Larotrectinib in adult patients with solid tumours: A multi-centre, open-label, phase i dose-escalation study

D. S. Hong, T. M. Bauer, J. J. Lee, A. Dowlati, M. S. Brose, A. F. Farago, Matthew Taylor, A. T. Shaw, S. Montez, F. Meric-Bernstam, S. Smith, B. B. Tuch, K. Ebata, S. Cruickshank, M. C. Cox, H. A. Burris, R. C. Doebele

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)325-331
    Number of pages7
    JournalAnnals of Oncology
    Volume30
    Issue number2
    DOIs
    StatePublished - Feb 1 2019

    Fingerprint

    Gene Fusion
    Neoplasms
    Maximum Tolerated Dose
    Anemia
    Appointments and Schedules
    Phosphotransferases
    Pharmacokinetics
    Adenosine Triphosphate
    Research Personnel
    Safety
    Mutation
    Pharmaceutical Preparations

    Keywords

    • Adult
    • Larotrectinib
    • Ntrk gene fusion
    • Phase i
    • Trk fusion cancer

    ASJC Scopus subject areas

    • Hematology
    • Oncology

    Cite this

    Hong, D. S., Bauer, T. M., Lee, J. J., Dowlati, A., Brose, M. S., Farago, A. F., ... Doebele, R. C. (2019). Larotrectinib in adult patients with solid tumours: A multi-centre, open-label, phase i dose-escalation study. Annals of Oncology, 30(2), 325-331. https://doi.org/10.1093/annonc/mdy539

    Larotrectinib in adult patients with solid tumours : A multi-centre, open-label, phase i dose-escalation study. / Hong, D. S.; Bauer, T. M.; Lee, J. J.; Dowlati, A.; Brose, M. S.; Farago, A. F.; Taylor, Matthew; Shaw, A. T.; Montez, S.; Meric-Bernstam, F.; Smith, S.; Tuch, B. B.; Ebata, K.; Cruickshank, S.; Cox, M. C.; Burris, H. A.; Doebele, R. C.

    In: Annals of Oncology, Vol. 30, No. 2, 01.02.2019, p. 325-331.

    Research output: Contribution to journalArticle

    Hong, DS, Bauer, TM, Lee, JJ, Dowlati, A, Brose, MS, Farago, AF, Taylor, M, Shaw, AT, Montez, S, Meric-Bernstam, F, Smith, S, Tuch, BB, Ebata, K, Cruickshank, S, Cox, MC, Burris, HA & Doebele, RC 2019, 'Larotrectinib in adult patients with solid tumours: A multi-centre, open-label, phase i dose-escalation study', Annals of Oncology, vol. 30, no. 2, pp. 325-331. https://doi.org/10.1093/annonc/mdy539
    Hong, D. S. ; Bauer, T. M. ; Lee, J. J. ; Dowlati, A. ; Brose, M. S. ; Farago, A. F. ; Taylor, Matthew ; Shaw, A. T. ; Montez, S. ; Meric-Bernstam, F. ; Smith, S. ; Tuch, B. B. ; Ebata, K. ; Cruickshank, S. ; Cox, M. C. ; Burris, H. A. ; Doebele, R. C. / Larotrectinib in adult patients with solid tumours : A multi-centre, open-label, phase i dose-escalation study. In: Annals of Oncology. 2019 ; Vol. 30, No. 2. pp. 325-331.
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    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.",
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    author = "Hong, {D. S.} and Bauer, {T. M.} and Lee, {J. J.} and A. Dowlati and Brose, {M. S.} and Farago, {A. F.} and Matthew 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.}",
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    T1 - Larotrectinib in adult patients with solid tumours

    T2 - A multi-centre, open-label, phase i dose-escalation study

    AU - Hong, D. S.

    AU - Bauer, T. M.

    AU - Lee, J. J.

    AU - Dowlati, A.

    AU - Brose, M. S.

    AU - Farago, A. F.

    AU - Taylor, Matthew

    AU - Shaw, A. T.

    AU - Montez, S.

    AU - Meric-Bernstam, F.

    AU - Smith, S.

    AU - Tuch, B. B.

    AU - Ebata, K.

    AU - Cruickshank, S.

    AU - Cox, M. C.

    AU - Burris, H. A.

    AU - Doebele, R. C.

    PY - 2019/2/1

    Y1 - 2019/2/1

    N2 - 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.

    AB - 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.

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    KW - Larotrectinib

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    KW - Phase i

    KW - Trk fusion cancer

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