Exposure–response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients

Introduction Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib. Patients and methods An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration–time Curve and trametinib trough concentrations (C min ), univariable and multivariable exposure–response analyses were performed. Results In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with C min ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib C min ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36–0.85, P = 0.007). Median PFS in patients with trametinib C min levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with C min below this threshold ( P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47–1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities. Conclusions Overall survival of metastasized melanoma patients with trametinib C min levels ≥ 15.6 ng/mL is ten months longer compared to patients with C min below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.