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
  • 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.

Products