piperidiny MeSH
- prediktivní hodnota testů MeSH
- proporcionální rizikové modely MeSH
- prospektivní studie MeSH
- protinádorové antimetabolity škodlivé účinky terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- pyridiny MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thiazoly škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
- Geografické názvy
- Evropa MeSH
- Spojené státy americké MeSH
- Názvy látek
- benzamidy MeSH
- deoxycytidin MeSH
- gemcitabin MeSH
- inhibitory proteinkinas MeSH
- masitinib MeSH Prohlížeč
- nádorové biomarkery MeSH
- oxidoreduktasy MeSH
- piperidiny MeSH
- protinádorové antimetabolity MeSH
- pyridiny MeSH
- thiazoly MeSH
