Abstract 81TiP
Background
Aberrations of the ALK oncogene drive tumor cell proliferation, survival, and metastasis in multiple adult and pediatric cancers. ALK gene fusions are detected in ∼5% of advanced non-small cell lung cancers (NSCLC); among these patients, the incidence of central nervous system (CNS) metastases at diagnosis is ∼40%. Although 5 tyrosine kinase inhibitors (TKIs) are approved by the FDA and EMA for ALK-positive NSCLC, therapeutic limitations remain, such as acquired resistance due to secondary and compound ALK mutations and/or neurologic adverse events attributed to off-target inhibition of TRK. NVL-655 is a novel, brain-penetrant ALK-selective TKI that exhibits preclinical activity against diverse ALK fusions and mutations, including G1202R and G1202R compound mutations, while sparing inhibition of TRK. The ALKOVE-1 study is evaluating the safety and preliminary activity of NVL-655 in patients with solid tumors harboring oncogenic ALK alterations, including those with acquired ALK resistance mutations and CNS metastases.
Trial design
ALKOVE-1 consists of a phase I dose escalation followed by a phase II expansion in cohorts defined by tumor type and prior therapies. Phase I includes adult patients with any solid tumor type harboring an oncogenic ALK gene fusion or activating mutation (by local testing), including ALK fusion-positive NSCLC after ≥ 1 prior 2nd or 3rd generation ALK TKI. Prior platinum-based chemotherapy and/or immunotherapy, CNS disease without progressive neurological symptoms or increasing corticosteroid doses, and evaluable but non-measurable disease are allowed. Patients will receive NVL-655 by daily oral administration. Primary phase I objectives are to determine the NVL-655 recommended phase II dose and, if applicable, maximum tolerated dose. Additional objectives include evaluation of safety/tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-655. Longitudinal analysis of circulating tumor DNA will be performed, including ALK mutation profiling and other relevant biomarkers. The phase I portion of the study is ongoing.
Clinical trial identification
NCT05384626 (May 20, 2022).
Legal entity responsible for the study
Nuvalent, Inc.
Funding
Nuvalent. Inc.
Disclosure
M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Carisma TherapeuticsEQRx, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Exelixis, Fate Therapeutics, Immunitas Therapeutics, Kartos Therapeutics, Merus, Palleon Pharmaceuticals, Syndax Pharmaceuticals, Dracen Pharmaceuticals, Dynavax, Eli Lilly, Elicio Therapeutics, EMD Serono, Erasca, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn, Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, and Y-mAbs Therapeutics; Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Molecular Axiom, Novartis, Pyramid Biosciences, Revolution Medicines, SeaGen, Takeda Pharmaceuticals, VBL Therapeutics, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Eli Lilly, Merck, Mirati Therapeutics, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics. S.I. Ou: Financial Interests, Personal, Ownership Interest: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Personal, Advisory Board: Elevation Oncology; Financial Interests, Personal, Other, corporate-sponsored research: Pfizer, Daiichi Sankyo, Revolution Medicine, Merus, Roche, Mirati, BluePrint Medicines, JNJ/Janssen; Financial Interests, Personal, Other: JNJ/Janssen, BeiGene, Pfizer, Eli Lilly, DAVA Oncology LLP, Caris Life Science. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Merck Serono, Peptomyc, F. Hoffmann-La Roche, Novartis, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono, Sanofi, Takeda, TouchONCOLOGY; Financial Interests, Institutional, Other, Grant for Oncology Innovation: Merck Healthcare KGAa; Financial Interests, Institutional, Other, Fundación Merck Salud: Fundación Merck Salud; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen-Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Personal, Leadership Role, President (2021–2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform). C. Baik: Financial Interests, Institutional, Principal Investigator: Rain Oncology, AbbVie, Nuvalent, Blueprint, TurningPoint, Eli Lilly, AstraZeneca, Janssen, Daiichi Sankyo, Spectrum, Pfizer, Loxo; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Boehringer Ingelheim, Janssen, Regeneron, Silverback, Pfizer, AstraZeneca, Guardant, TurningPoint, Takeda. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai pharmaceutical, EISAI, Inivata, Ipsen, Turning Point Therapeutics. J. Mazieres: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Pfizer, Jiangsu Hengruii, Blueprint, Daiichi Sankyo, Novartis, Amgen; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pierre Fabre, BMS. S. Gadgeel: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Genentech/Roche, Bristol Myers Squibb, Pfizer, Novartis, Blueprint, Daiichi Sankyo, Mirati, Eli Lilly, Merck, Esai, Blueprint, GSK; Financial Interests, Personal, Other, Data Safety Monitoring Board: AstraZeneca. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Eli Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd, RV More; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Personal, Member: ASCO, AACR, IASLC; Other, Personal, Other, Food/Beverage: Merck, PUMA, Merus; Other, Personal, Other, Other: Boehringer Ingelheim. G. Liu: Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Takeda, AstraZeneca, Amgen, EMD Serono, Merck, Jazz Pharmaceuticals, Novartis, Eli Lilly, Roche; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Takeda, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Pfizer, Takeda, AstraZeneca, Amgen, Boehringer Ingelheim; Financial Interests, Personal and Institutional, Funding: Pfizer, Takeda, AstraZeneca, Amgen; Financial Interests, Personal and Institutional, Principal Investigator: Pfizer, Takeda, AstraZeneca; Financial Interests, Personal and Institutional, Speaker's Bureau: EMD Serono. J.E. Reuss: Financial Interests, Institutional, Research Grant: Genentech/Roche, Verastem, Nuvalent, Mesothelioma Applied, Research Foundation, LUNGevity Foundation, MedStar Health Institute; Financial Interests, Personal, Advisory Board: Sanofi/Genzyme, Genentech/Roche, Personalis, Guardant, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck. T. Kehrig: Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc. H.E. Pelish: Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc. V. Zhu: Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Invited Speaker: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent. All other authors have declared no conflicts of interest.