Summary: labeled warnings and safety profile

All labeled safety data derive from relapsed or refractory disease (FIREFLY-1, 137 participants with pLGG; pooled population of 172 participants including adults with solid tumors at a 600 mg flat dose); the first-line FIREFLY-2 trial is active, not recruiting, with primary completion estimated for June 2027, and no first-line safety results were identified. The US label has no contraindications and no boxed warning; the EU SmPC lists hypersensitivity as the only contraindication. Warnings and precautions cover hemorrhage (37% of the pooled population, including intratumoral hemorrhage in 9% and one fatal tumor hemorrhage), skin toxicity (rash 67%, grade 3 rash 12%; photosensitivity 12%), hepatotoxicity (increased AST 74% and ALT 42%), effect on growth (46% of 133 participants aged 18 years or younger, 35% grade 3 or higher), embryo-fetal toxicity, and possible tumor growth in NF1. In FIREFLY-1, serious adverse reactions occurred in 45% of participants; adverse reactions led to dose interruption in 57%, dose reduction in 24%, and permanent discontinuation in 7%. Growth velocity recovered after treatment stopped in 34 of 38 evaluable participants (89%) in a pooled analysis of three studies. The EU risk management plan lists growth retardation and intratumoral hemorrhage as important identified risks, decreased fertility as an important potential risk, and long-term safety as missing information.

Contraindications

“None .” (opens the source at this quote in a new tab)

“Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.” (opens the source at this quote in a new tab)

Boxed warning and REMS

No evidence found.

Hemorrhage

“Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with OJEMDA. In the pooled safety population [see Adverse Reactions (6.1) ], hemorrhagic events occurred in 37% of patients, including epistaxis in 26% and intratumoral hemorrhage in 9%. Serious events of bleeding occurred in 5% of patients including Grade 5 tumor hemorrhage in 1 patient (0.6%). OJEMDA was permanently discontinued for hemorrhage in 2% of patients.” (opens the source at this quote in a new tab)

“In FIREFLY-1, intratumoural haemorrhage (Including terms tumour haemorrhage and intracranial tumour haemorrhage) were observed in 13.9% patients, 3.6% patients reported Grade ≥ 3 events, 0.7% patient reported a Grade 5 event. Tovorafenib was permanently discontinued due to ITH events in 2.9% of patients.” (opens the source at this quote in a new tab)
“The risk of tumour haemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy.” (opens the source at this quote in a new tab)

“However, half (eight of 15) of the patients with intratumoral hemorrhage were asymptomatic, with areas of tumor hemorrhage identified on routine trial MRI only.” (opens the source at this quote in a new tab)

Skin toxicity including photosensitivity

“OJEMDA can cause rash, including maculopapular rash and photosensitivity. In the pooled safety population [see Adverse Reactions (6.1) ], rash occurred in 67% of patients treated with OJEMDA, including Grade 3 rash in 12%. Rash resulted in dose interruption in 15% of patients and dose reduction in 7% of patients. OJEMDA was permanently discontinued due to rash in 1% of patients (n=2).” (opens the source at this quote in a new tab)
“In the pooled safety population [see Adverse Reactions (6.1) ], photosensitivity occurred in 12% of patients treated with OJEMDA, including Grade 3 events in 0.6% of patients (n=1).” (opens the source at this quote in a new tab)

Rash incidence, time course, and resolution: FIREFLY-1 post hoc analysis

“93% (128/137) of pts had a treatment-emergent rash.” (opens the source at this quote in a new tab)
“First rash episode median time to onset (TTO) was 0.43 mos, with 47% (60) G1, 41% (52) G2, and 13% (16) G3. First rash episodes resolved for 74% (95/128) of pts within a median of 2.67 mos.” (opens the source at this quote in a new tab)
“Only 1 (1%) pt had a rash-related tovorafenib discontinuation. 18% (23) of pts had dose interruptions due to rash. 11% (14) of pts had a dose reduction due to rash; of those, 57% (8) required no additional dose reductions due to rash.” (opens the source at this quote in a new tab)

Hepatotoxicity

“OJEMDA can cause hepatotoxicity. In the pooled safety population [see Adverse Reactions (6.1) ] , increased alanine aminotransferase (ALT) occurred in 42% and increased aspartate aminotransferase (AST) occurred in 74%, including Grade 3 ALT in 4% and increased AST in 2% of patients treated with OJEMDA. The median time to onset of increased ALT or AST was 14 days (range: 3 to 280 days).” (opens the source at this quote in a new tab)
“Monitor liver function tests, including ALT, AST and bilirubin, before initiation of OJEMDA, one month after initiation and then every three months thereafter and as clinically indicated.” (opens the source at this quote in a new tab)

Effect on growth: US prescribing information

“OJEMDA can cause reductions in growth velocity. In FIREFLY-1 [see Adverse Reactions (6.1) ] , treatment-emergent adverse effects on growth were reported in 46% of 133 patients 18 years of age or younger; 35% were Grade 3 or higher. Reduction in growth velocity resulted in dose interruption in 5% of patients, dose reduction in 2.3% of patients, and permanent discontinuation in 3% of patients.” (opens the source at this quote in a new tab)
“Growth velocity improved after interruption of treatment with OJEMDA. Among 81 evaluable patients, the median annualized growth velocity ranged from 0.86 to 1.8 cm/year during the 2-year treatment period. Of those, 17 patients had height measurements recorded at least 90 days off-treatment and had a 4.2 cm/year median annualized growth velocity.” (opens the source at this quote in a new tab)
“Among 35 patients who experienced reductions in growth velocity who had hand radiographs taken to assess bone age, there was no evidence of premature closure of the epiphyseal growth plates or advancement of bone age.” (opens the source at this quote in a new tab)

Effect on growth: proposed mechanism and off-treatment recovery across three studies

“Based on preclinical data, CRAF plays an essential role in chondrocyte maturation, a required step in linear bone growth.” (opens the source at this quote in a new tab)
“Median on-treatment AGV was 1.7 cm/yr [n = 36, interquartile range (IQR) 0.4 - 2.2] at 12 mo and 2.3 cm/yr (n = 25, IQR 0 - 3.3) at 24 mo.” (opens the source at this quote in a new tab)
“Thirty-four (89%) patients had recovery of AGV, and 28 (74%) had an increase in Z-score towards baseline indicating catch-up growth.” (opens the source at this quote in a new tab)
“Preliminary findings indicate tumor-associated precocious puberty/Tanner stage 4 in females may be a risk factor for slow AGV recovery.” (opens the source at this quote in a new tab)

Effect on growth: comorbidities in participants with decreased growth velocity

“Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex.” (opens the source at this quote in a new tab)

Effect on growth: PNOC014 phase 1

“Eleven of 12 patients (92%) on drug for more than 6 months and not postpubertal experienced grade 3 growth suppression.” (opens the source at this quote in a new tab)
“For patients who received treatment for more than 6 months (n = 19), the average growth velocity was 0.94 cm/year (range: 0-3.6).” (opens the source at this quote in a new tab)

Embryo-fetal toxicity

“Based on findings from animal studies and its mechanism of action, OJEMDA may cause fetal harm when administered to a pregnant woman. Tovorafenib was embryo lethal in rats at doses approximately 0.8-fold the human exposure at the recommended dose based on area under the curve (AUC).” (opens the source at this quote in a new tab)

NF1-associated tumors

“Based on nonclinical data in NF1 models without BRAF alterations, tovorafenib may promote tumor growth in patients with NF1 tumors [see Nonclinical Toxicology (13.2) ]. Confirm evidence of a BRAF alteration prior to initiation of treatment with OJEMDA .” (opens the source at this quote in a new tab)

“Additionally, we observed significant growth in the tumor of one patient with neurofibromatosis type 1 (NF1), raising concern for possible inadvertent paradoxical activation of the MAPK pathway as had been seen with other BRAF inhibitors.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: serious adverse reactions, dose modifications, and discontinuations in FIREFLY-1

“Serious adverse reactions occurred in 45% of patients who received OJEMDA. Serious adverse reactions in >2% of patients included viral infection (9%), pneumonia (4%), and sepsis (4%). A fatal adverse reaction of tumor hemorrhage occurred in 1 patient (1%).” (opens the source at this quote in a new tab)
“Permanent discontinuation of OJEMDA due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of OJEMDA in more than one patient were tumor hemorrhage and reduction in growth velocity.” (opens the source at this quote in a new tab)
“Dosage interruptions of OJEMDA due to an adverse reaction occurred in 57% of patients. Adverse reactions which required dose interruption in ≥5% of patients included rash, pyrexia, vomiting, and hemorrhage.” (opens the source at this quote in a new tab)
“Dosage reductions of OJEMDA due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reduction in ≥2% of patients included rash, and fatigue.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: adverse reactions in 20% or more of participants in FIREFLY-1 (N=137)

Adverse reaction	All grades (%)	Grade 3 or 4 (%)
Rash	“77”	“12”
Hair color changes	“76”	“0”
Fatigue	“55”	“4”
Viral infection	“55”	“7”
Vomiting	“50”	“4”
Headache	“45”	“1”
Hemorrhage	“42”	“5”
Pyrexia	“39”	“4”
Dry skin	“36”	“0”
Constipation	“33”	“0”
Nausea	“33”	“0”
Dermatitis acneiform	“31”	“1”
Upper respiratory tract infection	“31”	“1.5”
Abdominal pain	“28”	“0”
Pruritus	“26”	“1”
Edema	“26”	“0”
Paronychia	“26”	“1.5”
Diarrhea	“22”	“1.5”
Stomatitis	“20”	“0”

Relapsed or refractory pLGG: laboratory abnormalities worsening from baseline in 20% or more of participants in FIREFLY-1

Laboratory abnormality	All grades (%)	Grade 3 or 4 (%)
Decreased hemoglobin	“90”	“15”
Decreased phosphate	“87”	“25”
Increased AST	“83”	“2”
Increased creatine phosphokinase	“83”	“11”
Increased LDH	“73”	“0”
Decreased potassium	“51”	“2”
Decreased lymphocytes	“50”	“2”
Increased ALT	“50”	“5”
Decreased leukocytes	“31”	“2”
Decreased albumin	“24”	“5”
Increased lymphocytes	“23”	“0”
Increased bilirubin	“22”	“1”
Decreased sodium	“20”	“2”

Creatine phosphokinase elevation and anemia: EU product information

“In FIREFLY-1, 62% of patients reported events of blood creatine phosphokinase (CPK) increased. 12.4% of patients reported Grade ≥ 3 events. All events were non-serious.” (opens the source at this quote in a new tab)
“In FIREFLY-1, anaemia was reported in 61.3% of patients. 13.1% of patients reported anemia events Grade ≥ 3.” (opens the source at this quote in a new tab)

Adverse events not observed in FIREFLY-1

“No signs of ocular toxicity, adverse impact on cardiac function or abnormal weight gain were observed in children treated with tovorafenib, unlike those observed with MEK inhibitors” (opens the source at this quote in a new tab)
“Although skin rashes were common in children treated with tovorafenib, no patients experienced life-threatening skin reactions, and development of squamous cell carcinomas and keratoacanthomas were not observed.” (opens the source at this quote in a new tab)

Fertility: nonclinical findings

“Based on findings in animals, OJEMDA may impact fertility in males and females of reproductive potential. The effects on male animal fertility were reversible. The effects on female animal fertility were not reversible” (opens the source at this quote in a new tab)

EU risk management plan safety concerns

Category	Quoted safety concern
Important identified risks	“Growth retardation”
Important identified risks	“Intratumoral haemorrhage”
Important potential risks	“Decreased fertility risk”
Missing information	“Long-term safety”

FDA postmarketing requirements related to safety

“PMRs have been issued to obtain additional data to characterize tovorafenib’s long-term safety, impact on growth and development, potential for gonadal toxicity, and drug-drug interactions.” (opens the source at this quote in a new tab)

First-line pLGG: safety results from FIREFLY-2