NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations

Alexander Drilon; Joshua C Horan; Anupong Tangpeerachaikul; Benjamin Besse; Sai-Hong Ignatius Ou; Shirish M Gadgeel; D Ross Camidge; Anthonie J van der Wekken; Linh Nguyen-Phuong; Adam Acker; Clare Keddy; Katelyn S Nicholson; Satoshi Yoda; Scot Mente; Yuting Sun; John R Soglia; Nancy E Kohl; James R Porter; Matthew D Shair; Viola Zhu; Monika A Davare; Aaron N Hata; Henry E Pelish; Jessica J Lin

doi:10.1158/2159-8290.CD-22-0968

NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations

Cancer Discov. 2023 Mar 1;13(3):598-615. doi: 10.1158/2159-8290.CD-22-0968.

Authors

Alexander Drilon^#¹, Joshua C Horan^#², Anupong Tangpeerachaikul^#², Benjamin Besse³, Sai-Hong Ignatius Ou⁴, Shirish M Gadgeel⁵, D Ross Camidge⁶, Anthonie J van der Wekken⁷, Linh Nguyen-Phuong⁸, Adam Acker⁸, Clare Keddy^{9

10}, Katelyn S Nicholson^{9

10}, Satoshi Yoda^{8

11}, Scot Mente², Yuting Sun², John R Soglia², Nancy E Kohl^{2

12}, James R Porter², Matthew D Shair², Viola Zhu², Monika A Davare^{9

10}, Aaron N Hata^{8

11}, Henry E Pelish², Jessica J Lin^{8

11}

Affiliations

¹ Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
² Nuvalent, Inc., Cambridge, Massachusetts.
³ Institut Gustave Roussy, Villejuif, France.
⁴ University of California Irvine Medical Center, Orange, California.
⁵ Henry Ford Cancer Institute, Detroit, Michigan.
⁶ University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado.
⁷ University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
⁸ Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
⁹ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.
¹⁰ Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, Oregon.
¹¹ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹² Kohl Consulting, Wellesley, Massachusetts.

^# Contributed equally.

Abstract

The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion-positive patients. This article is highlighted in the In This Issue feature, p. 517.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aminopyridines
Brain
Carcinoma, Non-Small-Cell Lung* / genetics
Humans
Lactams
Lactams, Macrocyclic / pharmacology
Lung Neoplasms* / genetics
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein-Tyrosine Kinases / genetics
Proto-Oncogene Proteins / genetics
Pyrazoles

Substances

Protein-Tyrosine Kinases
Aminopyridines
Lactams, Macrocyclic
Lactams
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrazoles
ROS1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding