Rationale and design of ON-TRK: a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib

James C H Yang, Marcia S Brose, Gilberto Castro, Edward S Kim, Ulrik N Lassen, Serge Leyvraz, Alberto Pappo, Fernando López-Ríos, John A Reeves, Marc Fellous, Frédérique Penault-Llorca, Erin R Rudzinski, Ghazaleh Tabatabai, Gilles Vassal, Alexander Drilon, Jonathan Trent, James C H Yang, Marcia S Brose, Gilberto Castro, Edward S Kim, Ulrik N Lassen, Serge Leyvraz, Alberto Pappo, Fernando López-Ríos, John A Reeves, Marc Fellous, Frédérique Penault-Llorca, Erin R Rudzinski, Ghazaleh Tabatabai, Gilles Vassal, Alexander Drilon, Jonathan Trent

Abstract

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.

Keywords: Larotrectinib; NTRK gene fusions; Non-interventional study; TRK fusion.

Conflict of interest statement

JCHY discloses consultancy or advisory roles for Boehringer Ingelheim, Novartis, AstraZeneca, Roche/Genentech, Clovis Oncology, Lilly, Merck Serono, Celgene, Astellas, Bayer, Pfizer, Ono Pharmaceutical, BMS, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Amgen, Takeda, and Incyte; travel/accommodation/expenses from Pfizer; honoraria from Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, BMS, Ono Pharmaceutical, Takeda, Lilly, and Pfizer.

MSB discloses research support to the University of Pennsylvania School of Medicine from Bayer, Loxo Oncology, Genentech, Eisai, Blueprint Medicines, Lilly, and Novartis; consultancy for Bayer, Loxo Oncology, Genentech, AstraZeneca, and Lilly; and honoraria from Clinical Care Options, Medscape, OncLive, and PeerView.

GC discloses travel/accommodation/expenses, honoraria, speaker bureau, and advisory roles for Bayer, and honoraria from Foundation Medicine.

UNL discloses advisory board roles for Bayer, Pfizer, and Novartis; and research funding from BMS, GSK, Pfizer, and Roche.

SL discloses an advisory role and travel grant support for Bayer.

AP discloses personal fees from Bayer.

FL-R discloses honoraria from BMS, Roche, Bayer, Lilly, AstraZeneca, Pfizer, MSD, and Thermo Fisher; and associated research funding paid to institution from BMS, Thermo Fisher, Roche, and Pfizer.

JAR and MF are employees of Bayer.

FP-L discloses advisory roles for Bayer, Roche, Illumina, and NanoString; and research grants paid to institution from Bayer, Roche, and NanoString.

ERR discloses consultancy and advisory roles for Bayer.

GT discloses advisory roles for AbbVie and Bayer; speaker fees from Medac and Novocure; research grants from Roche Diagnostics and Medac; an educational grant from Novocure; and travel grants from Novocure and Medac.

GV discloses advisory roles for Bayer, Hutchison Pharma, Roche/Genentech, AstraZeneca, Pfizer, Ipsen, and BMS without personal remuneration.

AD discloses honoraria/advisory board roles for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Elevation Oncology; associated research paid to institution: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; research funding from Foundation Medicine; royalties: Wolters Kluwer; other: Merck – Food/Beverage, Puma – Food/Beverage, Merus – Food/Beverage, Boehringer Ingelheim; CME Honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options.

JT discloses consultancy roles for Bayer, Deciphera, Blueprint Medicines, Epizyme, and Daiichi Sankyo.

ESK declares that he has no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. NTRK neurotrophic tyrosine receptor kinase, TRK tropomyosin receptor kinase

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