@article{fcfbd9d9535441cdaf730fbf864cd67e,
title = "Larotrectinib in adult patients with solid tumours: A multi-centre, open-label, phase i dose-escalation study",
abstract = "Background NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. Patients and methods This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. Results Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. Conclusions Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. ClincalTrials.gov number NCT02122913.",
keywords = "Adult, Larotrectinib, Ntrk gene fusion, Phase i, Trk fusion cancer",
author = "Hong, {D. S.} and Bauer, {T. M.} and Lee, {J. J.} and A. Dowlati and Brose, {M. S.} and Farago, {A. F.} and M. Taylor and Shaw, {A. T.} and S. Montez and F. Meric-Bernstam and S. Smith and Tuch, {B. B.} and K. Ebata and S. Cruickshank and Cox, {M. C.} and Burris, {H. A.} and Doebele, {R. C.}",
note = "Funding Information: We thank the participating patients and their families and contributing clinical staff across all sites. This study is supported and funded by Loxo Oncology Inc., Stamford, CT and Bayer AG, Berlin, Germany. Alturas Analytics Inc. (Moscow, Idaho) provided bioanalytical assessments. Medical writing services were provided by Jim Heighway, PhD of Cancer Communications and Consultancy Ltd, Knutsford, UK and were funded by Loxo Oncology Inc. and Bayer AG. Kathrina Marcelo-Lewis, PhD of the Department of Investigational Cancer Therapeutics at The University of Texas: MD Anderson Cancer Center also assisted in the writing of this manuscript. Funding Information: This study was supported by Loxo number is applicable). Funding Information: In relation to the work under consideration, DSH has received grant funding and non-financial support from Loxo Oncology. Outside of the submitted work, DSH has received grant funding from Bayer, Lilly, Genentech, Pfizer, Amgen, Mirati, Ignyta, Merck, Daiichi Sankyo, Eisai, Adaptimmune, Abbvie, AstraZeneca, Bristol-Myers Squibb, Genmab, Infinity, Kite, Kyowa, Medimmune, Molecular Template, Novartis, Fate Therapeutics, MiRNA, Mologen, NCI-CTEP, Seattle Genetics, and Takeda, has received non-financial support for travel, accomodations, expenses from Mirna, and has consultancy/advisory roles with Bayer (Advisory Board), Baxter, Guidepoint global, Takeda, Janssen, Alpha Insights, Axiom, Adaptimmune, Genentech, GLG, Group H, Infinity, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, and Trieza Therapeutics and an ownership interest in Molecular Match (Advisor), Presagia Inc (Advisor), and Oncoresponse (founder). TMB has consultancy/advisory roles with Ignyta, Guardant Health, Loxo Oncology, Pfizer, and Modern Therapeutics, his institution has received research funding from Daiichi Sanko, Medpacto Inc., Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genetech/ Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences Kolltan Pharmaceuticals, Peleton, Immunocore, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics and Jacobio. In relation to the work under consideration, MSB{\textquoteright}s institution has received grant funding from Loxo Oncology; outside of the submitted work MSB has received personal fees related to a consultancy role from Loxo Oncology and Bayer Healthcare. In relation to the work under consideration, AFF has received grant funding, personal fees and non-financial support from Bayer and Loxo Oncology. Outside of the submitted work, AFF has received grant funding, personal fees and non-financial support from Abbvie, Pharmamar, and Stemcentrx, grant funding from Ignyta, AstraZeneca, Bristol-Myers Squibb, Merck and Genentech, personal fees and nonfinancial support from Merrimack, and personal fees from Takeda and Foundation Medicine. Outside of the submitted work, MT has a consultancy role and has served on speakers bureau for Bristol-Myers Squibb and Eisai Inc and has consultancy/advisory roles with Blueprint Medicines, Loxo Oncology, Novartis, Array Biopharma, Trillium and Arqule. In relation to the work under consideration, ATS has received research funding for the study and outside of the submitted work, has received personal fees related to consultancy/advisory roles from Ignyta, TP Therapeutics, Pfizer, Novartis, Takeda, Ariad, Roche/Genentech, Blueprint Medicines, KSQ Therapeutics, Foundation Medicine, Guardant, Natera and Loxo Oncology. SS and SC are consultants for Loxo Oncology. BBT and KE are employees of and own stock in Loxo Oncology. MCC is an employee of and owns stock in Loxo Oncology, holds a patent 62/318 041 issued to Loxo Oncology, and owns stock in Bayer AG. In relation to the work under consideration, RCD has received grant funding and personal fees from Loxo Oncology and personal fees from Bayer and outside of the submitted work, has received grant funding and personal fees from Ignyta and personal fees related to advisory roles and or travel expenses from AstraZeneca, Ariad, Takeda, Spectrum and Guardant Health. RCD has a patent PCT/US13/57495 with royalties paid by Abbott Molecular, and a patent PCT/US2016/058951 pending. All remaining authors have declared no conflicts of interest.",
year = "2019",
month = feb,
day = "1",
doi = "10.1093/annonc/mdy539",
language = "English (US)",
volume = "30",
pages = "325--331",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "2",
}