Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

Abstract

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…Responders had a mean concentration of 56.4 mg/L, while nonresponders had a mean of 38.8 mg/L ( P = 0.013) 87, 88. Moreover, melanoma patients in the lowest exposure quartile (<40.4 mg/L) had a PFS of 1.5 months compared to that of 4.5 months of patients in the higher three quartiles ( P = 0.029) 85. This effect was confirmed in an independent cohort after 12 months of follow‐up with a threshold of 42 mg/L ( P = 0.005) 89…”

“…In melanoma patients, vemurafenib concentrations were significantly higher in those patients who developed Grade ≥2 rash compared to those who did not (mean ± standard deviation (SD) of 61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, P < 0.0001) 85. Another study found an exposure–dependent QTc prolongation for vemurafenib 86.…”

The Use of Dried Blood Spots for Pharmacokinetic Monitoring of Vemurafenib Treatment in Melanoma Patients

“…Patients with disease progression had lower plasma concentrations compared with patients with stable disease and those who were partial or complete responders. Three independent groups suggested a TDM target concentration of 42 μg/mL . Plasma concentrations exceeding 62 μg/mL have been associated with higher risk for the development of grade ≥ 2 rash .…”

Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

“…Vemurafenib plasma concentrations have been linked to the risk of disease progression [52][53][54] and/or toxicity (e.g. rash of at least grade 2 severity) [53].…”

“…rash of at least grade 2 severity) [53]. It has been suggested that therapeutic drug monitoring in the early stages of vemurafenib treatment may help identify patients at risk of nonresponse and toxicity [52,53], although more data are needed.…”