Upcoming poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025, to be held April 25-30, 2025, in Chicago, Illinois, include novel data characterizing the preclinical profiles of Nuvalent’s novel ALK-selective inhibitor, neladalkib (NVL-655), and novel ROS1-selective inhibitor, zidesamtinib (NVL-520).
ALK-selective inhibitor
Neladalkib is a novel brain-penetrant anaplastic lymphoma kinase (ALK-) selective inhibitor created to overcome limitations observed with currently available ALK inhibitors. The investigational agent remains active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R.[1]
In addition, neladalkib 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.
These characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy.
In early 2025 the U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation (BTD) to neladalkib for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with two or more ALK tyrosine kinase inhibitors (TKIs).[1]
The breakthrough therapy designation was based on the preliminary safety and activity of neladalkib in heavily pretreated patients with advanced ALK-positive NSCLC in the Phase 1 portion of the Phase 1/2 ALKOVE-1 clinical trial.
ROS1-selective inhibitor
In about 1% – 2% of cases ROS1 gene rearrangements exist non-small cell lung cancer (NSCLC). This molecular rearrangement typically occurs in younger, never, or light smokers with adenocarcinoma.
At the time of diagnosis, up to 40% of these patients present with accompanying brain metastases, and approximately 40% of patients develop resistance mutations following current front-line treatment.
Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients.
Treatment with first-generation inhibitors, including crizotinib (Xalkori®; Pfizer) and entrectinib (Rozlytrek®; Genentech/Roche), have demonstrated impressive efficacy, with objective response rates (ORR) exceeding 60%-70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood-brain barrier penetration have limited the long-term efficacy of early-generation agents.[2]
To date, there remains no clear standard of care for patients who have been previously treated with two or more ROS1 TKIs.
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created to overcome the observed limitations with currently available ROS1 inhibitors. The investigational drug 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.
Zidesamtinib is also 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.
In February 2024 zidesamtinib received breakthrough therapy designation (BTD) from the FDA 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.
Details of the poster presentations are as follows:
Title: Mutagenesis screens support potential best-in-class profile for neladalkib (NVL-655), a brain-penetrant and TRK-sparing ALK inhibitor
Authors: Anupong (Mee)Tangpeerachaikul, Henry E. Pelish
Abstract Number: 1729
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 1
Session Date and Time: April 28, 2025, from 9:00 a.m.– 12:00 p.m. CT
Location: Poster Section 21
Poster Board Number: 4
Title: Crystal structure of drug-resistant ROS1 G2032R in complex with zidesamtinib, a clinical-stage ROS1 inhibitor with best-in-class potential
Authors: Joseph M. Magrino, Anupong Tangpeerachaikul, Scot Mente, Henry E. Pelish
Abstract Number: 5616
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 3
Session Date and Time: April 29, 2025, from 2:00 p.m.– 5:00 p.m. CT
Location: Poster Section 20
Poster Board Number: 26
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Clinica trials
Expanded Access Program of Neladalkib (NVL-655) for Patients With Advanced ALK+ NSCLC (NVL-655-EAP) – ClinicalTrials.gov ID NCT06834074
Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC (ALKAZAR) – ClinicalTrials.gov ID NCT06765109
A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1) – ClinicalTrials.gov ID NCT05118789
Expanded Access Program of Zidesamtinib (NVL-520) for Patients with Advanced ROS1+ NSCLC (NVL-520-EAP) – ClinicalTrials.gov ID NCT06797362
Highlights of Prescribing Information
Crizotinib (Xalkori®; Pfizer)[Prescribing Information]
Entrectinib (Rozlytrek®; Genentech/Roche)[Prescribing Information]
Reference
[1] Lin JJ, Horan JC, Tangpeerachaikul A, Swalduz A, Valdivia A, Johnson ML, Besse B, Camidge DR, Fujino T, Yoda S, Nguyen-Phuong L, Mizuta H, Bigot L, Nobre C, Lee JB, Yu MR, Mente S, Sun Y, Kohl NE, Porter JR, Shair MD, Zhu VW, Felip E, Cho BC, Friboulet L, Hata AN, Pelish HE, Drilon A. NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. Cancer Discov. 2024 Dec 2;14(12):2367-2386. doi: 10.1158/2159-8290.CD-24-0231. PMID: 39269178; PMCID: PMC11609626.
[2] Morris TA, Khoo C, Solomon BJ. Targeting ROS1 Rearrangements in Non-small Cell Lung Cancer: Crizotinib and Newer Generation Tyrosine Kinase Inhibitors. Drugs. 2019 Aug;79(12):1277-1286. doi: 10.1007/s40265-019-01164-3. PMID: 31313100.
Featured image courtesy © 2016 – 2025 Fotolia/Adobe – Used with permission
DOI: 10.14229/onco.2025.03.29.001
