Stéphane Bouchet1, Sylvie Poulette2, Karine Titier1, Nicholas Moore1, Régis Lassalle3, Abdelilah Abouelfath3, Antoine Italiano4, Christine Chevreau5, Emmanuelle Bompas6, Olivier Collard7, Florence Duffaud8, Maria Rios9, Didier Cupissol10, Antoine Adenis11, Isabelle Ray-Coquard12, Olivier Bouché13, Axel Le Cesne14, Binh Bui4, Jean-Yves Blay12, Mathieu Molimard15. 1. Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France. 2. Univ. de Bordeaux, Bordeaux, F-33000, France. 3. Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM CIC Bordeaux CIC1401 Pharmaco-épidemiologie, Bordeaux, F-33000, France. 4. Institut Bergonié, Bordeaux, F-33000, France. 5. Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, F-31300, France. 6. Centre René Gauducheau, Nantes (Saint-Herblain), F-44805, France. 7. Institut de Cancérologie Lucien Neuwirth, Saint Priest-en-Jarez, F-42270, France. 8. CHU La Timone, Marseille, F-13385, France; Aix Marseille Université (AMU), France. 9. Institut de Cancérologie de Lorraine - Alexis Vautrin, Nancy, F-54500, France. 10. Centre Val d'Aurelle, Montpellier, F-34298, France. 11. Centre Oscar Lambret, Lille, F-59020, France. 12. Centre Léon Bérard, Lyon, F-69008, France; Université Claude Bernard Lyon 1, France. 13. CHU Robert Debré, Reims, F-51092, France. 14. Institut Gustave-Roussy, Villejuif, F-94805, France. 15. Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France. Electronic address: mathieu.molimard@u-bordeaux.fr.
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.
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 GISTpatients (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 GISTpatients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.
Authors: Nienke A G Lankheet; Ingrid M E Desar; Sasja F Mulder; David M Burger; Dinemarie M Kweekel; Carla M L van Herpen; Winette T A van der Graaf; Nielka P van Erp Journal: Br J Clin Pharmacol Date: 2017-07-04 Impact factor: 4.335
Authors: Remy B Verheijen; Huixin Yu; Jan H M Schellens; Jos H Beijnen; Neeltje Steeghs; Alwin D R Huitema Journal: Clin Pharmacol Ther Date: 2017-09-07 Impact factor: 6.875