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Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study.
- Source :
-
Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2019 Feb 01; Vol. 30 (2), pp. 325-331. - Publication Year :
- 2019
-
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.<br />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 3â+â3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity.<br />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 100âmg 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.<br />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.<br />Clincaltrials.gov Number: NCT02122913.<br /> (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Dose-Response Relationship, Drug
Female
Follow-Up Studies
Humans
Male
Middle Aged
Neoplasms pathology
Oncogene Proteins, Fusion genetics
Prognosis
Young Adult
Neoplasms drug therapy
Oncogene Proteins, Fusion antagonists & inhibitors
Protein Kinase Inhibitors therapeutic use
Pyrazoles therapeutic use
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1569-8041
- Volume :
- 30
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Annals of oncology : official journal of the European Society for Medical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 30624546
- Full Text :
- https://doi.org/10.1093/annonc/mdy539