Abstract
Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUCOHD/AUCDAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29–33.56); p = 0.023 and 10.61 (2.34–48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11–9.50); p = 0.032 and HR = 1.23 (1.35–10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUCOHD/AUCDAB deserves more investigation in a larger cohort of MM patients.
Highlights
Mutations in the RAS-RAF-MEK-ERK signaling pathway, a kinase cascade that regulates cellular growth and survival [1], have been reported in different types of cancers
Estimated CL/F, Q/F, and lag time are close to the values of 17.0 L/h, 3.30 L/h, and 0.482 h, respectively, reported in reference models built upon clinical trial data [12,18], respectively
Our analysis confirms the contribution of sex on CL/F found in the reference model [18], but not of bodyweight, which might be due to its different distribution between the two study populations
Summary
Mutations in the RAS-RAF-MEK-ERK signaling pathway, a kinase cascade that regulates cellular growth and survival [1], have been reported in different types of cancers. BRAF is reportedly mutated in 3–5% of non-small-cell lung cancer (NSCLC), 10% of colorectal cancers, 10–70% of thyroid cancers, and 52% of cutaneous melanomas [2]. Dabrafenib (DAB), a reversible ATP-competitive inhibitor, selectively inhibits BRAFV600E/K -mutant proteins [3]. In patients with BRAFV600 metastatic melanoma (MM), DAB in combination with trametinib (TRA), a MEK inhibitor, has demonstrated higher response rate and improved survival compared with DAB monotherapy [4]. The combination of DAB plus TRA (CombiDT) led to a long-term benefit with a survival rate of 34% at five years [4]
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