Tovorafenib

Avoid coadministration of tovorafenib with a strong or moderate CYP2C8 inhibitor.

Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure based on a mechanistic understanding of its elimination, which may increase the risk of adverse reactions with tovorafenib.

Avoid coadministration of tovorafenib with a strong or moderate CYP2C8 inducer.

Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure based on a mechanistic understanding of its elimination, which may reduce the effectiveness of tovorafenib.

Hormonal contraceptives: Avoid coadministration of hormonal contraceptives with tovorafenib. If coadministration is unavoidable, use an additional effective nonhormonal contraceptive method during coadministration and for 28 days after discontinuation of tovorafenib.

Other CYP3A substrates: Avoid coadministration of tovorafenib with certain CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures. If coadministration is unavoidable, monitor patients for loss of efficacy unless otherwise recommended in the Prescribing Information for CYP3A substrates.

Tovorafenib is a CYP3A inducer.

Tovorafenib is predicted to decrease exposure of certain CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures, which may reduce the effectiveness of these substrates.

Coadministration with hormonal contraceptives (CYP3A substrate) may decrease progestin-x and ethinyl estradiol exposure, which may lead to contraceptive failure and/or an increase in breakthrough bleeding.

Tovorafenib has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Tovorafenib has not been studied in patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) to severe (bilirubin > 3x ULN and any AST) hepatic impairment.

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.

Risk Summary

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 (see Data). 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.

Data

Animal Data

In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.

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.

Carcinogenicity studies with tovorafenib have not been conducted.

Tovorafenib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Tovorafenib was not genotoxic in cultured human lymphocytes without metabolic activation. Tovorafenib induced chromosomal aberrations in cultured human lymphocytes with metabolic activation at a single concentration in vitro. Tovorafenib was not genotoxic in an in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study in rats, animals were administered tovorafenib doses of 37.5, 75, or 150 mg/kg/day orally. Female animals, paired with untreated males, were dose for 14 days prior to pairing, during the mating period, and up to Gestation Day 6. Tovorafenib decreased the number of pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.

In repeat-dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings in female rats included reversible increased thickness of the vaginal mucosa, increased size and/or numbers of corpora hemorrhagicum and hemorrhage, and non-reversible cystic follicles, decreased corpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses ≥50 mg/kg once every other day (approximately 0.4-fold the human exposure at the recommended dose based on AUC). In male rats, tovorafenib reduced weights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of the testes and reduced epididymal sperm at doses ≥50 mg/kg once every other day (approximately 0.3-fold the human exposure at the recommended dose based on AUC).

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in WARNINGS AND PRECAUTIONS reflects exposure to tovorafenib taken orally once weekly at a dose based on body surface area in 140 patients with relapsed or refractory pediatric LGG or advanced solid tumors harboring a RAF alteration and a flat dose of 60 mg in 32 adult patients with advanced solid tumors until disease progression or intolerable toxicity. Among 172 patients treated with tovorafenib, 86% were exposed for 6 months or longer and 49% were exposed for 1 year or longer.

Pediatric low-grade glioma

The safety of tovorafenib was evaluated in 137 patients with relapsed or refractory pediatric LGG harboring a BRAF alteration in FIREFLY-1 (Arms 1 and 2). Patients received tovorafenib at a dose based on body surface area orally once weekly until disease progression or intolerable toxicity.

The median age of patients was 9 years (range 1 to 24 years); 53% male; 58% White, 7% Asian, 2% Black or African American, 6% other races, 25% race was not reported; 2.9% were Hispanic or Latino; and 90% Karnofsky/Lansky performance status of 80 to 100.

Serious adverse reactions occurred in 45% of patients who received tovorafenib. 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%).

Permanent discontinuation of tovorafenib due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of tovorafenib in more than one patient were tumor hemorrhage and reduction in growth velocity.

Dosage interruptions of tovorafenib 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.

Dosage reductions of tovorafenib due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reduction in ≥2% of patients included rash, and fatigue.

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 transferase, decreased potassium, and decreased sodium.

Table 1 and Table 2 present adverse reactions and laboratory abnormalities, respectively, identified in FIREFLY-1 (Arms 1 and 2).

Table 1. Adverse Reactions (≥20%) in Patients with Pediatric LGG Who Received Tovorafenib in FIREFLY-1 (Arms 1 and 2):

^a Includes terms erythema multiforme, eczema, rash erythematous, rash macular, rash follicular, rash pruritic, rash maculopapular, rash, rash popular, rash pustular, skin exfoliation, drug eruption, dermatitis, dermatitis bullous.
^b Includes terms lip edema, periorbital edema, edema peripheral, localized edema, face edema, vulval edema.
^c Includes terms viral infection, rhinovirus infection, enterovirus infection, viral upper respiratory tract infection, enterocolitis viral, oral herpes, gastroenteritis viral, influenza, influenza like illness, respiratory syncytial virus infection, enterovirus infection, coronavirus infection, COVID-19, SARS-COV-2 test positive, herpes simplex, parainfluenza virus infection, adenoviral upper respiratory infection, viraemia, adenovirus infection, conjunctivitis viral, eye infection viral, metapneumovirus infection, parvovirus infection, respiratory syncytial virus bronchiolitis, respiratory tract infection viral, viral pharyngitis, viral rhinitis, viral tonsillitis.
^d Includes terms retching, hematemesis.
^e Includes terms colitis, enterocolitis.
^f Includes terms mouth ulceration, mucosal inflammation, aphthous ulcer, cheilitis.
^g Includes terms tumor hemorrhage, gastrointestinal hemorrhage, subdural hemorrhage, epistaxis, intracranial tumor hemorrhage, upper gastrointestinal hemorrhage, lower gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, post procedural hemorrhage, hemoptysis, anal hemorrhage.
^* Includes one Grade 5 event.

Other clinically important adverse reactions observed in less than 20% of patients treated with tovorafenib were reductions in growth velocity and photosensitivity.

Table 2. Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Pediatric LGG Who Received Tovorafenib in FIREFLY-1 (Arms 1 and 2):

¹ Severity as defined by National Cancer Institute CTCAE v5.0
² The denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 67 to 137 patients.

Increased creatinine phosphokinase was a clinically important laboratory abnormality that worsened from baseline in patients treated with tovorafenib.