2. Academic Validation
  3. Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents

Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents

  • Br J Cancer. 2024 Jun 20. doi: 10.1038/s41416-024-02760-1.
Paola Roa 1 2,  Valentina Foglizzo 1 2,  Guilherme Harada 3,  Matteo Repetto 3 4,  Amanda Kulick 5,  Elisa de Stanchina 5,  Michelle de Marchena 1 2,  Supipi Auwardt 1 2,  Shaza Sayed Ahmed 1 2,  Nicole Virginia Bremer 1 2,  Soo-Ryum Yang 6,  Yangbo Feng 2 7,  Chao Zhou 8,  Norman Kong 8,  Ruixia Liang 8,  Haipeng Xu 8,  Bin Zhang 8,  Alberto Bardelli 9 10,  Eneda Toska 11 12,  Andrea Ventura 13,  Alexander Drilon # 3 14,  Emiliano Cocco # 15 16
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 2 Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA.
  • 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Department of Oncology and Haemato-Oncology, University of Milan, 20133, Milan, Italy.
  • 5 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 8 InnoCare Pharma Limited, Beijing, China.
  • 9 Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy.
  • 10 IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 11 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
  • 12 Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
  • 13 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 14 Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 15 Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA. exc2752@miami.edu.
  • 16 Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA. exc2752@miami.edu.
  • # Contributed equally.
PMID: 38902532 DOI: 10.1038/s41416-024-02760-1
Abstract

Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation Trk inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these Trk mutant tumors; however, there are no next-generation Trk inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation Trk inhibitors is a high priority.

Methods: In silico modeling and in vitro kinase assays were performed on Trk wild type (WT) and Trk mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive Trk WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations.

Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TrkA, TrkB, and TrkC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) Trk inhibitors against most Trk Inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for Trk kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05).

Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation Trk Inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.

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