VITRAKVI Capsule / Oral solution Ref.[10108] Active ingredients: Larotrectinib

Cardiac Electrophysiology

At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.

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 (C_max 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 (C_max) 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 C_max was 788 (81%) ng/mL and AUC_0-24hr was 4351 (97%) ng*h/mL.

Absorption

The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules and the C_max was 36% higher with the oral solution.

Effect of Food

The AUC of larotrectinib was similar and the C_max was reduced by 35% after oral administration of a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the C_max and AUC in the fasted state.

Distribution

The mean (CV%) volume of distribution (V_ss) of larotrectinib is 48 (38%) L following intravenous administration of larotrectinib in healthy subjects.

Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma concentration ratio is 0.9.

Elimination

The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of VITRAKVI in healthy subjects.

Metabolism

Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of a single [¹⁴C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma.

Excretion

Following oral administration of a single [¹⁴C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine.

Specific Populations

Age (range: 28 days to 82 years), sex, and body weight (range: 3.8 kg to 179 kg) had no clinically meaningful effect on the pharmacokinetics of larotrectinib.

Pediatric Patients

In pediatric patients, the larotrectinib geometric mean (CV) AUC_0-24hr by age subgroup was: 3348 (66) ng*h/mL in patients 1 month to <2 years (n=9), 4135 (36%) ng*h/mL in patients 2 to <12 years (n=15), and 3108 (69%) ng*h/mL and in patients 12 to <18 years (n=9).

Patients with Renal Impairment

Following oral administration of a single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC_0-INF of larotrectinib increased 1.5-fold and C_max increased 1.3-fold as compared to that in subjects with normal renal function (creatinine clearance ≥90 mL/min as estimated by Cockcroft-Gault). The pharmacokinetics of VITRAKVI in patients with moderate to severe renal impairment (creatinine clearance ≤60 mL/min) have not been studied.

Patients with Hepatic Impairment

Following oral administration of a single 100 mg dose of VITRAKVI capsules, the AUC_0-INF of larotrectinib increased 1.3-fold in subjects with mild hepatic impairment (Child-Pugh A), 2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) as compared to that in subjects with normal hepatic function. The C_max was similar in subjects with mild and moderate hepatic impairment and the C_max of larotrectinib increased 1.5-fold in subjects with severe hepatic impairment as compared to that in subjects with normal hepatic function [see Dosage and Administration (2.6), Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with a strong CYP3A inhibitor (itraconazole) increased the AUC_0-INF of larotrectinib by 4.3-fold and the C_max by 2.8-fold as compared to VITRAKVI administered alone [see Dosage and Administration (2.4), Drug Interactions (7.1)]. The effects of CYP3A moderate and weak inhibitors on the pharmacokinetics of larotrectinib have not been studied.

Effect of Strong CYP3A Inducers: Coadministration of a single 100 mg dose of VITRAKVI capsules with a strong CYP3A inducer (rifampin) decreased the AUC_0-INF of larotrectinib by 81% and of C_max by 71% as compared to VITRAKVI administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)]. The effects of CYP3A weak and moderate inducers on the pharmacokinetics of larotrectinib have not been studied.

Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with a P-gp inhibitor (rifampin) increased the AUC_0-INF of larotrectinib by 1.7-fold and the C_max by 1.8-fold as compared to VITRAKVI administered alone.

Effect of Larotrectinib on CYP3A4 Substrates: Coadministration of VITRAKVI capsules 100 mg twice daily with a sensitive CYP3A4 substrate (midazolam) increased both the AUC_0-INF and C_max of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC_0-INF and C_max of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold as compared to when midazolam was administered alone [see Drug Interactions (7.2)].

In Vitro Studies

Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP. Larotrectinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.

Effect of Larotrectinib on Transporters: Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations.

Effect of Larotrectinib on CYP Substrates: Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

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 (AUC_0-24hr) 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.

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.

The efficacy of VITRAKVI was evaluated in pediatric and adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label, single-arm clinical trials: Study LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease.

Adult patients received VITRAKVI 100 mg orally twice daily and pediatric patients (18 years or younger) received VITRAKVI 100 mg/m² up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three patients with infantile fibrosarcoma who had a documented ETV6 translocation identified by FISH. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

The assessment of efficacy was based on the first 55 patients with solid tumors with an NTRK gene fusion enrolled across the three clinical trials. Baseline characteristics were: median age 45 years (range 4 months to 76 years); 22% <18 years of age, and 78% ≥18 years of age; 53% male; 67% White; 7% Hispanic/Latino, 4% Asian, 4% Black; and ECOG performance status 0-1 (93%) or 2 (7%). Eighty-two percent of patients had metastatic disease and 18% had locally advanced, unresectable disease. Ninety-eight percent of patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. Of these, 82% (n=45) received prior systemic therapy with a median of two prior systemic regimens and 35% (n=19) received three or more prior systemic regimens. The most common cancers were salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). A total of 50 patients had NTRK gene fusions detected by NGS and 5 patients had NTRK gene fusions detected by FISH.

Efficacy results are summarized in Tables 4, 5, and 6.

Table 4. Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions:

⁺ Denotes ongoing response.
* Includes one pediatric patient with unresectable infantile fibrosarcoma who underwent resection following partial response and who remained disease-free at data cutoff.
^† Median duration of response not reached at time of data cutoff.
^‡ 3 patients with an ongoing response were followed <9 months from onset of response.
^§ 10 patients with an ongoing response were followed <12 months from onset of response.

Table 5. Efficacy Results by Tumor Type:

NA = not applicable due to small numbers or lack of response; CR = complete response; PR = partial response; NE = not evaluable; SD = stable disease; PD = progressive disease.
⁺ Denotes ongoing response.
* Observed values at data cutoff, not a range.

Table 6. Efficacy Results by NTRK Fusion Partner:

CR = complete response; PR = partial response; NE = not evaluable; SD = stable disease; NA = not applicable.
⁺ Denotes ongoing response.
* Fusion partners identified in the primary analysis set (N=55) may not represent all potential fusion partners.
^† Duration of response censored at the time of surgery for one pediatric patient with unresectable infantile fibrosarcoma who underwent resection following partial response and who remained disease-free at data cutoff.
^‡ Observed values at data cutoff, not a range.