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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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	82	12_Supplement	June 15 2022	3337	Cancer Res

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 amp	neuroblastoma	predicted - sensitive	NVL-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...
ALK act mut	neuroblastoma	predicted - sensitive	NVL-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...