Thavaneswaran, Subotheni

Sim, Hao-Wen

Grady, John

Espinoza, David

Huang, Min Li

Lin, Frank

McGrath, Margaret

Desai, Jayesh

Charakidis, Michail

Brown, Michael

Kansara, Maya

Simes, John

Thomas, David

2024-12-25

TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression.Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively.Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.

The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.

The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

SydPath Department of Anatomical Pathology, St Vincent's Hospital, Sydney, NSW 2010, Australia.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

Princess Alexandra Hospital, Brisbane 4102, Australia.

Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3002, Australia.

Royal Darwin Hospital, Darwin, NT 0810, Australia.

Charles Darwin University, Darwin, NT 0810, Australia.

RAH Cancer Clinical Trials Unit, Royal Adelaide Hospital, and Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.

The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW 2010, Australia.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

Oncologist . 2024 Dec 25:oyae339. doi: 10.1093/oncolo/oyae339. Online ahead of print.

1549-490X

https://pubmed.ncbi.nlm.nih.gov/39720993/?otool=iaurydwlib

https://hdl.handle.net/10137/13899

NTRK fusions

NTRK overexpression

TRK inhibitor

larotrectinib

A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling.

Journal Article

Publication