Initial US Approval

20181

Indications

The treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

Recommended Dose/Route

Adult and pediatric patients with a body surface area ≥1.0 m2, 100 mg orally twice daily, with or without food. Adult and pediatric patients with a body surface area <1.0 m2, 100 mg/m2 orally twice daily, with or without food/1

Larotrectinib: Dose Reduction

Larotrectinib: Dose Reduction

Pivotal Study

LOXO-TRK-140012 (NCT02122913), SCOUT3 (NCT02637687), and NAVIGATE4 (NCT02576431)

Key Inclusion Criteria: Eligible patients were required to have unresectable or metastatic solid tumors with a NTRK gene fusion. All patients were also required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease.

Treatment

Adult patients received larotrectinib 100 mg orally twice daily and pediatric patients (18 years or younger) received larotrectinib 100 mg/m2 up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression.1

Larotrectinib: Efficacy Data

Larotrectinib: Efficacy Data

Safety

The most common adverse reactions (≥20%), observed in patients receiving larotrectinib, including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, musculoskeletal pain, fatigue, hypoalbuminemia, neutropenia, increased alkaline phosphatase, cough, leukopenia, constipation, diarrhea, dizziness, hypocalcemia, nausea, vomiting, pyrexia, lymphopenia, and abdominal pain.1 The most common serious adverse reactions (≥2%) were pneumonia and pyrexia. Grade 3 or 4 adverse reactions occurred in 53% of patients. The most common adverse reactions (1% each) that resulted in permanent discontinuation of larotrectinib were increased ALT, increased AST, dehydration and fatigue. The most common adverse reactions (≥3%) resulting in dose interruption were increased ALT (4.7%), increased AST (4.3%), and neutrophil count decreased (4.3%).1

Dosage Interruption Due to AEs: 39%1

Dosage Modification Due to AEs: 8%1

Permanent Discontinuation Due to AEs: 9%1

References

1. Vitrakvi (larotrectinib). Package insert. Whippany, NJ, USA: Bayer Pharmaceuticals Inc.; December 2022.

2. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714. doi:10.1016/S1470-2045(18)30119-0

3. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

4. Waguespack SG, Drilon A, Lin JJ, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022;186(6):631-643. doi:10.1530/EJE-21-1259