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Rationale and design of ON-TRK: a novel prospective non-interventional study in patients with TRK fusion cancer
James C H Yang1, Marcia S Brose2,3, Gilberto Castro4
1National Taiwan University Cancer Center, Taipei City, Taiwan. chihyang@ntu.edu.tw.
Background:
Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods.
Methods:
ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients < 18 years old will be enrolled under a 'pediatric' cohort regardless of tumor type and will be followed for 5 years to evaluate the risk of potential long-term adverse effects of larotrectinib on their growth and development. The effectiveness of larotrectinib in the overall study population as well as in patient subgroups will also be evaluated. Procedures avoided in patients with infantile fibrosarcoma (e.g., amputation) and the number of patients who were able to undergo surgery with a curative intent (excluding amputation) because of the use of larotrectinib will be described. Larotrectinib treatment patterns in real-world practice, including dosing and duration of treatment, will be described.
Discussion:
The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA.
Study Registration:
This study is registered at ClinicalTrials.gov ( NCT04142437 ).
Protocol Version:
v2.5, 25 March 2021.
Insights
This study evaluates larotrectinib, a TRK inhibitor, in a broader population of TRK fusion cancer patients. It assesses long-term safety and effectiveness in real-world settings, fulfilling post-approval requirements.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Tropomyosin receptor kinase (TRK) fusion proteins are rare oncogenic drivers in various tumors.
- Larotrectinib is an FDA-approved TRK inhibitor for TRK fusion solid tumors.
- Accelerated approval was based on limited early-phase trial data, necessitating further evaluation.
Purpose of the Study:
- To evaluate the safety profile of larotrectinib in a broader patient population.
- To assess the long-term effectiveness of larotrectinib in real-world practice.
- To fulfill post-approval regulatory requirements for larotrectinib.
Main Methods:
- Prospective, non-interventional, open-label, multicenter study (ON-TRK).
- Adults grouped by tumor type (≥2 years follow-up); pediatric patients (<18 years) followed for 5 years.
- Evaluation of safety, effectiveness, treatment patterns, and impact on surgical interventions.
Main Results:
- Study aims to describe safety and effectiveness in real-world practice.
- Will evaluate larotrectinib's impact on avoiding procedures like amputation in infantile fibrosarcoma.
- Will describe treatment patterns, including dosing and duration.
Conclusions:
- The study fulfills post-approval requirements from regulatory bodies like the FDA and EMA.
- It contributes to the risk management plan for larotrectinib.
- Provides essential data for understanding larotrectinib's real-world application and long-term outcomes.
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