Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting

Eur J Cancer. 2016 Apr;57:31-8. doi: 10.1016/j.ejca.2015.12.029. Epub 2016 Feb 4.

Abstract

Background: Imatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined. The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST.

Patients and methods: Advanced GIST patients (n=96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively.

Results: Small bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p=0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p=0.0256) and for both stomach (p=0.043) and small bowel (p=0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p=0.0271) in the whole population independently of the anatomical localisation.

Conclusion: Concentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

Keywords: Gastrointestinal stromal tumour; Imatinib; Therapeutic drug monitoring.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics*
  • Disease Progression
  • Drug Monitoring
  • Female
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Stromal Tumors / blood
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Humans
  • Imatinib Mesylate / metabolism
  • Imatinib Mesylate / pharmacokinetics*
  • Intestine, Small / chemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Prospective Studies
  • Stomach / chemistry
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Imatinib Mesylate