Advertisement

TRK inhibitor activity and resistance in TRK fusion-positive cancers in adults

  • Guilherme Harada
    Affiliations
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA

    Oncology Center, Sirio-Libanes Hospital, Rua Dona Adma Jafet, 91, Sao Paulo CEP 01308-050, Brazil
    Search for articles by this author
  • Alexander Drilon
    Correspondence
    Corresponding author.
    Affiliations
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2nd Avenue, New York 10017, USA

    Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York 10065, USA
    Search for articles by this author

      Highlights

      • The approvals of TRK-inhibitors were a landmark in the tissue-agnostic approach.
      • Larotrectinib and entrectinib showed robust clinical activity in adult patients.
      • TRK inhibitors are well-tolerated and have a favorable safety profile.
      • Next-generation TRK inhibitors were developed to overcome resistance mechanisms.

      ABSTRACT

      NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Schram A.M.
        • Berger M.F.
        • Hyman D.M.
        Precision oncology: charting a path forward to broader deployment of genomic profiling.
        PLoS Med. 2017; 14e1002242
        • Tao J.J.
        • Schram A.M.
        • Hyman D.M.
        Basket studies: redefining clinical trials in the era of genome-driven oncology.
        Annu Rev Med. 2018; 69: 319-331
        • Martin-Zanca D.
        • Hughes S.H.
        • Barbacid M.
        A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences.
        Nature. 1986; 319: 743-748
        • Pulciani S.
        • Santos E.
        • Lauver A.V.
        • Long L.K.
        • Aaronson S.A.
        • Barbacid M.
        Oncogenes in solid human tumours.
        Nature. 1982; 300: 539-542
        • Drilon A.
        • Siena S.
        • Ou S.I.
        • Patel M.
        • Ahn M.J.
        • Lee J.
        • Bauer T.M.
        • Farago A.F.
        • Wheler J.J.
        • Liu S.V.
        • Doebele R.
        • Giannetta L.
        • Cerea G.
        • Marrapese G.
        • Schirru M.
        • Amatu A.
        • Bencardino K.
        • Palmeri L.
        • Sartore-Bianchi A.
        • Vanzulli A.
        • Cresta S.
        • Damian S.
        • Duca M.
        • Ardini E.
        • Li G.
        • Christiansen J.
        • Kowalski K.
        • Johnson A.D.
        • Patel R.
        • Luo D.
        • Chow-Maneval E.
        • Hornby Z.
        • Multani P.S.
        • Shaw A.T.
        • De Braud F G
        Safety and Antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
        Cancer Discov. 2017; 7: 400-409
        • Ardini E.
        • Menichincheri M.
        • Banfi P.
        • Bosotti R.
        • De Ponti C.
        • Pulci R.
        • Ballinari D.
        • Ciomei M.
        • Texido G.
        • Degrassi A.
        • Avanzi N.
        • Amboldi N.
        • Saccardo M.B.
        • Casero D.
        • Orsini P.
        • Bandiera T.
        • Mologni L.
        • Anderson D.
        • Wei G.
        • Harris J.
        • Vernier J.M.
        • Li G.
        • Felder E.
        • Donati D.
        • Isacchi A.
        • Pesenti E.
        • Magnaghi P.
        • Galvani A.
        Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications.
        Mol Cancer Ther. 2016; 15: 628-639
        • Drilon A.
        • Laetsch T.W.
        • Kummar S.
        • DuBois S.G.
        • Lassen U.N.
        • Demetri G.D.
        • Nathenson M.
        • Doebele R.C.
        • Farago A.F.
        • Pappo A.S.
        • Turpin B.
        • Dowlati A.
        • Brose M.S.
        • Mascarenhas L.
        • Federman N.
        • Berlin J.
        • El-Deiry W.S.
        • Baik C.
        • Deeken J.
        • Boni V.
        • Nagasubramanian R.
        • Taylor M.
        • Rudzinski E.R.
        • Meric-Bernstam F.
        • Sohal D.P.S.
        • Ma P.C.
        • Raez L.E.
        • Hechtman J.F.
        • Benayed R.
        • Ladanyi M.
        • Tuch B.B.
        • Ebata K.
        • Cruickshank S.
        • Ku N.C.
        • Cox M.C.
        • Hawkins D.S.
        • Hong D.S.
        • Hyman D.M.
        Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.
        N Engl J Med. 2018; 378: 731-739
        • Cocco E.
        • Scaltriti M.
        • Drilon A.
        NTRK fusion-positive cancers and TRK inhibitor therapy.
        Nat Rev Clin Oncol. 2018; 15: 731-747
        • Roskoski Jr., R.
        Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes.
        Pharmacol Res. 2016; 103: 26-48
        • Vaishnavi A.
        • Capelletti M.
        • Le A.T.
        • Kako S.
        • Butaney M.
        • Ercan D.
        • Mahale S.
        • Davies K.D.
        • Aisner D.L.
        • Pilling A.B.
        • Berge E.M.
        • Kim J.
        • Sasaki H.
        • Park S.
        • Kryukov G.
        • Garraway L.A.
        • Hammerman P.S.
        • Haas J.
        • Andrews S.W.
        • Lipson D.
        • Stephens P.J.
        • Miller V.A.
        • Varella-Garcia M.
        • Jänne P.A.
        • Doebele R.C.
        Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
        Nat Med. 2013; 19: 1469-1472
        • Federman N.
        • McDermott R.
        Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer.
        Expert Rev Clin Pharmacol. 2019; 12: 931-939
        • Ghilardi J.R.
        • Freeman K.T.
        • Jimenez-Andrade J.M.
        • Mantyh W.G.
        • Bloom A.P.
        • Kuskowski M.A.
        • Mantyh P.W.
        Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain.
        Mol Pain. 2010; 6: 87
        • Doebele R.C.
        • Davis L.E.
        • Vaishnavi A.
        • Le A.T.
        • Estrada-Bernal A.
        • Keysar S.
        • Jimeno A.
        • Varella-Garcia M.
        • Aisner D.L.
        • Li Y.
        • Stephens P.J.
        • Morosini D.
        • Tuch B.B.
        • Fernandes M.
        • Nanda N.
        • Low J.A.
        An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101.
        Cancer Discov. 2015; 5: 1049-1057
        • Hong D.S.
        • Shen L.
        • van Tilburg C.M.
        • Tan D.S.-.W.
        • Kummar S.
        • Lin J.J.
        • Doz F.P.
        • McDermott R.S.
        • Albert C.M.
        • Berlin J.
        • Bielack S.S.
        • Lassen U.N.
        • Tahara M.
        • Norenberg R.
        • Shurshalina A.
        • Fellous M.M.
        • Nogai H.
        • R-h Xu
        • Laetsch T.W.
        • Drilon A.E
        Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer.
        J Clin Oncol. 2021; 39: 3108
        • Drilon A.E.
        • Farago A.F.
        • Tan D.S.-.W.
        • Kummar S.
        • McDermott R.S.
        • Berlin J.
        • Patel J.D.
        • Brose M.S.
        • Leyvraz S.
        • Tahara M.
        • Solomon B.M.
        • Reeves J.A.
        • Fellous M.M.
        • Brega N.
        • Childs B.H.
        • Lassen U.N.
        • Hong D.S.
        Activity and safety of larotrectinib in adult patients with TRK fusion cancer: an expanded data set.
        J Clin Oncol. 2020; 38: 3610
        • Menichincheri M.
        • Ardini E.
        • Magnaghi P.
        • Avanzi N.
        • Banfi P.
        • Bossi R.
        • Buffa L.
        • Canevari G.
        • Ceriani L.
        • Colombo M.
        • Corti L.
        • Donati D.
        • Fasolini M.
        • Felder E.
        • Fiorelli C.
        • Fiorentini F.
        • Galvani A.
        • Isacchi A.
        • Borgia A.L.
        • Marchionni C.
        • Nesi M.
        • Orrenius C.
        • Panzeri A.
        • Pesenti E.
        • Rusconi L.
        • Saccardo M.B.
        • Vanotti E.
        • Perrone E.
        • Orsini P.
        Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (Pan-TRKs) inhibitor.
        J Med Chem. 2016; 59: 3392-3408
        • Fischer H.
        • Ullah M.
        • de la Cruz C.C.
        • Hunsaker T.
        • Senn C.
        • Wirz T.
        • Wagner B.
        • Draganov D.
        • Vazvaei F.
        • Donzelli M.
        • Paehler A.
        • Merchant M.
        • Yu L.
        Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein.
        Neuro-oncology. 2020; 22: 819-829
        • Doebele R.C.
        • Drilon A.
        • Paz-Ares L.
        • Siena S.
        • Shaw A.T.
        • Farago A.F.
        • Blakely C.M.
        • Seto T.
        • Cho B.C.
        • Tosi D.
        • Besse B.
        • Chawla S.P.
        • Bazhenova L.
        • Krauss J.C.
        • Chae Y.K.
        • Barve M.
        • Garrido-Laguna I.
        • Liu S.V.
        • Conkling P.
        • John T.
        • Fakih M.
        • Sigal D.
        • Loong H.H.
        • Buchschacher Jr., G.L.
        • Garrido P.
        • Nieva J.
        • Steuer C.
        • Overbeck T.R.
        • Bowles D.W.
        • Fox E.
        • Riehl T.
        • Chow-Maneval E.
        • Simmons B.
        • Cui N.
        • Johnson A.
        • Eng S.
        • Wilson T.R.
        • Demetri G.D
        Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.
        Lancet Oncol. 2020; 21: 271-282
        • Rolfo C.D.
        • De Braud F.G.
        • Doebele R.C.
        • Drilon A.E.
        • Siena S.
        • Patel M.
        • Cho B.C.
        • Liu S.V.
        • Ahn M.-.J.
        • Chiu C.-.H.
        • Farago A.F.
        • Goto K.
        • Lee J.
        • Bazhenova L.
        • John T.
        • Fakih M.
        • Simmons B.P.
        • Pitcher B.
        • Huang X.
        • Demetri G.D.
        Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: an updated integrated analysis.
        J Clin Oncol. 2020; 38: 3605
        • John T.
        • Chiu C.H.
        • Cho B.C.
        • Fakih M.
        • Farago A.F.
        • Demetri G.D.
        • Goto K.
        • Doebele R.C.
        • Siena S.
        • Drilon A.
        • Patel M.R.
        • Liu S.V.
        • Ahn M.J.
        • Bazhenova L.
        • Overbeck T.R.
        • Nieva J.
        • Kim S.W.
        • Veronese L.
        • Day B.M.
        • De Braud F.
        364O intracranial efficacy of entrectinib in patients with NTRK fusion-positive solid tumours and baseline CNS metastases.
        Ann Oncol. 2020; 31: S397-S3S8
        • Drilon A.
        TRK inhibitors in TRK fusion-positive cancers.
        Ann Oncol. 2019; 30: viii23-viii30
        • Awad M.M.
        • Katayama R.
        • McTigue M.
        • Liu W.
        • Deng Y.L.
        • Brooun A.
        • Friboulet L.
        • Huang D.
        • Falk M.D.
        • Timofeevski S.
        • Wilner K.D.
        • Lockerman E.L.
        • Khan T.M.
        • Mahmood S.
        • Gainor J.F.
        • Digumarthy S.R.
        • Stone J.R.
        • Mino-Kenudson M.
        • Christensen J.G.
        • Iafrate A.J.
        • Engelman J.A.
        • Shaw A.T.
        Acquired resistance to crizotinib from a mutation in CD74-ROS1.
        N Engl J Med. 2013; 368: 2395-2401
        • Gainor J.F.
        • Dardaei L.
        • Yoda S.
        • Friboulet L.
        • Leshchiner I.
        • Katayama R.
        • Dagogo-Jack I.
        • Gadgeel S.
        • Schultz K.
        • Singh M.
        • Chin E.
        • Parks M.
        • Lee D.
        • DiCecca R.H.
        • Lockerman E.
        • Huynh T.
        • Logan J.
        • Ritterhouse L.L.
        • Le L.P.
        • Muniappan A.
        • Digumarthy S.
        • Channick C.
        • Keyes C.
        • Getz G.
        • Dias-Santagata D.
        • Heist R.S.
        • Lennerz J.
        • Sequist L.V.
        • Benes C.H.
        • Iafrate A.J.
        • Mino-Kenudson M.
        • Engelman J.A.
        • Shaw A.T.
        Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.
        Cancer Discov. 2016; 6: 1118-1133
        • Fuse M.J.
        • Okada K.
        • Oh-Hara T.
        • Ogura H.
        • Fujita N.
        • Katayama R.
        Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers.
        Mol Cancer Ther. 2017; 16: 2130-2143
        • Cocco E.
        • Schram A.M.
        • Kulick A.
        • Misale S.
        • Won H.H.
        • Yaeger R.
        • Razavi P.
        • Ptashkin R.
        • Hechtman J.F.
        • Toska E.
        • Cownie J.
        • Somwar R.
        • Shifman S.
        • Mattar M.
        • Selçuklu S.D.
        • Samoila A.
        • Guzman S.
        • Tuch B.B.
        • Ebata K.
        • de Stanchina E.
        • Nagy R.J.
        • Lanman R.B.
        • Houck-Loomis B.
        • Patel J.A.
        • Berger M.F.
        • Ladanyi M.
        • Hyman D.M.
        • Drilon A.
        • Scaltriti M.
        Resistance to TRK inhibition mediated by convergent MAPK pathway activation.
        Nat Med. 2019; 25: 1422-1427
        • Katayama R.
        • Gong B.
        • Togashi N.
        • Miyamoto M.
        • Kiga M.
        • Iwasaki S.
        • Kamai Y.
        • Tominaga Y.
        • Takeda Y.
        • Kagoshima Y.
        • Shimizu Y.
        • Seto Y.
        • Oh-Hara T.
        • Koike S.
        • Nakao N.
        • Hanzawa H.
        • Watanabe K.
        • Yoda S.
        • Yanagitani N.
        • Hata A.N.
        • Shaw A.T.
        • Nishio M.
        • Fujita N.
        • Isoyama T.
        The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.
        Nat Commun. 2019; 10: 3604
        • Drilon A.
        • Nagasubramanian R.
        • Blake J.F.
        • Ku N.
        • Tuch B.B.
        • Ebata K.
        • Smith S.
        • Lauriault V.
        • Kolakowski G.R.
        • Brandhuber B.J.
        • Larsen P.D.
        • Bouhana K.S.
        • Winski S.L.
        • Hamor R.
        • Wu W.I.
        • Parker A.
        • Morales T.H.
        • Sullivan F.X.
        • DeWolf W.E.
        • Wollenberg L.A.
        • Gordon P.R.
        • Douglas-Lindsay D.N.
        • Scaltriti M.
        • Benayed R.
        • Raj S.
        • Hanusch B.
        • Schram A.M.
        • Jonsson P.
        • Berger M.F.
        • Hechtman J.F.
        • Taylor B.S.
        • Andrews S.
        • Rothenberg S.M.
        • Hyman D.M.
        A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors.
        Cancer Discov. 2017; 7: 963-972
        • Drilon A.
        • Ou S.I.
        • Cho B.C.
        • Kim D.W.
        • Lee J.
        • Lin J.J.
        • Zhu V.W.
        • Ahn M.J.
        • Camidge D.R.
        • Nguyen J.
        • Zhai D.
        • Deng W.
        • Huang Z.
        • Rogers E.
        • Liu J.
        • Whitten J.
        • Lim J.K.
        • Stopatschinskaja S.
        • Hyman D.M.
        • Doebele R.C.
        • Cui J.J.
        • Shaw A.T.
        Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations.
        Cancer Discov. 2018; 8: 1227-1236
        • Drilon A.
        • Zhai D.
        • Rogers E.
        • Deng W.
        • Chen X.
        • Sprengeler P.
        • Reich S.H.
        • Murray B.W.
        1119 - molecular characteristics of repotrectinib that enable potent inhibition of TRK fusion proteins and broad mutant selectivity. AACR.
        Virtual Meeting. 2021; (2021)
        • Wang J.
        • yu x
        • Zhu S.
        • Chen Q.
        • Sun J.
        • Xia Y.
        • Zhang Y.
        • Chan C.-.C.
        • Li J.
        • Chen S.
        Preclinical evaluation of SIM1803-1A, a small molecule Trk/ROS1 dual inhibitor for wild and mutate NTRK/ROS1 fusion solid malignancies.
        J Clin Oncol. 2020; 38 (e): e21663
        • Regina A.
        • Elagoz A.
        • Albert V.
        • Boudreault J.
        • Wang H.
        • Ouellet M.
        • Brunei-Latour N.
        • Bellavance E.
        • White P.
        • Ciblat S.
        • Bishop W.R.
        • Abstract Pal K.
        2198: PBI-200: a novel, brain penetrant, next generation pan-TRK kinase inhibitor.
        Cancer Res. 2019; 79: 2198
        • Hyman D.
        • Kummar S.
        • Farago A.
        • Geoerger B.
        • Mau-Sorensen M.
        • Taylor M.
        • Garralda E.
        • Nagasubramanian R.
        • Natheson M.
        • Song L.
        • Capra M.
        • Jorgensen M.
        • Ho A.
        • Shukla N.
        • Smith S.
        • Huang X.
        • Tuch B.
        • Ku N.
        • Laetsch T.W.
        • Drilon A.
        • Hong D.
        Abstract CT127: phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi).
        Cancer Res. 2019; 79: CT127
        • Papadopoulos K.P.
        • Borazanci E.
        • Shaw A.T.
        • Katayama R.
        • Shimizu Y.
        • Zhu V.W.
        • Sun T.Y.
        • Wakelee H.A.
        • Madison R.
        • Schrock A.B.
        • Senaldi G.
        • Nakao N.
        • Hanzawa H.
        • Tachibana M.
        • Isoyama T.
        • Nakamaru K.
        • Deng C.
        • Li M.
        • Fan F.
        • Zhao Q.
        • Gao Y.
        • Seto T.
        • Jänne P.A.
        • Ou S-HI.U.S
        Phase I first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors.
        Clin Cancer Res. 2020; 26: 4785
        • Cocco E.
        • Lee J.E.
        • Kannan S.
        • Schram A.M.
        • Won H.H.
        • Shifman S.
        • Kulick A.
        • Baldino L.
        • Toska E.
        • Arruabarrena-Aristorena A.
        • Kittane S.
        • Wu F.
        • Cai Y.
        • Arena S.
        • Mussolin B.
        • Kannan R.
        • Vasan N.
        • Gorelick A.N.
        • Berger M.F.
        • Novoplansky O.
        • Jagadeeshan S.
        • Liao Y.
        • Rix U.
        • Misale S.
        • Taylor B.S.
        • Bardelli A.
        • Hechtman J.F.
        • Hyman D.M.
        • Elkabets M.
        • de Stanchina E.
        • Verma C.S.
        • Ventura A.
        • Drilon A.
        • Scaltriti M.
        TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors.
        Cancer Discov. 2021; 11: 126-141
      1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): non-small cell lung cancer. 2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Acessed.

        • Park K.
        • Yu C.J.
        • Kim S.W.
        • Lin M.C.
        • Sriuranpong V.
        • Tsai C.M.
        • Lee J.S.
        • Kang J.H.
        • Chan K.C.
        • Perez-Moreno P.
        • Button P.
        • Ahn M.J.
        • Mok T.
        First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the aspiration study.
        JAMA Oncol. 2016; 2: 305-312
        • Rolfo C.
        • Drilon A.
        • Hong D.
        • McCoach C.
        • Dowlati A.
        • Lin J.J.
        • Russo A.
        • Schram A.M.
        • Liu S.V.
        • Nieva J.J.
        • Nguyen T.
        • Eshaghian S.
        • Morse M.
        • Gettinger S.
        • Mobayed M.
        • Goldberg S.
        • Araujo-Mino E.
        • Vidula N.
        • Bardia A.
        • Subramanian J.
        • Sashital D.
        • Stinchcombe T.
        • Kiedrowski L.
        • Price K.
        • Gandara D.R.
        NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types.
        Br J Cancer. 2021;
        • Yablonovitch A.
        • Gnerre S.
        • Yen J.
        • Shell S.
        • Helman E.
        • Fairclough S.
        • Nagy R.J.
        • Odegaard J.
        • Chudova D.
        • Abstract Talasaz A.
        537: NTRK1 fusion detection from clinical cfDNA NGS using a <em>de novo</em>fusion caller.
        Cancer Res. 2021; 81: 537
        • Hong D.S.
        • DuBois S.G.
        • Kummar S.
        • Farago A.F.
        • Albert C.M.
        • Rohrberg K.S.
        • van Tilburg C.M.
        • Nagasubramanian R.
        • Berlin J.D.
        • Federman N.
        • Mascarenhas L.
        • Geoerger B.
        • Dowlati A.
        • Pappo A.S.
        • Bielack S.
        • Doz F.
        • McDermott R.
        • Patel J.D.
        • Schilder R.J.
        • Tahara M.
        • Pfister S.M.
        • Witt O.
        • Ladanyi M.
        • Rudzinski E.R.
        • Nanda S.
        • Childs B.H.
        • Laetsch T.W.
        • Hyman D.M.
        • Drilon A.
        Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.
        Lancet Oncol. 2020; 21: 531-540
        • Drilon A.
        • Kummar S.
        • Albert C.M.
        • Nagasubramanian R.
        • Hechtman J.F.
        • Reeves J.A.
        • Beckmann G.
        • Rudolph M.
        • Wierzbińska J.A.
        • Dima L.
        • Brega N.
        • Laetsch T.W.
        • Hong D.S.
        Abstract CT020: long-term outcomes of patients with TRK fusion cancer treated with larotrectinib.
        Cancer Res. 2021; 81 (CT): CT020
        • Omote S.
        • Matsuoka N.
        • Arakawa H.
        • Nakanishi T.
        • Tamai I.
        Effect of tyrosine kinase inhibitors on renal handling of creatinine by MATE1.
        Sci Rep. 2018; 8: 9237
        • Smeyne R.J.
        • Klein R.
        • Schnapp A.
        • Long L.K.
        • Bryant S.
        • Lewin A.
        • Lira S.A.
        • Barbacid M.
        Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.
        Nature. 1994; 368: 246-249
        • Lin J.C.
        • Tsao D.
        • Barras P.
        • Bastarrachea R.A.
        • Boyd B.
        • Chou J.
        • Rosete R.
        • Long H.
        • Forgie A.
        • Abdiche Y.
        • Dilley J.
        • Stratton J.
        • Garcia C.
        • Sloane D.L.
        • Comuzzie A.G.
        • Rosenthal A.
        Appetite enhancement and weight gain by peripheral administration of trkB agonists in non-human primates.
        PLoS ONE. 2008; 3: e1900
        • Lyons W.E.
        • Mamounas L.A.
        • Ricaurte G.A.
        • Coppola V.
        • Reid S.W.
        • Bora S.H.
        • Wihler C.
        • Koliatsos V.E.
        • Tessarollo L.
        Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities.
        Proc Natl Acad Sci U S A. 1999; 96: 15239-15244
        • Richardson C.A.
        • Leitch B.
        Phenotype of cerebellar glutamatergic neurons is altered in stargazer mutant mice lacking brain-derived neurotrophic factor mRNA expression.
        J Comp Neurol. 2005; 481: 145-159
        • Klein R.
        • Silos-Santiago I.
        • Smeyne R.J.
        • Lira S.A.
        • Brambilla R.
        • Bryant S.
        • Zhang L.
        • Snider W.D.
        • Barbacid M.
        Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements.
        Nature. 1994; 368: 249-251
        • Klein R.
        • Smeyne R.J.
        • Wurst W.
        • Long L.K.
        • Auerbach B.A.
        • Joyner A.L.
        • Barbacid M.
        Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death.
        Cell. 1993; 75: 113-122
        • Indo Y.
        • Tsuruta M.
        • Hayashida Y.
        • Karim M.A.
        • Ohta K.
        • Kawano T.
        • Mitsubuchi H.
        • Tonoki H.
        • Awaya Y.
        • Matsuda I.
        Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.
        Nat Genet. 1996; 13: 485-488
        • Gray J.
        • Yeo G.
        • Hung C.
        • Keogh J.
        • Clayton P.
        • Banerjee K.
        • McAulay A.
        • O'Rahilly S.
        • Farooqi I.S.
        Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity.
        Int J Obes. 2007; 31: 359-364
        • Yeo G.S.
        • Connie Hung C.C.
        • Rochford J.
        • Keogh J.
        • Gray J.
        • Sivaramakrishnan S.
        • O'Rahilly S.
        • Farooqi I.S
        A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.
        Nat Neurosci. 2004; 7: 1187-1189
        • Liu D.
        • Flory J.
        • Lin A.
        • Offin M.
        • Falcon C.J.
        • Murciano-Goroff Y.R.
        • Rosen E.
        • Guo R.
        • Basu E.
        • Li B.T.
        • Harding J.J.
        • Iyer G.
        • Jhaveri K.
        • Gounder M.M.
        • Shukla N.N.
        • Roberts S.S.
        • Glade-Bender J.
        • Kaplanis L.
        • Schram A.
        • Hyman D.M.
        • Drilon A.
        Characterization of on-target adverse events caused by TRK inhibitor therapy.
        Annals Oncol. 2020; 31: 1207-1215