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Ref Type abstract
PMID
Authors Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair and Joshua C. Horan
Title Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation
Journal Vol Issue Date Pages Journal Short Title
Cancer Res 81 13 Suppl 2021
URL https://cancerres.aacrjournals.org/content/81/13_Supplement/1468
Abstract Text ALK is a proto-oncogene that encodes the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. In advanced non-small cell lung cancer (NSCLC), ALK rearrangements are detected in about 4% of patients; at the time of diagnosis, 30% to 40% of these patients present with accompanying central nervous system (CNS) metastases. Brain-penetrant tyrosine kinase inhibitors (TKIs) alectinib, brigatinib, ceritinib, and lorlatinib are FDA-approved treatments for ALK-positive NSCLC; however, durability of response to these treatments has been limited in many cases by the emergence of mutations in ALK that confer resistance. A major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. Although patients with tumors harboring the ALK G1202R mutation have responded to lorlatinib, many have subsequently relapsed by emergence of ALK compound mutations, such as G1202R/L1196M and G1202R/G1269A. Novel ALK inhibitor NUV-655 (NVL-655) was designed for broader coverage of ALK resistance mutations, activity in the CNS, and selectivity over structurally related tropomyosin receptor kinase B (TRKB). Avoiding TRKB inhibition is preferred, as CNS adverse events associated with TRKB inhibition have been reported for brain-penetrant TKIs. In recombinant enzyme assays, NUV-655 (NVL-655) inhibited the kinase activity of ALK and ALK G1202R/L1196M with Kiapp < 5 nM in the presence of 1 mM ATP and with selectivity over TRKB. Across a panel of 335 wild-type kinases, NUV-655 (NVL-655) inhibited only 5 other kinases by >50% within 10-fold of its IC50 for ALK. NUV-655 (NVL-655) also selectively inhibited ALK in cells. It inhibited the growth of Ba/F3 cells driven by expression of EML4-ALK variant 1 (v1) with either wild-type kinase domain or drug-resistance mutations G1202R, G1202R/L1196M, or G1202R/G1269A at IC50 values < 10 nM and with selectivity over TRKB. In vivo, NUV-655 (NVL-655) induced regression at well-tolerated doses in a Ba/F3 EML4-ALKv1 G1202R/L1196M xenograft model. Furthermore, NUV-655 (NVL-655) demonstrated brain penetrance in rodent pharmacokinetic studies. In conclusion, NUV-655 (NVL-655) offers a preclinical profile that addresses a medical need for ALK-positive NSCLC patients; it is a brain-penetrant and TRKB-sparing small-molecule inhibitor of ALK with activity against the solvent front drug-resistance mutations G1202R, G1202R/L1196M, and G1202R/G1269A.

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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
NUV-655 NUV-655 9 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
NUV-655 NVL-655|NUV655|NVL655 ALK Inhibitor 31 NUV-655 is a brain-penetrant inhibitor of ALK, with activity against ALK fusions and mutations, which may result in decreased cell growth and tumor regression (Cancer Res 2021;81(13_Suppl):Abstract nr 1468).
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
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor sensitive NUV-655 Preclinical - Cell line xenograft Actionable In a preclinical study, NUV-655 treatment resulted in decreased growth in cells expressing both EML4-ALK and ALK G1202R and L1196M in culture and resulted in tumor regression in cell-line xenograft models (Cancer Res 2021;81(13_Suppl):Abstract nr 1468). detail...
EML4 - ALK ALK G1202R Advanced Solid Tumor predicted - sensitive NUV-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 treatment resulted in decreased cell growth in a cell line expressing EML4-ALK fusion and ALK G1202R in culture (Cancer Res 2021;81(13_Suppl):Abstract nr 1468). detail...
EML4 - ALK Advanced Solid Tumor predicted - sensitive NUV-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 treatment resulted in decreased cell growth in a cell line expressing EML4-ALK fusion in culture (Cancer Res 2021;81(13_Suppl):Abstract nr 1468). detail...
EML4 - ALK ALK G1202R ALK G1269A Advanced Solid Tumor predicted - sensitive NUV-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 treatment resulted in decreased cell growth in a cell line expressing EML4-ALK fusion and ALK mutations, G1202R and G1269A, in culture (Cancer Res 2021;81(13_Suppl):Abstract nr 1468). detail...