Nuvalent Presents New Preclinical Data Supporting Profiles of HER2-Selective Inhibitor, NVL-330, and ROS1-Selective Inhibitor, Zidesamtinib, at AACR Annual Meeting 2024
Preclinical data continue to support NVL-330's broad activity against HER2 oncogenic alterations, selectivity over wild-type EGFR, and differentiated brain-penetrant profile
Zidesamtinib shown to be effective at suppressing on-target ROS1 resistance mutations in preclinical mutagenesis screens
"Today's presentations continue to reinforce the differentiated profiles of our drug candidates," said
In 2024, the company expects to initiate a Phase 1 trial for its HER2 program and to share updated data from the ARROS-1 trial at a medical meeting.
AACR Presentation Overviews:
Title: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations
Authors: Yuting Sun*1,
Abstract Number: 1979
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 2
Session Date and Time: Monday April 8, 2024, from 9:00 –
Location: Poster Section 25
Presentation summary:
- NVL-330 had broad preclinical activity on HER2 oncogenic alterations, including HER2 exon20ins, HER2 activating point mutations, and amplified wild-type HER2.
- In a preclinical comparison with the selective tyrosine kinase inhibitor, zongertinib, NVL-330 demonstrated:
- Similar potency and selectivity over wild-type EGFR; and,
- Higher CNS penetrance.
- In a preclinical comparison with antibody drug conjugate, T-DXd (Enhertu), NVL-330 demonstrated:
- Deeper response and higher CNS penetrance in an intracranial tumor model; and,
- Activity in cells with acquired resistance to T-DXd.
Title: Mutagenesis screens support potential best-in-class profile for selective, brain-penetrant, and TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520)
Authors: Anupong Tangpeerachaikul*1,
Abstract Number: LB182
Session Title:
Session Date and Time: Monday April 8, 2024, from 1:30 –
Location: Poster Section 52
Presentation summary:
- Comparison of the clinical concentration of zidesamtinib to its efficacious in vitro concentration suggests a potential for a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in humans, including in the CNS.
- Zidesamtinib effectively suppressed on-target resistance in ENU mutagenesis screens with both ROS1 and ROS1 G2032R fusions, predicting that on-target resistance is unlikely when used as either a first-line or a later-line therapy.
- On-target resistance is predicted to be more likely for earlier-generation ROS1 inhibitors crizotinib, entrectinib, and potentially repotrectinib as a first-line therapy.
- These mutagenesis screens provide additional preclinical support for zidesamtinib's potential to drive deep and durable responses for patients with ROS1-driven cancers.
*Presenter, corresponding author; 1
About NVL-330
NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2-mutant tumors, including those with HER2 exon 20 insertion mutations, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases.
About zidesamtinib (NVL-520)
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC. Zidesamtinib is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors.
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Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding
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