Name: Tovorafenib (DAY101) in RAF-altered pediatric low-grade glioma requiring first-line systemic therapy: Pharmacodynamics
Published: 2026-09-17T18:16:08-04:00

Exposure-response relationships: US prescribing information

“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.” (opens the source at this quote in a new tab)
“Higher tovorafenib exposure is associated with increased risk of skin rash, elevated liver enzymes (AST and ALT), and elevated creatine phosphokinase.” (opens the source at this quote in a new tab)

Dose optimization from 420 to 380 mg/m2 based on exposure-response analyses

“There were no clinically significant differences in exposure-response relationships for ORR observed over the actual dose range of 290 to 476 mg/m 2 (0.76-1.25 times the approved recommended dosage) evaluated in Arm 1” (opens the source at this quote in a new tab)
“Based on pharmacokinetic/pharmacodynamic modeling, this dose reduction was also anticipated to partially mitigate the reductions in growth velocity observed in children in FIREFLY-1” (opens the source at this quote in a new tab)

Exposure-safety analyses: EMA assessment

“Logistic regression analysis identified statistically significant positive correlations between Cmin and reporting of the following AEs: Grade ≥2 elevated ALT, Grade ≥2 or Grade ≥3 elevated AST, Grade ≥2 fatigue, Grade ≥1 or ≥2 facial edema, Grade ≥2 or Grade ≥3 skin rash, and Grade ≥3 TEAE.” (opens the source at this quote in a new tab)
“Separate PK/PD models demonstrated a correlation between tovorafenib concentration and hemoglobin, AST, and CPK. Higher tovorafenib concentrations were associated with decreased hemoglobin and increased AST and CPK.” (opens the source at this quote in a new tab)
“The claimed dose has been investigated in the pivotal clinical study. No therapeutic window could be drawn from the available data.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“At the recommended tovorafenib dose of 380 mg/m2 orally once weekly (not to exceed 600 mg), a mean increase in the QT interval > 20 milliseconds was not observed.” (opens the source at this quote in a new tab)
“In hERG-transfected HEK293 cells, hERG channel was inhibited indicating potential for QT prolongation. Half-maximal inhibitory concentration was 8.9 μM which is 32-fold higher than the clinical plasma unbound concentration in adults.” (opens the source at this quote in a new tab)

Tumor pharmacodynamic biomarkers: adult melanoma (pERK)

“There were median decreases from baseline in the level of pERK staining on Day 21 of ≥70% in the BRAF mutation-positive treatment-naïve cohort (-94.5% [range: -100% to -89%])” (opens the source at this quote in a new tab)
“No PD biomarker investigation was performed in the phase II paediatric glioma study FIREFLY-1.” (opens the source at this quote in a new tab)

Preclinical activity in pediatric low-grade astrocytoma models

“In genetically engineered murine models of paediatric low-grade astrocytoma with either KIAA1549:BRAF fusion or the BRAFV600E expression (p53-/- mouse neuroprogenitor cells stably transduced with the indicated constructs) described by Sun et al. (2017), tovorafenib inhibited pERK in a concentration-dependent manner and reduced cell proliferation with an” (opens the source at this quote in a new tab)

Preclinical NF1 model without BRAF alteration

“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%).” (opens the source at this quote in a new tab)