Tovorafenib

Tovorafenib is a Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases.

Tovorafenib exhibited antitumor activity in cultured cells and xenograft tumor models harboring BRAF V600E and V600D mutations, and in a xenograft model harboring a BRAF fusion.

Exposure response relationships

Tovorafenib exposure is associated with reduction in height-for-age z-scores in pediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib.

Higher tovorafenib exposure is associated with increased risk of skin rash, elevated liver enzymes (AST and ALT), and elevated creatinine phosphokinase.

The exposure-response relationship for overall response rate based on RAPNO-LGG (Response Assessment in Pediatric Neuro-Oncology), and RANO-LGG (Response Assessment in Neuro-Oncology) were not clinically significant over the dosage range of 290 to 476 mg/m² (0.76-1.25 times the approved recommended dosage).

Cardiac electrophysiology

At the recommended tovorafenib dosage of 380 mg/m² orally once weekly (not to exceed 600 mg), a mean increase in the QT interval >20 milliseconds was not observed.

Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated. Tovorafenib steady state maximum concentration (C_max) is 6.9 µg/mL (23%) and the area under the concentration-time curve (AUC) is 508 µg*h/mL (31%). Time to reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.

Absorption

Tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (T_max) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.

Effect of Food

No clinically significant differences in tovorafenib C_max and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the T_max was delayed to 6.5 hours.

Distribution

Tovorafenib apparent volume of distribution is 60 L/m² (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro.

Elimination

Tovorafenib terminal half-life is approximately 56 hours (33%) and the apparent clearance is 0.7 L/h/m² (31%).

Metabolism

Tovorafenib is primarily metabolized by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9, and CYP2C19 metabolize tovorafenib to a minor extent.

Excretion

Following a single oral dose of radiolabeled tovorafenib, 65% of the total radiolabeled dose was recovered in the feces (8.6% unchanged) and 27% of the dose was recovered in the urine (0.2% unchanged).

Specific Populations

No clinically significant differences of tovorafenib were observed based on age (range: 1 to 94 years), sex, race (White, Black, Asian), mild hepatic impairment [bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST], and mild-to-moderate renal impairment (eGFR) ≥30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A Substrates: Midazolam (CYP3A4 substrate) steady-state C_max and AUC are predicted to decrease by at least 20% following coadministration with tovorafenib.

In vitro Studies

CYP450 Enzymes: Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19 and CYP3A, but does not inhibit CYP1A2, CYP2B6, and CYP2D6 at clinically relevant concentrations.

Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19 at clinically relevant concentrations.

Transporter Systems: Tovorafenib is not a substrate of BCRP, P-glycoprotein (P-gp), OATP1B1 and OATP1B3. Tovorafenib has not been evaluated as a substrate of OAT1, OAT3, MATE1, MATE2-K and OCT2. Tovorafenib inhibits BCRP at clinically relevant concentrations.

In vitro, tovorafenib increased phosphorylation of ERK at clinically relevant concentrations in cells with neurofibromatosis Type 1-loss of function (NF1-LOF) suggesting activation, rather than inhibition, of the MAP kinase pathway. In an NF1 genetically engineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did not have antitumor activity, and while not statistically significant, an increase in tumor volume was noted in 2/12 mice (approximately 17%).