Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.

Abstract Background Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. Methods We analysed PCD/T in patients treated with D + T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. Results We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0 ng/mL; interquartile range (IQR) [4–945]) and of PCT (median: 8.6 ng/mL; IQR [5–39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P = 0.06). However, no difference was observed between mean PCD/T of progressing patients (n = 21; 125 ± 183 ng/mL and 9.3 ± 3.6 ng/mL, respectively) and responders (complete, partial or stable response) (n = 13; 159 ± 225 ng/mL, P = 0.58 and 10.6 ± 24.4 ng/mL, P = 0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n = 16) was significantly higher for female subjects (n = 18; 11.5 ± 4.8 ng/mL) than for male subjects (8.8 ng/mL ± 2.9, P = 0.01), but no difference was observed between sex and CPD (P = 0.32). Conclusion Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.