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

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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Publication Details

Journal
Cancer Discovery
Published
2024-09-13
DOI
https://doi.org/10.1158/2159-8290.cd-24-0231
Citations
43
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
Field-Weighted Citation Impact
18.01

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article

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

Joshua C. Horan, Benjamin Besse, Yuting Sun, Luc Friboulet et al.
43 citations
Cancer Discovery
Lung Cancer Treatments and Mutations
18.01
article

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

Joshua C. Horan, Benjamin Besse, Yuting Sun, Luc Friboulet, Toshio Fujino, Nancy E. Kohl, Anupong Tangpeerachaikul, Aurélie Swalduz, Jii Bum Lee, Linh Nguyen-Phuong, Satoshi Yoda, Melissa L. Johnson, Hayato Mizuta, Matthew D. Shair, Alexander Edward Dela Cruz Drilon, Byoung Chul Cho, Augusto Valdivia, Mi Ra Yu, Catline Nobre, Ludovic Bigot, Scot Mente, Henry E. Pelish, D. Ross Camidge, Viola W. Zhu, W. Marston Linehan, Aaron N. Hata, Enriqueta Felip, James R. Porter
article en
43 citations

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.

Cancer DiscoveryVol. 14(12)
Hebron University (PS), Memorial Sloan Kettering Cancer Center (US), Wellesley College (US), Yonsei University (KR), Cornell University (US), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Kettering University (US), Massachusetts General Hospital (US), Sarah Cannon (US), Centre Léon Bérard (FR), Vall d'Hebron Hospital Universitari (ES), Covalent Associates (United States) (US), Nancy Lurie Marks Family Foundation (US), University of Colorado Anschutz Medical Campus (US)
National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 0%
Lung Cancer Treatments and Mutations
18.01
DOIOpen Access PDFOpenAlex
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