Larotrectinib
Larotrectinib, sold under the brand name Vitrakvi, is a potent, oral, and highly selective tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients with solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions without a known acquired resistance mutation, where the tumors are metastatic or unresectable and surgical resection would likely result in severe morbidity, and for whom there are no satisfactory prior treatments or the disease has progressed following treatment.[1][2] Developed by Loxo Oncology and marketed by Bayer, larotrectinib targets the TRKA, TRKB, and TRKC proteins encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively, which become constitutively active due to gene fusions in certain cancers, driving uncontrolled cell proliferation.[2][3] By binding to these fusion proteins, larotrectinib inhibits downstream signaling pathways, thereby suppressing tumor growth in NTRK fusion-positive malignancies, which occur in approximately 0.5–1% of all solid tumors across various histologies such as salivary gland cancer, infantile fibrosarcoma, and lung adenocarcinoma.[2][4] This tumor-agnostic approval, initially granted by the U.S. Food and Drug Administration (FDA) on November 26, 2018, as accelerated approval with priority review, breakthrough therapy, and orphan drug designations, was converted to full approval on April 10, 2025, marking it as one of the early therapies approved based on a specific genetic alteration rather than tumor type or location.[1][5][6] Pooled analyses from three clinical trials (LOXO-TRK-14001, SCOUT, and NAVIGATE), involving 339 patients with NTRK fusion-positive solid tumors, demonstrated an overall response rate of 60% (95% confidence interval: 55–65%), with a median duration of response of 43.3 months; responses were durable regardless of patient age or tumor histology.[7][1] Common adverse reactions occurring in at least 20% of patients include anemia, elevated aspartate aminotransferase (AST), constipation, cough, diarrhea, dizziness, elevated alanine aminotransferase (ALT), fatigue, nausea, and vomiting, while serious risks encompass hepatotoxicity, interstitial lung disease/pneumonitis, and treatment-related neurotoxicity such as confusion or hallucinations.[1][8] Administered as capsules or oral solution twice daily at 100 mg for adults and pediatric patients with body surface area (BSA) ≥1 m² or 100 mg/m² (maximum 100 mg per dose) for those with BSA <1 m², with or without food, larotrectinib requires NTRK fusion confirmation via FDA-approved companion diagnostics like next-generation sequencing or fluorescence in situ hybridization.[8][7] Ongoing research explores its role in combination therapies and resistance mechanisms, such as acquired solvent-front mutations in NTRK, to expand its utility in precision oncology.[3][9]Medical Uses
Indications
Larotrectinib is indicated for the treatment of adult and pediatric patients, including infants one month of age and older, with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, that are unresectable or metastatic, or for which surgical resection is likely to result in severe morbidity. In April 2025, the FDA granted full approval based on confirmatory trials.[10] This approval encompasses a broad range of solid tumor types where NTRK fusions drive oncogenesis, prioritizing cases where alternative treatments are limited or ineffective. As a tissue-agnostic therapy, larotrectinib was the second drug approved by the U.S. Food and Drug Administration (FDA) based on a specific tumor biomarker—NTRK gene fusion—rather than the tumor's anatomical location or histological subtype. It applies to rare cancers such as salivary gland tumors (where NTRK fusions occur in approximately 2-3% of cases), infantile fibrosarcoma (up to 90% prevalence), and certain thyroid cancers (around 1-2% prevalence).[11][12] Overall, NTRK gene fusions are rare, affecting less than 1% of solid tumors across all types, but they represent actionable drivers in these uncommon malignancies.[13] Patient selection for larotrectinib requires confirmation of an NTRK gene fusion through molecular testing, and it is not indicated for routine use in tumors lacking this biomarker. FDA-approved companion diagnostic tests, including next-generation sequencing (NGS) assays like FoundationOne CDx or fluorescence in situ hybridization (FISH), are recommended to identify eligible patients accurately.[14] The drug demonstrates efficacy across age groups, with compassionate use extending its application to neonates in select cases of NTRK fusion-positive tumors like infantile fibrosarcoma.[15]Dosage and Administration
Larotrectinib is administered orally at a recommended dose of 100 mg twice daily for adults and pediatric patients with a body surface area (BSA) of 1 m² or greater, taken continuously with or without food until disease progression or unacceptable toxicity.[7] For pediatric patients with a BSA less than 1 m², the dose is 100 mg/m² twice daily, not to exceed the adult dose.[7] The drug is available in capsule formulations of 25 mg and 100 mg strengths, as well as an oral solution at 20 mg/mL concentration, which facilitates use in pediatric patients or those with swallowing difficulties; capsules and oral solution are interchangeable on a milligram-to-milligram basis.[7] Capsules should be swallowed whole with water and not chewed or crushed, while the oral solution must be refrigerated and discarded after 90 days for 100 mL bottles or 31 days for 50 mL bottles following first opening.[7] Missed doses should not be taken within 6 hours of the next scheduled dose, and if vomiting occurs after administration, the next dose should proceed as planned without repetition.[7] Dose modifications are required for adverse reactions and specific clinical conditions. For Grade 3 or 4 non-hepatotoxic adverse reactions, larotrectinib should be withheld until resolution to baseline or Grade 1, then resumed at the next lower dose (first reduction: 75 mg or 75 mg/m² twice daily; second: 50 mg or 50 mg/m² twice daily; third: 100 mg once daily or 25 mg/m² twice daily for BSA ≥1 m², or 25 mg/m² twice daily for BSA <1 m²), with permanent discontinuation if unresolved after 4 weeks or following three reductions if intolerable.[7] For hepatotoxicity, withhold for AST or ALT elevations ≥5 × ULN (with bilirubin ≤2 × ULN) until recovery to ≤Grade 1 or baseline, then resume at the next lower dose, permanently discontinuing for Grade 4 events post-resumption or for elevations >3 × ULN with bilirubin >2 × ULN without alternative etiology; monitor liver function tests frequently during Grade 2 elevations.[7] Adjustments are also needed for drug interactions and hepatic impairment. Coadministration with strong CYP3A4 inhibitors should be avoided, but if unavoidable, reduce the dose by 50% and resume the original dose after 3-5 half-lives post-discontinuation; for strong or moderate CYP3A4 inducers, avoid strong inducers and double the dose for unavoidable use, resuming the original after 3-5 half-lives.[7] In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, initiate at 50% of the recommended dose.[7] Monitoring includes baseline and periodic assessments of liver function tests and complete blood counts to detect potential toxicities, with dose adjustments guided by these results.[7]Pharmacology
Mechanism of Action
Larotrectinib is a selective small-molecule tyrosine kinase inhibitor that specifically targets the tropomyosin receptor kinases TRKA, TRKB, and TRKC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively.[5][16] These receptors normally play roles in neuronal development and maintenance, but in cancer, chromosomal rearrangements involving NTRK genes result in gene fusions that produce constitutively active chimeric TRK fusion proteins.[17] These fusions lead to ligand-independent activation of TRK kinases, driving oncogenesis through downstream signaling pathways such as MAPK/ERK, PI3K/AKT, and PLCγ, which promote uncontrolled cell proliferation, survival, and tumor growth.[17][18] Larotrectinib exerts its therapeutic effect by competitively binding to the ATP-binding site of the TRK kinase domains, thereby inhibiting autophosphorylation and the activation of downstream signaling cascades.[5] This blockade disrupts the oncogenic signaling in TRK fusion-positive tumor cells, leading to reduced phosphorylation of TRK proteins and suppression of tumor cell proliferation and survival.[16] In preclinical models, larotrectinib demonstrates high potency against wild-type TRKA, TRKB, and TRKC, with IC50 values ranging from 5 to 11 nM in enzymatic assays.[5][17] The inhibitor exhibits high selectivity for TRK kinases, showing minimal off-target activity against other kinases such as ALK or ROS1 at clinically relevant concentrations, with over 100-fold selectivity compared to related kinases like TNK2 (IC50 approximately 576 nM).[5][17] At the cellular level, larotrectinib induces apoptosis and cell cycle arrest specifically in NTRK fusion-positive cancer cells, while showing no antitumor activity in NTRK wild-type tumors.[16][17] Acquired resistance to larotrectinib can emerge through secondary mutations in the TRK kinase domain, such as solvent-front mutations (e.g., TRKA G595R or TRKC G623R), which sterically hinder drug binding and restore TRK signaling.[5][18]Pharmacokinetics
Larotrectinib is rapidly absorbed following oral administration, with a mean absolute bioavailability of 34% (range: 32%–37%) for the capsule formulation.[7] The time to reach maximum plasma concentration (Tmax) is approximately 1 hour after dosing.[7] Administration with a high-fat meal reduces the maximum plasma concentration (Cmax) by 35% but does not significantly affect the area under the plasma concentration-time curve (AUC), indicating that larotrectinib can be taken with or without food.[7] Steady-state plasma concentrations are achieved within 3 days of repeated dosing, and the pharmacokinetics are approximately linear across the recommended dose range.[7] The apparent volume of distribution at steady state (Vss/F) is 48 L (coefficient of variation [CV] 38%), suggesting moderate tissue distribution.[7] Larotrectinib is 70% bound to plasma proteins, independent of concentration, and primarily to albumin.[7] The blood-to-plasma concentration ratio is 0.9.[7] Larotrectinib penetrates the central nervous system.[7] Larotrectinib undergoes hepatic metabolism primarily via cytochrome P450 3A4 (CYP3A4), with unchanged drug accounting for 19% of circulating plasma radioactivity and an O-linked glucuronide metabolite representing 26%.[7] No active metabolites have been identified. The mean apparent oral clearance (CL/F) of larotrectinib is 98 L/h (CV 44%), and the terminal half-life is 2.9 hours.[7] Following administration of a single radiolabeled dose, approximately 58% of the radioactivity is recovered in feces (with 5% as unchanged drug) and 39% in urine (with 20% as unchanged drug).[7] In special populations, no clinically significant differences in pharmacokinetics are observed based on age (from 1 month to 82 years), sex, or body weight (3.8–179 kg).[7] Pediatric patients achieve similar systemic exposure to adults when dosed on a body surface area basis, with AUC0-24h values ranging from 3108 to 4135 ng·h/mL across age groups.[7] No dose adjustment is required for mild hepatic impairment (AUC increase 1.3-fold) or for renal impairment of any severity (AUC increase 1.5-fold in end-stage renal disease). However, moderate hepatic impairment increases AUC 2-fold and severe hepatic impairment increases it 3.2-fold, necessitating dose reductions by 50% for moderate to severe hepatic impairment.[7] Drug interactions significantly affect larotrectinib exposure due to its metabolism by CYP3A4. Strong CYP3A4 inhibitors, such as itraconazole, increase AUC by 4.3-fold and Cmax by 2.8-fold, while strong inducers like rifampin decrease AUC by 81% and Cmax by 71%; dose adjustments are recommended accordingly.[7] Moderate CYP3A inhibitors, such as fluconazole, are predicted to increase AUC 2.7-fold.[7] Larotrectinib may increase exposure to CYP3A4 substrates (e.g., midazolam AUC increased 1.7-fold) and P-glycoprotein substrates.[7]Adverse Effects
Common Adverse Effects
Common adverse effects of larotrectinib are defined as those occurring in 20% or more of patients in clinical trials.[7] In pooled analyses from adult and pediatric safety populations (n=444), the most frequently reported adverse reactions, including laboratory abnormalities, were elevated aspartate aminotransferase (AST; 62%), elevated alanine aminotransferase (ALT; 61%), anemia (45%), fatigue (31%), vomiting (30%), diarrhea (26%), and pyrexia (26%).[7] These effects were predominantly grade 1 or 2 in severity, with grade 3-4 events occurring in 8% for elevated ALT, 7% for elevated AST, and 8% for anemia.[7] Hepatotoxicity, manifested as elevated ALT and AST levels, is often transient and reversible upon dose interruption or reduction, with monitoring recommended every 2 weeks for the first 2 months of treatment and monthly thereafter.[7] Anemia is typically mild (grade 1-2) and managed supportively, while weight increase (reported in 17% as associated edema) is linked to fluid retention and may require monitoring for peripheral edema.[7] Pyrexia is usually low-grade and not associated with infection, resolving with supportive care such as antipyretics.[7] Fatigue is commonly reported but seldom leads to discontinuation.[7] Decreased white blood cell count, observed as leukopenia in 37% of patients (3.8% grade 3-4), is another frequent laboratory abnormality.[7] Most adverse effects are manageable with supportive care or dose modifications, such as interruptions (45% of patients) or reductions (11%), and permanent discontinuation due to adverse reactions occurred in 12% of cases.[7] In pediatric patients, rates of certain gastrointestinal effects are higher compared to adults, with vomiting occurring in 51% (versus 18% in adults) and diarrhea in 34% (versus 21% in adults); these remain mostly mild and self-limiting.[7]| Adverse Reaction/Laboratory Abnormality | All Grades (%) | Grade 3-4 (%) |
|---|---|---|
| Increased AST | 62 | 7 |
| Increased ALT | 61 | 8 |
| Anemia | 45 | 8 |
| Leukopenia (decreased WBC) | 37 | 3.8 |
| Fatigue | 31 | 2.5 |
| Vomiting | 30 | 1.1 |
| Pyrexia | 26 | 2.3 |
| Diarrhea | 26 | 2.9 |
| Weight increase (edema) | 17 | 4.1 |