2. Academic Validation
  3. NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations

NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations

  • Cancer Discov. 2024 Sep 13:OF1-OF20. doi: 10.1158/2159-8290.CD-24-0231.
Jessica J Lin 1,  Joshua C Horan 2,  Anupong Tangpeerachaikul 2,  Aurélie Swalduz 3,  Augusto Valdivia 4,  Melissa L Johnson 5,  Benjamin Besse 6,  D Ross Camidge 7,  Toshio Fujino 1,  Satoshi Yoda 1,  Linh Nguyen-Phuong 1,  Hayato Mizuta 6,  Ludovic Bigot 6,  Catline Nobre 6,  Jii Bum Lee 8,  Mi Ra Yu 8,  Scot Mente 2,  Yuting Sun 2,  Nancy E Kohl 9,  James R Porter 2,  Matthew D Shair 2,  Viola W Zhu 2,  Enriqueta Felip 4,  Byoung Chul Cho 8,  Luc Friboulet 6,  Aaron N Hata 1,  Henry E Pelish 2,  Alexander Drilon 10
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • 2 Nuvalent, Inc., Cambridge, Massachusetts.
  • 3 Centre Léon Bérard, Lyon, France.
  • 4 Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 5 Sarah Cannon Research Institute, Nashville, Tennessee.
  • 6 Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France.
  • 7 University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
  • 8 Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 9 Kohl Consulting, Wellesley, Massachusetts.
  • 10 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
PMID: 39269178 DOI: 10.1158/2159-8290.CD-24-0231
Abstract

Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung Cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting Trk inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over Trk with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung Cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

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