Tovorafenib (Monograph)

Brand name: Ojemda
Drug class: Antineoplastic Agents

Introduction

Tovorafenib, a Type II RAF kinase inhibitor, is an antineoplastic agent.

Uses for Tovorafenib

Tovorafenib has the following uses:

Tovorafenib is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.

This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Tovorafenib Dosage and Administration

General

Tovorafenib is available in the following dosage form(s) and strength(s):

Tablets: 100 mg

For Oral Suspension: 25 mg/mL

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to initiation of treatment with tovorafenib.
Recommended dosage of tovorafenib in patients ≥6 months of age based on body surface area (BSA) is 380 mg/m² orally once weekly; maximum recommended dosage is 600 mg orally once weekly. A recommended dosage for patients with BSA less than 0.3 m² has not been established.
Administer tovorafenib as an immediate-release tablet or as an oral suspension with or without food.
Tablets: Swallow tablets whole with water. Do not chew, cut, or crush.
Oral Suspension: See full prescribing information for preparation and administration instructions.

Cautions for Tovorafenib

Contraindications

None.

Warnings/Precautions

Hemorrhage

Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with tovorafenib. In the pooled safety population, 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%). Tovorafenib was permanently discontinued for hemorrhage in 2% of patients.

Advise patients and caregivers of the risk of hemorrhage during treatment with tovorafenib. Monitor for signs and symptoms of hemorrhage and evaluate as clinically indicated. Withhold and resume at a reduced dose upon improvement, or permanently discontinue based on severity.

Skin Toxicity Including Photosensitivity

Tovorafenib can cause rash, including maculopapular rash and photosensitivity. In the pooled safety population, rash occurred in 67% of patients treated with tovorafenib, including Grade 3 rash in 12%. Rash resulted in dose interruption in 15% of patients and dose reduction in 7% of patients. Tovorafenib was permanently discontinued due to rash in 1% of patients (n=2). In the pooled safety population, dermatitis acneiform occurred in 26% of patients treated with tovorafenib, including Grade 3 dermatitis acneiform in 0.6% of patients (n=1). Dose reduction was required in 2% of patients (n=3) due to dermatitis acneiform. Monitor for new or worsening skin reactions. Consider dermatologic consultation and initiate supportive care as clinically indicated. Withhold, reduce the dose, or permanently discontinue tovorafenib based on severity of adverse reaction.

In the pooled safety population, photosensitivity occurred in 12% of patients treated with tovorafenib, including Grade 3 events in 0.6% of patients (n=1). Advise patients to use precautionary measures against ultraviolet exposure such as use of sunscreen, sunglasses, and/or protective clothing during treatment with tovorafenib. Withhold, reduce the dose, or permanently discontinue tovorafenib based on severity of the adverse reaction.

Hepatotoxicity

Tovorafenib can cause hepatotoxicity. In the pooled safety population, 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 tovorafenib. The median time to onset of increased ALT or AST was 14 days (range: 3 to 280 days). Increased ALT or AST leading to dose interruption occurred in 5% of patients and dose reductions were required in 1.2% of patients. Increased bilirubin occurred in 23% of patients, including Grade 3 increased bilirubin in 0.6% of patients (n=1) treated with tovorafenib. Hyperbilirubinemia leading to dose discontinuation occurred in a single adult patient with an advanced non-CNS solid tumor.

Monitor liver function tests, including ALT, AST and bilirubin, before initiation of tovorafenib, one month after initiation and then every three months thereafter and as clinically indicated. Withhold and resume at the same or reduced dose upon improvement, or permanently discontinue tovorafenib based on the severity.

Effect on Growth

Tovorafenib can cause reductions in growth velocity. In the FIREFLY-1 study, treatment-emergent adverse effects on growth occurred in 15% of patients 18 years of age or younger, including Grade 3 events in 5% of patients. Tovorafenib was permanently discontinued for reduction in growth velocity in 2% of patients (n=2). Growth velocity recovered after interruption of treatment with tovorafenib. Routinely monitor patient growth during treatment with tovorafenib.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, tovorafenib 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 AUC. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with tovorafenib and for 28 days after the last dose, since tovorafenib can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.

NF1 Associated Tumors

Based on nonclinical data in NF1 models without BRAF alterations, tovorafenib may promote tumor growth in patients with NF1 tumors. Confirm evidence of a BRAF alteration prior to initiation of treatment with tovorafenib.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, tovorafenib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of tovorafenib in pregnant women. Oral administration of tovorafenib to pregnant rats during the period of organogenesis resulted in embryo lethality at exposures 0.8 times the human exposure at the recommended dose based on AUC. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of tovorafenib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Due to the potential for serious adverse reactions in breastfed children from tovorafenib, advise lactating women not to breastfeed during treatment with tovorafenib and for 2 weeks following the last dose.

Females and Males of Reproductive Potential

Tovorafenib can cause fetal harm when administered to pregnant women.

Verify pregnancy status in females of reproductive potential prior to initiating tovorafenib.

Advise females of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 28 days after the last dose. Tovorafenib can render hormonal contraceptives ineffective.

Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.

Based on findings in animals, tovorafenib may impact fertility in males and females of reproductive potential. The effects on male fertility were reversible. The effects on female fertility were not reversible.

Pediatric Use

The safety and effectiveness of tovorafenib in pediatric patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation have been established based on data from a multicenter, open-label, single-arm clinical trial.

The efficacy of tovorafenib was evaluated in 76 patients with relapsed or refractory pediatric LGG. The safety of tovorafenib was evaluated in 137 patients with relapsed or refractory pediatric LGG in the FIREFLY-1 study (Arms 1 and 2). Of these 137 patients, 2% (n=3) were 6 months to < 2 years of age, 67% (n=92) were 2 years to < 12 years of age, and 31% (n=42) were >12 years of age. C_max and AUC in pediatric patients 11 months to 17 years of age were within the range of values observed in adults given the same dose per body surface area.

The safety and effectiveness of tovorafenib in patients younger than 6 months of age have not been established.

Patients with LGG treated with tovorafenib for up to 24 months showed reductions from baseline in Z-scores for height compared to age and sex-matched normative data. Among 19 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. Patients followed after interruption of treatment with tovorafenib showed recovery of growth and increase in Z-scores. Monitor growth routinely during treatment.

Hepatic Impairment

No dose adjustment is recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and alanine aminotransferase (AST) > ULN or bilirubin > 1× to 1.5× ULN and any AST) hepatic impairment. Tovorafenib has not been studied in patients with moderate (bilirubin > 1.5× to 3× ULN and any AST) to severe (bilirubin > 3× ULN and any AST) hepatic impairment.

Renal Impairment

No dose adjustment is recommended for patients with mild-to-moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation). Tovorafenib has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Common Adverse Effects

The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.

The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Moderate and Strong CYP2C8 Inhibitors: Avoid coadministration with tovorafenib.
Moderate and Strong CYP2C8 Inducers: Avoid coadministration with tovorafenib.
Certain CYP3A Substrates: Avoid coadministration of tovorafenib with CYP3A substrates where minimal concentration changes can cause reduced efficacy.
Hormonal contraceptives: Avoid coadministration with tovorafenib.

Actions

Mechanism of Action

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.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Advise patients that tovorafenib can cause bleeding and to contact their healthcare provider for signs or symptoms of bleeding.
Advise patients that tovorafenib can cause skin toxicities and to contact their healthcare provider for worsening or intolerable rash.
Advise patients that tovorafenib can cause photosensitivity. Advise patients to limit direct ultraviolet exposure during treatment with tovorafenib. Recommend that patients use precautionary measures such as use of sunscreen, sunglasses, and/or protective clothing during treatment with tovorafenib.
Advise patients that tovorafenib can cause liver toxicity and to contact their healthcare provider for signs or symptoms of liver dysfunction. Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with tovorafenib.
Advise patients and caregivers that treatment with tovorafenib may cause a reduction in growth velocity, and that growth will be monitored during treatment.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females to inform their healthcare provider of a known or suspected pregnancy during treatment with tovorafenib.
Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 28 days after discontinuation of treatment with tovorafenib.
Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.
Advise women not to breastfeed during treatment with tovorafenib and for 2 weeks after the last dose of tovorafenib.
Advise males and females of reproductive potential of the potential risk for impaired fertility with tovorafenib.
Inform patients and caregivers on how to take tovorafenib and what to do for missed or vomited doses.
Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration.
Advise patients not to take the tovorafenib tablets out of the blister pack until ready to use. Discard the bottle (including any unused portion) and syringe after dosing.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.