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Repotrectinib is a next-generation ROS1\/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1\/2 trial assessing repotrectinib, a next-generation ROS1\/TRK TKI, in adults with advanced solid tumors, including\n                    <jats:italic>NTRK<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3\u2009months and 25.7\u2009months. In the TKI-naive cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200951; 95% confidence interval (CI)), the response rate was 59% (44\u201372); the median DOR was not estimable (NE); and the median PFS was 30.3\u2009months (9.0\u2013NE). In the TKI-pretreated cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200969; 95% CI), the response rate was 48% (36\u201360); the median DOR was 9.8\u2009months (7.4\u201313.0); and the median PFS was 7.4\u2009months (3.9\u20139.7). Of 30 TKI-pretreated patients with\n                    <jats:italic>NTRK<\/jats:italic>\n                    solvent front mutations, 16 had a response (53%; 95% CI: 34\u201372). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with\n                    <jats:italic>NTRK<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with\n                    <jats:italic>NTRK<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    solid tumors. ClinicalTrials.gov identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT03093116\" ext-link-type=\"uri\">NCT03093116<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04079-7","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T10:02:36Z","timestamp":1770199356000},"page":"682-689","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Repotrectinib in NTRK fusion\u2013positive advanced solid tumors: a phase 1\/2 trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5090-8189","authenticated-orcid":false,"given":"Benjamin","family":"Besse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7373-3916","authenticated-orcid":false,"given":"Jessica J.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila","family":"Bazhenova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3023-2510","authenticated-orcid":false,"given":"Koichi","family":"Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7343-633X","authenticated-orcid":false,"given":"Adrianus Johannes","family":"de Langen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5124-7132","authenticated-orcid":false,"given":"Dong-Wan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3843-101X","authenticated-orcid":false,"given":"Christoph","family":"Springfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2087-4963","authenticated-orcid":false,"given":"Sanjay","family":"Popat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-0206","authenticated-orcid":false,"given":"Darren W. T.","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misako","family":"Nagasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Yong","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina S.","family":"Baik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Hervieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6099-4236","authenticated-orcid":false,"given":"Victor","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanthi","family":"Kollengode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haisu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe Y.","family":"Calvet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy B.","family":"Hammell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6806-9061","authenticated-orcid":false,"given":"Alexander","family":"Drilon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3059-5730","authenticated-orcid":false,"given":"Benjamin J.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"4079_CR1","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41571-018-0113-0","volume":"15","author":"E Cocco","year":"2018","unstructured":"Cocco, E., Scaltriti, M. & Drilon, A. 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(to institution); consulting\/advisory role for AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical, CureVac AG, Daiichi-Sankyo, F. Hoffmann-La Roche Ltd., Pharmamar, Regeneron, Sanofi Aventis and Turning Point Therapeutics (to institution); and research funding from AstraZeneca, BeiGene, Genmab A\/S, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Ose Immunotherapeutics, Pharmamar, Roche-Genentech, Sanofi and Takeda (to institution). J.J.L. discloses compensated consulting\/advisory role for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Ellipses, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Yuhan, Merus, Regeneron, Pfizer, Roche, Gilead, Janssen, Nuvation Bio, Eli Lilly, Triana and Turning Point Therapeutics; institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche-Genentech, Linnaeus Therapeutics, Nuvalent, Bristol Myers Squibb and Novartis; and travel support from Pfizer, Merus, Takeda and Bristol Myers Squibb. L.B. discloses consulting\/advisory role for Roche-Genentech, Regeneron, Merck, Neuvogen, Bayer, Sanofi, Novocure, AbbVie, InterVenn Biosciences, Elevation Oncology, Janssen Oncology, Gilead Sciences, Anheart Therapeutics, BioAtla, Pfizer, Teligene, Boehringer Ingelheim, Summit Pharmaceuticals, Bristol Myers Squibb GmbH & Co. KG, AstraZeneca and Daiichi-Sankyo. K.G. discloses honoraria from Amgen K.K., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Japan Corp., Janssen Pharmaceutical K.K., Thermo Fisher Scientific K.K., Merck Biopharma Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Riken Genesis Co., Ltd., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd. and Takeda; consulting\/advisory role for Amgen Inc., Amgen K.K., Bayer HealthCare Pharmaceuticals Inc., Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Guardant Health Japan Corp., GlaxoSmithKline K.K., Haihe Biopharma Co., Ltd., iTeos Therapeutics Inc., Syneos Health Clinical K.K., Novartis Pharma K.K. and Pharma Mar, S.A.; and research funding from Amgen K.K., AstraZeneca K.K., AbbVie GK, AnHeart Therapeutics Inc., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol Myers Squibb K.K., Blueprint Medicines Corporation., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Japan Corp., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., Merck Sharp & Dohme K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer R&D Japan G.K., Precision Medicine Asia Co., Ltd., Riken Genesis Co., Ltd., Sumitomo Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Turning Point Therapeutics, Inc. A.J.D. discloses grants from Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca and Boehringer Ingelheim and non-financial support from Merck Serono and Roche. D.-W.K. discloses research funding from Alpha Biopharma, Amgen, AstraZeneca\/Medimmune, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GlaxoSmithKline, Hanmi, IMBDx, InnoN, IQVIA, Janssen, Merck, Merus, Mirati Therapeutics, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche-Genentech, Takeda, Turning Point Therapeutics, Xcovery and Yuhan (to institution); and other relationships with Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GlaxoSmithKline, IMBDx, Janssen, Merus, Mirati Therapeutics, Merck Sharp & Dohme, Meck, Novartis, Pfizer, Roche, Takeda and Yuhan. J.W. discloses consulting\/advisory role for Amgen, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, Eli Lilly, Loxo, Merck, Mirati, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Pierre Fabre, Roche, Seattle Genetics and Takeda; speaker\u02bcs bureau participation for Bayer and Chugai; and research funding from Bristol Myers Squibb, Janssen, Novartis and Pfizer (to institution). C.S. discloses consulting\/advisory role for AstraZeneca, Bayer, Incyte, Merck Sharp & Dohme, Roche, Servier and Taiho. S.P. discloses leadership role at British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, the Ruth Strauss Foundation, the Mesothelioma Applied Research Foundation and the ETOP-IBCSG Partners Foundation Board; consulting\/advisory role for Anheart Therapeutics, Amgen, AstraZeneca, Bayer, Arcus Biosciences, Bristol Myers Squibb, Boehringer Ingelheim, Ellipses, EQRx, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Guardant Health, IO Biotech, Janssen, Eli Lilly, Merck Serono, Mirati, Merck Sharp & Dohme, Novocure, Novartis, Pfizer, Pharmamar, Pierre Fabre, Roche, Takeda, Turning Point Therapeutics and Regeneron; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche and Takeda; and travel support from Gilead. D.W.T.L. discloses consulting\/advisory role for Janssen, Takeda, Amgen, Daiichi-Sankyo, Alentis Therapeutics and Merck Sharp & Dohme and research funding from Bristol Myers Squibb and Taiho Pharmaceuticals. M.N. discloses stock or other ownership in mBrace Therapeutics; honoraria from AstraZeneca, Daiichi-Sankyo, Novartis, EMD Serono, Pfizer, Eli Lilly, Genentech, Regeneron, Bristol Myers Squibb\/Mirati, Janssen and AnHeart Therapeutics; consulting\/advisory role for Caris Life Sciences; speaker\u02bcs bureau participation for Janssen, Pfizer, Bristol Myers Squibb\/Mirati, Takeda and Blueprint Medicines; research funding from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Jannsen, Bristol Myers Squibb\/Mirati and AnHeart Therapeutics; and travel support from AnHeart Therapeutics. J.Y.H. discloses honoraria from Merck Sharp & Dohme, AstraZeneca and Eisai and consulting\/advisory role for AstraZeneca and Eisai. C.S.B. discloses consulting\/advisory role for AstraZeneca, Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Genentech and Janssen and research funding from Blueprint Medicines, Daiichi-Sankyo, Nuvalent, Black Diamond, AbbVie, Bristol Myers Squibb, Turning Point Therapeutics, AstraZeneca, Eli Lilly, Pfizer, Jansen, Boehringer Ingelheim and Ellipses. A.H. has no relevant financial relationships to disclose. V.M. discloses employment with START Madrid-FJD; consulting\/advisory role for AbbVie, Roche, Bayer, Bristol Myers Squibb, Janssen, Syneos, Affimed and AstraZeneca; and research funding from Achilles, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Arcus, Ascendis Pharma, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Biomea, BioInvent International AB, Bristol Myers Squibb, Boheringer Ingelheim, Boston Therapeutics, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GlaxoSmithKline, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Eli Lilly, Loxo, Monta Bioscience, MedSir, Menarini, Merck, Merus, Millennium, Merck Sharp & Dohme, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Relay Therapeutics, Revolution Medicines, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics and Upshersmith. N.Y. has no relevant financial relationships to disclose. K.K. discloses employment with, leadership role at, stock or other ownership and other relationship with Bristol Myers Squibb. H.Y. discloses employment with and stock or other ownership in Bristol Myers Squibb. Y.X. discloses employment with and stock or other ownership in Bristol Myers Squibb. C.Y.C. discloses employment with, stock or other ownership in and travel support from Bristol Myers Squibb. Y.Y. discloses employment with and stock or other ownership in Bristol Myers Squibb. A.B.H. discloses employment with, stock or other ownership in, research funding from, patents, royalties or other intellectual property from and travel support from Bristol Myers Squibb. A.D. discloses honoraria from 14ner\/Elevation Oncology, Amgen, AbbVie, AnHeart Therapeutics, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta\/Genentech\/Roche, Janssen, Loxo\/Bayer\/Eli Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare Therapeutics, Springer Healthcare, Takeda\/Ariad\/Millenium, Treeline Biosciences, Turning Point Therapeutics, Tyra Biosciences, Verastem and Zymeworks; advisory boards for Bayer, MonteRosa, AbbVie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo\/Eli Lilly, AnHeart Therapeutics, Bristol Myers Squibb and Nuvalent; consulting for MonteRosa, InnoCare, Boundless Bio, Treeline Biosciences, Nuvalent, 14ner\/Elevation Oncology, Entos, Prelude, Bayer, Applied Pharmaceutical Science, Bristol Myers Squibb, Enlaza, Pfizer, Roche-Genentech, Nuvalent, Two River and Eli Lilly\/Loxo; associated research support (paid to institution) from Foundation Medicine, GlaxoSmithKline, Teva, Taiho and PharmaMar; equity in mBrace and Treeline Biosciences; copyright: selpercatinib-osimertinib (US 18\/041,617, pending); royalties from Wolters Kluwer and UpToDate; other relationship with (food\/beverage) Merck, Puma, Merus and Boehringer Ingelheim; continuing medical education (CME) honoraria from 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. B.J.S. discloses honoraria from Bristol Myers Squibb, Pfizer, Roche, AstraZeneca, Merck, Eli Lilly, Amgen and D3Bio and patents, royalties or other intellectual property from UpToDate.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}