lso 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 atexposures 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 toxicologystudies conducted in rats and rabbits, administration of larotrectinib led to increased foodconsumption and increased body weight at doses resulting in exposures 0.6 times the humanexposure at the 100 mg twice daily clinical dose. Obesity has also been one phenotypic outcomeof some human syndromes resulting from congenital mutations in NTRK2 resulting in altered
TRK signaling.
14 CLINICAL STUDIES
The efficacy of VITRAKVI was eva luated in pediatric and adult patients with unresectable ormetastatic 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 followingsystemic therapy for their disease, if available, or would have required surgery with significantmorbidity for locally advanced disease.
Adult patients received VITRAKVI 100 mg orally twice daily and pediatric patients (18 years oryounger) received VITRAKVI 100 mg/m2 up to a maximum dose of 100 mg orally twice dailyuntil unacceptable toxicity or disease progression. Identification of positive NTRK gene fusionstatus was prospectively determined in local laboratories using next generation sequencing(NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in threepatients with infantile fibrosarcoma who had a documented ETV6 translocation identified byFISH. The major efficacy outcome measures were overall response rate (ORR) and duration ofresponse (DOR), as determined by a blinded independent review committee (BIRC) according toRECIST v1.1.
The assessment of efficacy was based on the first 55 patients with solid tumors with an NTRKgene fusion enrolled across the three clinical trials. Baseline characteristics were: median age45 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 localladvanced, unresectable disease. Ninety-eight percent of patients had received prior treatment fortheir 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 glandtumors (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 genefusions 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
Efficacy Parameter VITRAKVI
N = 55
Overall response rate (95% CI) 75% (61%, 85%)
Complete response rate 22%
Partial response rate* 53%
Duration |
