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Ref Type Abstract
PMID
Authors Anupong Tangpeerachaikul; Ludovic Bigot; Luc Friboulet; Henry E. Pelish
Title Abstract 3337: Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer
URL https://aacrjournals.org/cancerres/article/82/12_Supplement/3337/701418/Abstract-3337-Preclinical-activity-of-NVL-655-in
Abstract Text Abstract The ALK receptor tyrosine kinase can be aberrantly activated by gene fusions, point mutations, or amplification to promote cancer. ALK fusions are detected in approximately 5% of advanced non-small cell lung cancers (NSCLC), 50% of inflammatory myofibroblastic tumors, 50% of adult and 90% of childhood anaplastic large cell lymphomas, and rare cases of cholangiocarcinomas. Over 90 fusion partners of ALK have been identified, each exerting a different influence on the biochemical properties of the fusion protein and its preclinical sensitivity to ALK inhibitors. Besides fusions, ALK point mutations and amplification account for up to 14% and 2% of sporadic neuroblastomas, respectively, with most activating mutations occurring at residues F1174, F1245, or R1275. Some activating mutations, such as those occurring at F1174 and I1171, also confer resistance to FDA-approved ALK inhibitors. Because ALK plays an oncogenic role in diverse cancer types, it is an important therapeutic target for other indications beyond NSCLC. NVL-655 is a novel, brain-penetrant ALK-selective inhibitor that exhibits preclinical activity against ALK alterations, including resistance mutations, while also sparing inhibition of TRKB. TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved ALK inhibitor lorlatinib. We previously reported the preclinical activity of NVL-655 in several NSCLC models bearing ALK-fusions, including human cell lines, a human cell-line derived xenograft, and a patient-derived xenograft. Here we report a broader characterization of NVL-655 in ALK-driven cancer models beyond NSCLC, alongside other ALK inhibitors that are either FDA-approved or in development. In biochemical assays, NVL-655 showed potent inhibition (IC50 < 10 nM) of ALK with mutations at residues 1151, 1174, or 1275, all of which have been identified in neuroblastoma. In cell-based assays, NVL-655 was observed to inhibit proliferation of a human anaplastic large cell lymphoma cell line harboring NPM1-ALK fusion and human neuroblastoma cell lines harboring ALK activating mutations or amplification. In conclusion, the preclinical profile of NVL-655 supports its potential to address a medical need for patients with ALK-driven disease in both NSCLC and other cancers such as anaplastic large cell lymphoma and neuroblastoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK act mut neuroblastoma predicted - sensitive NUV-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 inhibited proliferation of neuroblastoma cell lines harboring activating mutations in ALK in culture (Cancer Res (2022) 82 (12_Supplement): 3337). detail...
ALK amp neuroblastoma predicted - sensitive NUV-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 inhibited proliferation of neuroblastoma cell lines with ALK amplification in culture (Cancer Res (2022) 82 (12_Supplement): 3337). detail...