Summary: dosing regimen and population context

The approved US and EU dose is 380 mg/m2 orally once weekly (maximum 600 mg), with the 100 mg tablet used for BSA of 0.90 m2 or more and the 25 mg/mL oral suspension for BSA of 0.30 to 0.89 m2; no dose is established for BSA below 0.3 m2. Treatment continues until disease progression or intolerable toxicity (EU: also loss of clinical benefit). The approved dose is lower than the 420 mg/m2 dose studied in PNOC014, FIREFLY-1 (actual range 290 to 476 mg/m2), and the first-line FIREFLY-2 trial; FDA selected 380 mg/m2 because exposure-response analyses showed no clinically significant relationship with response across the studied range, while higher exposure was associated with rash, liver enzyme elevation, and creatine phosphokinase elevation. The approved indications concern relapsed or refractory disease; no first-line dosing recommendation exists outside FIREFLY-2.

Recommended dosage: US prescribing information

“The recommended dosage of OJEMDA based on body surface area (BSA) is 380 mg/m2 orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food” (opens the source at this quote in a new tab)
“Continue once weekly dosing until disease progression or intolerable toxicity.” (opens the source at this quote in a new tab)

Tablet dosing by body surface area

BSA (m2)	Recommended dosage
0.30-0.89	“Administer OJEMDA oral suspension once weekly”
0.90-1.12	“400 mg once weekly”
1.13-1.39	“500 mg once weekly”
1.40 or more	“600 mg once weekly”

Oral suspension (25 mg/mL) dosing by body surface area

BSA (m2)	Dose volume (mL)	Dosage
0.30-0.35	“5”	“125 mg once weekly”
0.36-0.42	“6”	“150 mg once weekly”
0.43-0.48	“7”	“175 mg once weekly”
0.49-0.54	“8”	“200 mg once weekly”
0.55-0.63	“9”	“225 mg once weekly”
0.64-0.77	“11”	“275 mg once weekly”
0.78-0.83	“12”	“300 mg once weekly”
0.84-0.89	“14”	“350 mg once weekly”
0.90-1.05	“15”	“375 mg once weekly”
1.06-1.25	“18”	“450 mg once weekly”
1.26-1.39	“21”	“525 mg once weekly”
1.40 or more	“24”	“600 mg once weekly”

Dose reductions for adverse reactions: tablets

BSA (m2)	First dosage reduction	Second dosage reduction
1.13-1.39	“400 mg once weekly”	“Administer OJEMDA oral suspension once weekly”
1.40 or more	“500 mg once weekly”	“400 mg once weekly”

Dosage modifications by adverse reaction

Adverse reaction and severity	Quoted modification
Hemorrhage, intolerable grade 2 or any grade 3	“If improved to Grade 0-1, resume at lower dosage.”
Hemorrhage, recurrent grade 4	“Permanently discontinue OJEMDA.”
Hepatotoxicity, grade 3 AST, ALT, or bilirubin	“If laboratory abnormality resolves within 8 days, resume OJEMDA at the same dose.”
Hepatotoxicity, grade 3 AST, ALT, or bilirubin	“If laboratory abnormality does not resolve within 8 days, resume OJEMDA at lower dosage.”

Testing before initiation

“Select patients for treatment with OJEMDA based on the presence of BRAF fusion or rearrangement, or BRAF V600 mutation in tumor specimens” (opens the source at this quote in a new tab)
“Before initiating OJEMDA, evaluate liver function tests, including ALT, AST and bilirubin” (opens the source at this quote in a new tab)

Recommended dose and duration: EU product information

“The recommended dose of tovorafenib based on body surface area (BSA) is 380 mg/m2 once weekly. The maximum recommended dose is 600 mg once weekly (see Table 1).” (opens the source at this quote in a new tab)
“Treatment with tovorafenib should be continued once weekly until disease progression, loss of clinical benefit, or unacceptable toxicity.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: dose studied in FIREFLY-1 and optional drug holiday

“Patients received tovorafenib approximately 420 mg/m2 orally once weekly (range: 290 to 476 mg/m2, 0.76-1.25 times the recommended dose) according to body surface area with a maximum dose of 600 mg until disease progression, loss of clinical benefit, or unacceptable toxicity.” (opens the source at this quote in a new tab)
“Per protocol, patients could also enter an optional drug holiday after completing 26 cycles of therapy/24 months of treatment and at the investigator discretion: 43% (33/76) patients were on a drug holiday, 14% (11/76) patients remained on treatment.” (opens the source at this quote in a new tab)

Rationale for the approved dose lower than the phase 2 dose

“As greater tovorafenib exposure is associated with increased risk of Grade ≥2 adverse events including skin rash, elevated liver enzymes, and elevated creatine phosphokinase, a modest reduction from 420 to 380 mg/m 2 was recommended to optimize the dose and improve the benefit-to-risk ratio in pediatric patients” (opens the source at this quote in a new tab)

Recommended phase 2 dose: PNOC014

“The recommended phase II dose was 420 mg/m2 administered orally, once every week.” (opens the source at this quote in a new tab)

First-line pLGG: dosing in FIREFLY-2

“Dosage is adjusted for body surface area (BSA) calculated per the Mösteller Formula [√((height × weight)/3600)].” (opens the source at this quote in a new tab)
“Upon resolution and/or reversion, dosing may be restarted at the same dose or a lower dose, at the discretion of the local investigator.” (opens the source at this quote in a new tab)