Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer
- PMID: 40068370
- DOI: 10.1016/j.ejca.2025.115338
Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer
Abstract
Background: Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.
Methods: Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.
Results: As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients with CRC, 16 (62 %) had known microsatellite instability-high (MSI-H) status. For the 43 IRC-eligible patients, overall response rate was 28 % (95 % confidence interval [CI] 15-44) for all patients and 44 % (95 % CI 24-65) for those with CRC. In patients overall and in those with CRC, median duration of response was 27 months (95 % CI 6-not estimable [NE]) and 27 months (95 % CI 6-NE), median progression-free survival was 6 months (95 % CI 5-9) and 7 months (95 % CI 6-NE), and median overall survival was 13 months (95 % CI 7-29) and 29 months (95 % CI 7-NE), respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in seven (16 %) patients. There were no deaths due to TRAEs.
Conclusion: Larotrectinib demonstrated long durability, extended survival and manageable safety in patients with TRK fusion GI cancer, including those with MSI-H CRC. This supports the wider adoption of next-generation sequencing testing for NTRK gene fusions in patients with GI cancer.
Keywords: Colorectal cancer; Gastrointestinal cancer; Larotrectinib; NTRK gene fusion; TRK fusion.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CQ reports consulting fees from AstraZeneca and CARsgen Therapeutics; and speaker fees for Jiangsu Hengrui, Zai Lab and CStone Pharmaceuticals. LS reports receiving funding from Beijing Xiantong Biomedical Technology Co., Ltd, Qilu Pharmaceutical Co., Ltd, Zaiding Pharmaceutical (Shanghai) Co., Ltd, Jacobio Pharmaceuticals Co., Ltd. and Beihai Kangcheng (Beijing) Medical Technology Co.,Ltd; consulting fees from MSD, Merck, Boehringer Ingelheim and Harbour; and speaker fees for Hutchison Whampoa, Hengrui, ZaiLab and CStone. TA reports attending advisory board meetings and receiving consulting fees from Abbvie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen/Pfizer, Servier and Takeda; honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Roche, Sanofi, Seagen and Servier; support for meetings from Bristol Myers Squibb and Merck & Co. Inc; and a data monitoring committee member role for Inspirna. HCC reports receiving grants/research support from Lilly, GlaxoSmithKline, MSD, Merck-Serono, Bristol Myers Squibb/Ono, Taiho, Amgen, BeiGene, Incyte and Zymeworks; honoraria from Merck-Serono and Lilly; consultation for Taiho, Celltrion, MSD, Lilly, Bristol Myers Squibb, Merck-Serono, Gloria, BeiGene, Amgen, Zymeworks, Y-Biologics, Seagen and MD Biolab. TLC reports receiving honorarium from Mirata and being a paid member of the molecular tumour board at Intermountain Health until 2023. EG reports receiving grants/research support from Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, BeiGene and Janssen; consulting honoraria from Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seagen, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, Sanofi, Incyte, Medscape, Pfizer and Amgen; speakers’ honoraria from Merck Sharp & Dohme, Roche, Thermo Fisher, Novartis and Seagen; employment from NEXT Oncology; and stocks from 1TRIALSP. AI reports providing an advisory role and receiving honoraria from Bayer, Daiichi-Sankyo, Epizyme, Ipsen, Roche and Springworks; and research grants from AstraZeneca, Bayer, Merck, MSD, PharmaMar and Roche. DTR reports an advisory role for Bayer and BeiGene; travel support from Bayer and Johnson&Johnson; and honoraria from Lilly, Roche and Bristol Myers Squibb as well as research support by Seagen. TL has nothing to disclose. D-IB and CEM are employees of Bayer. NN is an external employee of Bayer. R-HX has nothing to disclose. DSH reports receiving research/grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo Oncology, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seagen and Takeda; travel/accommodation/expenses from Loxo Oncology, MiRNA, ASCO, AACR, SITC and Genmab; consulting/advisory roles for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seagen, Takeda and Trieza Therapeutics; and ownership interests in Molecular Match (advisor), OncoResponse (founder) and Presagia Inc (advisor). AD reports honoraria from 14ner/Elevation Oncology, Amgen, Abbvie, AnHeart Therapeutics, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1 Capital, LLC, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millennium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem, and Zymeworks; advisory board participation with Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo/Lilly, and AnHeart Therapeutics; consulting with MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude, Bayer, Applied Pharmaceutical Science, Bristol Myers Squibb, Enlaza, Pfizer, Roche/Genentech, Two River and Eli Lilly/Loxo; associated research paid to institution from Foundation Medicine, GSK, Teva, Taiho, and PharmaMar; equity with mBrace and Treeline; copyright with Selpercatinib-Osimertinib (US 18/041,617, pending); royalties from Wolters Kluwer and UpToDate; other funding (food/beverage expenses) from Merck, Puma, and Boehringer Ingelheim; and CME honoraria with Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education, Projects in Knowledge, Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, and WebMD. JB reports receiving research funding from Bayer, Astellas, Atreca, Dragonfly, I-Mab, Incyte, EMD Serono, Pfizer, Bristol Myers Squibb, Transcenta Therapeutics, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23andMe, Incendia, Hibercell and Riboscience; advisory board participation with Bayer, Mirati, MEKanistic Therapeutics, Merck Sharp & Dohme, Nested Therapeutics and Taiho; and serving on data safety monitoring boards for AstraZeneca, Boehringer Ingelheim and Novocure.
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