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Cancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Weill Cornell Medical College, New York, New York.
3
Nemours Children's Hospital, Orlando, Florida.
4
Array BioPharma, Boulder, Colorado.
5
Loxo Oncology, Inc., Stamford, Connecticut.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Loxo Oncology, Inc., Stamford, Connecticut. hymand@mskcc.org rothenberg@loxooncology.com.
11
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. hymand@mskcc.org rothenberg@loxooncology.com.

Abstract

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.

PMID:
28578312
PMCID:
PMC5581710
DOI:
10.1158/2159-8290.CD-17-0507
[Indexed for MEDLINE]
Free PMC Article

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