Vitrakvi Larotrectinib 25 mg Capsule, 60-count — NDC 50419-390-01 (Billing 50419-0390-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 IC 50 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.

12.2Pharmacodynamics Cardiac Electrophysiology At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.

12.3Pharmacokinetics 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 [ 14 C] 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 [ 14 C] 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,… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 IC 50 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.

12.3Pharmacokinetics 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 [ 14 C] 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 [ 14 C] 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 mo… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.

14 CLINICAL STUDIES 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/m 2 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) (89%), fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR). NTRK gene fusions were inferred in 14 patients who had a documented ETV6 or NTRK 3 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 339 patients with solid tumors with an NTRK gene fusion enrolled across the three clinical trials. Baseline characteristics were: median age 38 years (range: 18 days to 90 years); 39% <18 years of age; 51% female; 57% White, 28% Asian, 2.4% Black or African American; 6% Hispanic or Latino and ECOG performance status (PS) 0-1 (88%) or 2 (10%). Sixty-three percent of patients had metastatic disease, including patients with brain metastases, and 22% had locally advanced, unresectable disease.

Ninety-two percent of patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy, including RAI. Seventy percent of all patients had received prior systemic therapy in the unresectable or metastatic setting excluding RAI; 30% were treatment naive, 33% had received 1 prior therapy and 37% percent had received 2 or more prior therapies with a median of one prior systemic regimen. Efficacy results are summarized in Tables 5, 6, and 7.

Table 5 Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions Efficacy Parameter VITRAKVI N = 339 + Denotes ongoing response. Overall response rate (95% CI) 60% (55%, 65%) Complete response rate 24% 5% were pathological complete response. Patients undergoing a surgical resection whose post-operative pathologic assessment showed no viable tumor cells and negative margins were pathological complete responders provided that no other sites of disease were present.

Partial response rate 36% Duration of response (DOR) N = 204 Median (months) (95% CI)

43.3Kaplan-Meier estimates (32.5, NE NE: Not evaluable ) Range (months) 0.0+, 73.7+ % with Observed DOR> 12 months 64% % with Observed DOR> 24 months 45% Table 6 Efficacy Results by Tumor Type Tumor Type Patients (N=339) ORR DOR Range (months) % 95% CI NA = not applicable due to small numbers or lack of response; NE = not evaluable; SD = stable disease; PD = progressive disease. + Denotes ongoing response. Soft tissue sarcoma 70 70% (58%, 80%) 0.0+, 72.7+ Infantile fibrosarcoma 49 94% (83%, 99%) 1.6+, 73.7+ Primary CNS 49 27% (15%, 41%) 1.9+, 57.5+ Lung 30 70% (51%, 85%) 1.9+, 56.2+ Thyroid 30 63% (44%, 80%) 3.7, 72.4+ Differentiated 23 78% (56%, 93%) 4.9, 72.4+ Non-differentiated 7 14% (0%, 58%)

3.7Observed values at data cutoff, not a range. Salivary gland 25 84% (64%, 95%) 7.4, 65.2+ MASC 14 79% (49%, 95%) 7.7,

59.1Colorectal Colorectal Tumor Type includes 23 colon cancers and 1 rectal cancer. 24 46% (26%, 67%) 3.9, 45.2+ Breast 14 57% (29%, 82%) 7.4, 58.2+ Secretory 6 83% (36%, 100%) 11.1, 58.2+ Non-secretory 8 38% (9%, 76%) 7.4, 12.5+ Melanoma 11 45% (17%, 77%) 1.9+, 23.2… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 (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.

13.2Animal 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.