2.1 Patient Selection

Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens [see Clinical Studies (14)].

In patients with secretory breast cancer, mammary analogue secretory cancer (MASC), congenital mesoblastic nephroma (CMN), or infantile fibrosarcoma, consider treatment without confirmation of NTRK rearrangements in tumor specimens.

Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.

2.2 Recommended Dosage

2.3 Dosage Modifications for Adverse Reactions

For Grade 2 and higher liver function test abnormalities, refer to Section 2.4, Table 2, Dosage Modifications for Hepatotoxicity.

For all other Grade 3 or 4 adverse reactions:

• Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks.
• Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks.

The recommended dosage reductions for VITRAKVI for adverse reactions are provided in Table 1.

Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.

2.4 Dosage Modifications for Hepatotoxicity

The recommended dosage modifications for VITRAKVI liver function test abnormalities are provided in Table 2.

For CTCAE Grade 2 ALT and/or AST elevation, monitor liver function frequently as clinically indicated, to establish whether a dose interruption or reduction is required [see Warnings and Precautions (5.3)].

2.5 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors

Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications for Coadministration with Strong or Moderate CYP3A4 Inducers

Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. Additionally, for coadministration with a moderate CYP3A4 inducer, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.7 Dosage Modifications for Patients with Hepatic Impairment

Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.8 Administration

VITRAKVI capsule or oral solution may be used interchangeably.

Do not make up a missed dose within 6 hours of the next scheduled dose.

If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time.

Capsules

• 25 mg: white opaque hard gelatin capsule, size 2, with blue printing of "BAYER" cross and "25 mg" on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate.
• 100 mg: white opaque hard gelatin capsule, size 0, with blue printing of "BAYER" cross and "100 mg" on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate.

Oral Solution packaged in one bottle containing 100 mL

• 20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.

Oral Solution packaged in two bottles each containing 50 mL

• 20 mg/mL: colorless to yellow or orange or red or brownish solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.

5.1 Central Nervous System Effects

Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances.

In patients who received VITRAKVI (n=444), all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients.

Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients. Among the 49 patients with cognitive impairment, 6% required a dose modification, and 18% required dose interruption.

Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥ 1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%). Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption.

Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification, and 5% required dose interruption.

Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification, and 3.7% required dose interruption.

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)].

5.2 Skeletal Fractures

Skeletal fractures can occur in patients taking VITRAKVI.

Among 444 patients who received VITRAKVI across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients.

Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures.

5.3 Hepatotoxicity

Hepatotoxicity including drug-induced liver injury (DILI) has occurred in patients taking VITRAKVI.

In patients who received VITRAKVI (n=444), increased AST of any grade occurred in 62% of patients and increased ALT of any grade occurred in 61%. Grade 3-4 increased AST or ALT occurred in 7% and 8% of patients, respectively [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 1.9 months (range: 4 days to 3.8 years). The median time to onset of increased ALT was 1.9 months (range: 1 day to 4.9 years). Increased AST and ALT leading to dose modifications occurred in 1.6% and 3.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 4 (0.9%) patients.

There have been reports from clinical studies and postmarketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 × ULN.

Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and monitor every 2 weeks during the first 2 months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue VITRAKVI based on severity [see Dosage and Administration (2.4)].

5.4 Embryo-Fetal Toxicity

Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of VITRAKVI [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trial 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.

Unless noted, data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 444 patients, including 62% patients exposed for greater than 6 months, 44% patients exposed for greater than 1 year, and 30% patients exposed for greater than 2 years. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 75)], one pediatric dose-finding trial [SCOUT (n = 154)], and one single arm trial [NAVIGATE (n = 215)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment.

Across these 444 patients, the median age was 44 years (range: 18 days to 90 years); 35% were younger than 18 years; 53% were female; 59% were White, 24% were Asian and, 4% were Black; and 7% were Hispanic/Latino. Most adults (91%) received VITRAKVI 100 mg orally twice daily and 91% of pediatrics (< 18 years) received VITRAKVI 100 mg/m2 twice daily up to a maximum dose of 100 mg twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m2 twice daily to 120 mg/m2 twice daily in pediatrics [see Use in Specific Populations (8.4)].

The most common serious adverse reactions (≥ 2%) were pneumonia, pyrexia, and dyspnea. Grade 3 or 4 adverse reactions occurred in 60% of patients; adverse reactions leading to dose interruption or modification occurred in 45% and 11% of patients, respectively, and 12% permanently discontinued VITRAKVI for adverse reactions.

The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT and increased AST.

The most common adverse reactions (≥ 3%) resulting in dose interruption were increased ALT (6%), increased AST (5%), neutrophil count decreased (4.7%), pyrexia (4.3%), and vomiting (3.2%). Most (64%) adverse reactions leading to dose interruption occurred during the first three months of exposure.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash.

Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 20% of patients are summarized in Table 3 and Table 4, respectively.

Clinically relevant adverse reactions occurring in ≤ 10% of patients include fractures (7%).

7.1 Effects of Other Drugs on VITRAKVI

7.2 Effects of VITRAKVI on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients. [see Adverse Reactions (6.1), Clinical Studies (14)].

The efficacy of VITRAKVI was evaluated in 131 pediatric patients and is described in the Clinical Studies section [see Clinical Studies (14)]. The safety of VITRAKVI was evaluated in 154 pediatric patients who received VITRAKVI. Of these 154 patients, 31% were <1 month to < 2 years (n = 47), 49% were 2 years to < 12 years (n = 75), and 21% were 12 years to < 18 years (n = 32); 25% had metastatic disease, 44% had locally advanced disease, and 31% had primary CNS; and 82% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy, including radioactive iodine therapy (RAI). The most common cancers were infantile fibrosarcoma (32%), primary CNS tumors (31%), soft tissue sarcoma (27%), and thyroid cancer (4%). The median duration of exposure was 14.8 months (range: 0.4 months to 87.4 months).

Due to the small number of pediatric and adult patients, the single arm design of clinical studies of VITRAKVI, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adverse reactions occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were vomiting (51% versus 18%), pyrexia (47% versus 15%), cough (36% versus 23%), diarrhea (34% versus 21%), upper respiratory tract infection (33% versus 10%), headache (25% versus 13%), nasopharyngitis (20% versus 7%), nasal congestion (18% versus 7%), gastroenteritis (13% versus 2%), and rhinitis (12% versus 0%).

Laboratory abnormalities occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were AST increased (75% versus 55% in adults), ALT increased (69% versus 57% in adults), neutrophil count decrease (59% versus 20% in adults), leukocyte count decrease (46% versus 32% in adults), hyperkalemia (39% versus 16%), glucose decrease (29% versus 13% in adults), and lymphocyte increase (25% versus 1%). Three of the 154 pediatric patients discontinued VITRAKVI due to an adverse reaction associated with a laboratory abnormality (1 patient with Grade 3 increased ALT and 2 patients with Grade 3 decreased neutrophil count).

The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Of 444 patients in the overall safety population who received VITRAKVI, 20% of patients were ≥ 65 years of age and 6% of patients were ≥ 75 years of age. No overall differences in safety or effectiveness of VITRAKVI were observed between patients 65 years and older and younger adult patients.

8.6 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3)]. Reduce VITRAKVI dose as recommended [see Dosage and Administration (2.7)].

8.7 Renal Impairment

No dose adjustment is recommended for patients with renal impairment of any severity [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.

In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of larotrectinib were studied in healthy subjects and adult and pediatric patients with locally advanced or metastatic solid tumors. In healthy subjects who received a single dose of VITRAKVI capsules, systemic exposure (Cmax and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (Cmax) of larotrectinib were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC0-24hr was 4351 (97%) ng*h/mL.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with larotrectinib. Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation. In vivo, larotrectinib was negative in the mouse micronucleus test.

Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose). Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC0-24hr) at the 100 mg twice daily clinical dose.

In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose). Decreased fertility occurred in a juvenile animal study [see Use in Specific Populations (8.4)]. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose.

13.2 Animal Toxicology and/or Pharmacology

In general toxicology studies conducted in rats and monkeys and in reproductive toxicology studies conducted in rats and rabbits, administration of larotrectinib led to increased food consumption and increased body weight at doses resulting in exposures 0.6 times the human exposure at the 100 mg twice daily clinical dose. Obesity has also been one phenotypic outcome of some human syndromes resulting from congenital mutations in NTRK2 resulting in altered TRK signaling.

Capsules

25 mg: Hard gelatin opaque white capsule size #2 with blue printing of "BAYER" cross and "25 mg" on the body of the capsule.

100 mg: Hard gelatin opaque white capsule size #0 with blue printing of "BAYER" cross and "100 mg" on the body of the capsule.

Store capsules at room temperature 20°C to 25°C (68°F to 77°F); temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].

Central Nervous System Effects

Advise patients to notify their healthcare provider if they experience new or worsening neurotoxicity. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions [see Warnings and Precautions (5.1)].

Skeletal Fractures

Inform patients that bone fractures can occur in patients taking VITRAKVI. Advise patients to report symptoms such as pain, changes in mobility, or deformity to their healthcare provider [see Warnings and Precautions (5.2)].

Hepatotoxicity

Advise patients that they will need to undergo laboratory tests to monitor liver function [see Warnings and Precautions (5.3)].

Embryo-Fetal Toxicity

Advise males and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during the treatment with VITRAKVI and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with VITRAKVI and for 1 week following the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that VITRAKVI may impair fertility [See Nonclinical Toxicology (13.1)].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John's wort, grapefruit or grapefruit juice while taking VITRAKVI [see Drug Interactions (7.1, 7.2)].