Hannah Yejin Kim1, Janna K Duong2, Maria Gonzalez3, Georgina V Long3,4,5, Alexander M Menzies3,4,5, Helen Rizos6, Su Yin Lim6, Jenny Lee6, Alan V Boddy2. 1. Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, NSW, Australia. hkim0212@uni.sydney.edu.au. 2. Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, NSW, Australia. 3. Melanoma Institute Australia, Wollstonecraft, NSW, Australia. 4. Faculty of Medicine and Health, School of Medicine, The University of Sydney, Sydney, NSW, Australia. 5. Royal North Shore Hospital, St Leonards, NSW, Australia. 6. Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW, Australia.
Abstract
PURPOSE: The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia. METHODS: 34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC-MS assays, in addition to analysis of a panel of cytokines. RESULTS: Pyrexia was experienced by 71% of the patients, with an additional 17% requiring dose interruption related to a pyrexia-like prodrome. Dabrafenib concentrations ranged from 4.0 to 4628 ng/ml and trametinib from 1.0 to 45 ng/ml in 34 patients. N-desmethyl-dabrafenib was the most prevalent metabolite, followed by carboxy- and hydroxy-dabrafenib. No definitive association between pyrexia and AUC or Cmin of the drugs, or metabolites could be observed. The level of IL-1B at the early during treatment (EDT) (as a % of pre-treatment) was higher in the pyrexia group (median 109% (range 32-681%) than in the no-incidence group [56% (26-79%)] (p = 0.029). Similarly, the level of IL-6 at EDT was higher in the pyrexia group [181% (34-3156%) vs 73% (57-101%)] (p = 0.028). CONCLUSIONS: No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.
PURPOSE: The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAFV600E/Kmelanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia. METHODS: 34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC-MS assays, in addition to analysis of a panel of cytokines. RESULTS:Pyrexia was experienced by 71% of the patients, with an additional 17% requiring dose interruption related to a pyrexia-like prodrome. Dabrafenib concentrations ranged from 4.0 to 4628 ng/ml and trametinib from 1.0 to 45 ng/ml in 34 patients. N-desmethyl-dabrafenib was the most prevalent metabolite, followed by carboxy- and hydroxy-dabrafenib. No definitive association between pyrexia and AUC or Cmin of the drugs, or metabolites could be observed. The level of IL-1B at the early during treatment (EDT) (as a % of pre-treatment) was higher in the pyrexia group (median 109% (range 32-681%) than in the no-incidence group [56% (26-79%)] (p = 0.029). Similarly, the level of IL-6 at EDT was higher in the pyrexia group [181% (34-3156%) vs 73% (57-101%)] (p = 0.028). CONCLUSIONS: No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.
Authors: Lauriane Goldwirt; B Louveau; C Lebbé; S Mourah; B Baroudjian; C Allayous; F Jouenne; L Da Meda; L-T Vu; H Sauvageon; F Herms; J Delyon Journal: Cancer Chemother Pharmacol Date: 2021-05-31 Impact factor: 3.333