Goodman & Gilman's: Annual FDA Approvals

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Tropomyosin receptor kinase (TRK) inhibitor⁴⁸

NTRK gene fusion-positive solid tumors^†

Larotrectinib is the first-in-class tropomyosin receptor kinase (TRK) A, B, and C inhibitor. TRKs A, B, and C are encoded by the neurotrophic receptor tyrosine kinase genes, NTRK1, NTRK2, and NTRK3, respectively.⁴⁹ TRKs interact with endogenous neurotrophin ligands and are involved in activities that regulate the natural growth, differentiation, and survival of neurons.^97,98 Chromosomal rearrangements involving NTRK gene fusion with various partners create variants that result in the production of chimeric TRK fusion proteins that act as oncogenic drivers to promote cell proliferation and survival in tumor cell lines.^97,98 Over 60 NTRK gene fusions have been identified across a wide range of different tumor types,⁹⁸ making these proteins highly relevant targets for drug development.^2,98,99 Larotrectinib is a highly selective TRK inhibitor that appears to have activity regardless of tumor type, patient age, or fusion partner and appears to be associated with minimal off-target inhibition of other kinases.⁹⁹ In tumor cells that overexpress TRKs, inhibition by larotrectinib appears to prevent TRK activation to result in both apoptosis and the inhibition of cell growth.^97,98 In tumor models, larotrectinib has activity against cancers characterized by (1) constitutively activated TRK proteins resulting from gene fusions, (2) deletion of protein regulatory domains, and (3) overexpression of TRK proteins.⁴⁹ Larotrectinib lacks activity in cell lines with point mutations in the kinase domain, and treatment-emergent resistance has been well documented.^49,99 Alternative drugs for patients who acquire larotrectinib resistance are in the development pipeline.^2,99

Larotrectinib was simultaneously developed in pediatric and adult populations. It is indicated for the treatment of adult and pediatric patients with solid tumors (1) that have a NTRK gene fusion without a known acquired resistance mutation; (2) that are metastatic; (3) where surgical resection would be expected to result in severe morbidity; (4) that have no satisfactory alternative treatments; or (5) that have progressed following treatment.⁴⁹ Besides being first in the TRK class, larotrectinib represents the first new drug application granted FDA approval for a tissue-agnostic, biomarker-based cancer indication.¹⁰⁰ (Supplemental approval of pembrolizumab in 2017 for high-level microsatellite instability solid tumors was FDA’s first tissue-agnostic cancer drug approval.)^99,101 Other tissue-agnostic cancer drugs are in development.¹⁰² A companion diagnostic for larotrectinib to detect NTRK gene fusion is currently in development using the TruSight^TM Tumour 170 platform (Illumina, Inc.).^2,98,103,104

Larotrectinib has held an orphan drug designation for soft tissue sarcomas since 2015 and was granted orphan status for solid tumors expressing NTRK fusion proteins in 2017.²¹ FDA approval of the later was based on an across-trial evaluation of the first 55 patients with NTRK fusion-positive cancers enrolled in three multicenter, open-label, single-arm clinical trials (NCT02122913 [adult dose-finding], NCT02637687 [pediatric dose-finding], and (NCT02576431 [a basket trial]).^49,98 Evaluated patients had 17 unique cancers.⁹⁸ Among these patients, larotrectinib therapy was associated with a 75% overall response rate that was durable for ≥6 months in 32 subjects and ≥12 months in 17 subjects.¹⁰⁵ At the time of data lock, only one patient with breast cancer and disease progression had been considered a treatment failure.⁴⁹

Premarket safety testing was performed in 176 patients with 70 (40%) exposed to larotrectinib for ≥6 months and 35 (20%) exposed ≥1 year.⁴⁹ Test subjects had a median age of 51 years (range: 28 days to 82 years); 25% were ≤18 years, 22% were ≥65 years, and 5% were ≥75 years. NTRK gene fusions were present in 60% of patients, and the cancer types represented included soft tissue sarcoma (16%), salivary gland (11%), lung (10%), thyroid (9%), colon (8%), infantile fibrosarcoma (8%), primary central nervous system (7%), and melanoma (5%).⁴⁹ Noteworthy premarket adverse effects reported in association with larotrectinib therapy include neurotoxicity (delirium, dysarthria, dizziness, tremor, gait disturbance, memory impairment, paresthesia, and encephalopathy) and hepatotoxicity (increased transaminases occurred in nearly half of premarket study patients), and embryo-fetal toxicity is presumed.⁴⁹

The starting dose of larotrectinib is 100 mg/m² (max 100 mg) orally twice-daily. Dosage adjustments are necessary for patients who are co-administered strong CYP3A4 inhibitors or inducers, those with moderate to severe hepatic impairment, and patients who develop serious adverse reactions.⁴⁹ Larotrectinib should be permanently discontinued in patients who are unable to tolerate the drug after three dose modifications.⁴⁹ The half-life of larotrectinib is 2.9 hours, it is metabolized mainly by CYP3A4, and elimination is in the feces (58%) and urine (39%).⁴⁹ The chemical structure of larotrectinib is shown in Figure P1-5.

• Chapter 14. Neurotransmission in the Central Nervous System > Figure 14–18

• eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals