Pooled Analysis of Phase I/II Trials of Larotrectinib in TRK Fusion–Positive Solid Tumors

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In a pooled analysis of phase I/II trials reported in The Lancet Oncology, Hong et al found that the tropomyosin receptor kinase (TRK) inhibitor larotrectinib produced a high response rate in pediatric and adult patients with advanced TRK fusion–positive solid tumors.

Larotrectinib received accelerated approval in this setting in November 2018 on the basis of findings in a primary analysis set of 55 adult and pediatric patients. These patients are included in the current pooled analysis.

Study Details

The analysis included 159 pediatric or adult patients with locally advanced or metastatic non­–central nervous system primary disease from phase I adult, phase I/II pediatric, and phase II adolescent and adult trials. Patient had previously received standard therapy if available. Larotrectinib was given in capsule or liquid formulation on a continuous 28-day schedule, with most adults receiving 100 mg twice daily and most pediatric patients receiving 100 mg/m² (maximum of 100 mg) twice daily. The primary endpoint was investigator-assessed objective response.

Patient ages ranged from younger than 1 month old to 84 years. The most common tumor types included in the analysis were soft-tissue sarcoma (44%), thyroid cancer (16%), salivary gland cancer (13%), and lung cancer (8%).


Among all patients, objective response was observed in 121 (79%), with complete response in 24 (16%). An additional 19 patients (12%) had stable disease. Objective response was observed in 74 (73%) of 102 adult patients and 47 (92%) of 51 pediatric patients. Among all responders, median duration of response was 35.2 months at time of analysis; an estimated 80% of responses were ongoing at 12 months. Median progression-free survival was 28.3 months, with an estimated 12-month rate of 67%. Median overall survival was 44.4 months, with an estimated 12-month rate of 88%.


  • Objective response was achieved in 79% of patients.
  • Median duration of response was 35.2 months.

Adverse Events

In a safety population of 260 patients treated with larotrectinib regardless of TRK fusion status, grade 3 and grade 4 larotrectinib-related adverse events occurred in 33 patients (13%) and 2 patients (< 1%), respectively; the most common were increased alanine aminotransferase (3%), anemia (2%), and decreased neutrophil count (2%). Larotrectinib-related serious adverse events occurred in 13 patients (5%), with the most common being increased alanine aminotransferase, increased aspartate aminotransferase, and nausea (each in two patients, < 1%).  No treatment-related deaths were reported.

The investigators concluded, “These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumors for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.”

Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bayer and Loxo Oncology. For full disclosures of the study authors, visit

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