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 language | English (US) |
|---|---|
| Pages (from-to) | 325-331 |
| Number of pages | 7 |
| Journal | Annals of Oncology |
| Volume | 30 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2019 |
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Keywords
- Adult
- Larotrectinib
- Ntrk gene fusion
- Phase i
- Trk fusion cancer
ASJC Scopus subject areas
- Hematology
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
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.
KW - Adult
KW - Larotrectinib
KW - Ntrk gene fusion
KW - Phase i
KW - Trk fusion cancer
UR - http://www.scopus.com/inward/record.url?scp=85061967519&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061967519&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdy539
DO - 10.1093/annonc/mdy539
M3 - Article
C2 - 30624546
AN - SCOPUS:85061967519
VL - 30
SP - 325
EP - 331
JO - Annals of Oncology
JF - Annals of Oncology
SN - 0923-7534
IS - 2
ER -