Relationship Between Apparent Systemic Clearance of Vemurafenib and Toxicity in Patients With Melanoma.

Vemurafenib, a B rapidly accelerated fibrosarcoma inhibitor, is commonly used in combination of cobimetinib for the treatment of melanoma. In the current study, we evaluated the relationship between vemurafenib exposure, as measured by the estimated apparent clearance (CLB ) at steady state and any grade ≥3 toxicity, grade ≥3 skin rash, or toxicity requiring dose modification using pooled data from 3 prospective clinical trials involving 898 patients. A total of 69% had any grade ≥3 toxicity; grade ≥3 skin rash in 15% and 47% had a dose reduction/interruption or cessation. The median vemurafenib CLB was 1.35 L/h (interquartile range, 1.15-1.65 L/h). Lower vemurafenib CLB was significantly associated with an increased risk of grade ≥3 toxicity (hazard ratio [HR], 0.62; P < .001), grade ≥3 rash (HR, 0.29; P < .001), and adverse events requiring vemurafenib dose reduction/interruption or cessation (HR, 0.5; P < .001). When the patients were divided into 3 groups based on the vemurafenib CLB thresholds, those with low CLB (<1.22 L/h) had significantly increased incidence of any grade ≥3 toxicity or skin rash or dose adjustment, interruption, or cessation at 12 months and at day 28 when compared to those with medium (≥1.22 and <1.55 L/h) or high (>1.55 L/h) vemurafenib CLB . In conclusion, the estimated CLB of vemurafenib is associated with severe toxicities and dose adjustment or cessation, suggesting that an early estimation of vemurafenib exposure may be useful in identifying patients at risk of experiencing toxicity.

Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma.

Purpose To validate a plasma vemurafenib steady-state trough concentration (Css,min) threshold that predicts survival outcomes of patients with BrafV600 mutated melanoma. METHODS: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal Css,min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib Css,min and survival was modelled using Cox proportional hazards regression. RESULTS: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib Css,min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib Css,min, the threshold was still associated with overall survival and not in the monotherapy cohort. CONCLUSION: A plasma vemurafenib Css,min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.