2. Academic Validation
  3. NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations

NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations

  • Cancer Discov. 2022 Dec 13;CD-22-0968. doi: 10.1158/2159-8290.CD-22-0968.
Alexander Drilon 1,  Joshua C Horan 2,  Anupong Tangpeerachaikul 3,  Benjamin Besse 4,  Sai-Hong Ignatius Ou 5,  Shirish M Gadgeel 6,  D Ross Camidge 7,  Anthonie J van der Wekken 8,  Linh Nguyen-Phuong 9,  Adam Acker 10,  Clare Keddy 11,  Katelyn S Nicholson 12,  Satoshi Yoda 13,  Scot Mente 14,  Yuting Sun 15,  John R Soglia 16,  Nancy E Kohl 17,  James R Porter 14,  Matthew D Shair 14,  Viola Zhu 3,  Monika A Davare 12,  Aaron N Hata 13,  Henry E Pelish 2,  Jessica J Lin 9
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 2 Nuvalent, Inc., Cambridge, MA, United States.
  • 3 Nuvalent, Inc., Cambridge, United States.
  • 4 Institut Gustave Roussy, Villejuif, France.
  • 5 University of California, Irvine, Orange, California, United States.
  • 6 Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI, United States.
  • 7 University of Colorado Cancer Center, Aurora, Colorado, United States.
  • 8 University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
  • 9 Massachusetts General Hospital, Boston, Massachusetts, United States.
  • 10 Massachusetts General Hospital, Boston, United States.
  • 11 Oregon Health & Science University, Portland, OR, United States.
  • 12 OHSU, Portland, OR, United States.
  • 13 Massachusetts General Hospital, Charlestown, MA, United States.
  • 14 Nuvalent, Inc., United States.
  • 15 Nuvalent, Cambridge, MA, United States.
  • 16 Nuvalent, United States.
  • 17 Kohl Consulting, Wellesley, MA, United States.
PMID: 36511802 DOI: 10.1158/2159-8290.CD-22-0968
Abstract

ROS1 tyrosine kinase inhibitors (TKIs) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion-positive cancers, although none simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10-to-1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has a ~100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As clinical proof-of-concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion-positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurological toxicities.

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