Abstract 78TiP
Background
Oncogenic ROS1 gene rearrangements are implicated in the pathogenesis of various adult and pediatric cancers, including up to 3% of non-small cell lung cancers (NSCLC), where up to 40% of patients present with central nervous system (CNS) metastases. Tyrosine kinase inhibitors (TKIs) approved by the FDA and EMA for ROS1-positive NSCLC (crizotinib and entrectinib) are limited by acquired resistance, frequently mediated by secondary ROS1 kinase domain mutations. In addition, dual TRK/ROS1 kinase inhibitors, including entrectinib, are associated with neurologic adverse events. NVL-520 is a novel, brain-penetrant ROS1-selective kinase inhibitor that exhibits preclinical activity against a diverse array of ROS1 rearrangements and mutations, including G2032R, while sparing inhibition of TRKB. The ARROS-1 study evaluates the safety and activity of NVL-520 in patients with solid tumors harboring ROS1 fusions, including those with resistance mutations and CNS metastases.
Trial design
ARROS-1 (NCT05118789) consists of a phase 1 dose escalation followed by phase 2 expansion in cohorts defined by tumor type and prior therapies that are designed to support potential registration. Phase 1 includes adult patients with any solid tumor type harboring a ROS1 gene fusion (by local testing), with evaluable disease, who have received ≥ 1 ROS1 TKI. Prior platinum-based chemotherapies and/or immunotherapies, as well as stable CNS disease, are allowed. Patients will receive NVL-520 by daily oral administration. Primary phase 1 objectives are to determine the NVL-520 recommended phase 2 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-520. Longitudinal analysis of circulating tumor DNA will be performed, including ROS1 mutation profiling and other relevant biomarkers. The phase 1 portion of the study is ongoing.
Clinical trial identification
NCT05118789 (November 12, 2021).
Legal entity responsible for the study
Nuvalent, Inc.
Funding
Nuvalent, Inc.
Disclosure
B. Besse: Financial Interests, Institutional, Research Grant: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer; Financial Interests, Institutional, Research Grant: Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. M. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo; Financial Interests, Institutional, Other, consulting: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera, CytomX, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, GlaxoSmithKlein; Financial Interests, Institutional, Research Grant: Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKlein, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial-Sloan Kettering, Merck, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics; Financial Interests, Institutional, Research Grant: Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicine, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals; Financial Interests, Institutional, Research Grant: Shattuck Labs, Silicon Therapeutics, StemCentRx, Takeda, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL and Y-mAbs Therapeutics; Financial Interests, Institutional, Other, consulting: Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Oncorus, Regeneron, Ribon Therapeutics, Sanofi-Aventis and Turning Point Therapeutics. S.I. Ou: Financial Interests, Personal, Advisory Board: Pfizer, Daiichi Sankyo, Lilly, BeiGene, JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology. S. Gadgeel: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, On a phase III IDMC: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Blueprint; Financial Interests, Personal, Advisory Board: Daichii; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merk; Financial Interests, Personal, Research Grant: Merk. A. Spira: Financial Interests, Institutional, Leadership Role: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merk, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer; Financial Interests, Personal, Advisory Role: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development; Financial Interests, Institutional, Advisory Role: Array BioPharma, AstraZeneca/MedImmune, Merk, Bristol Myers Squibb; Financial Interests, Personal, Funding, Research funding: LAM Therapeutics; Financial Interests, Institutional, Funding, Research funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo; Financial Interests, Institutional, Funding, Research funding: Arch Therapeutics, Gritstone, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine. J. Lin: Financial Interests, Personal, Advisory Role, consultant: Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Turning Point Therapeutics, Mirati Therapeutics, Bayer, Novartis, and Elevation Oncology; Financial Interests, Personal, Other, honorarium and travel support : Pfizer; Financial Interests, Institutional, Funding, research funding: Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Pfizer, Nuvalent, Linnaeus Therapeutics, and Novartis; Financial Interests, Personal, Funding, CME funding : OncLive, MedStar Health, and Northwell Health. E. Felip: Financial Interests, Personal, Advisory Board: Amgen; AstraZeneca; Bayer; Beigene; Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Glaxo Smith Kline, Janssen, Medical Trends, MSD, Merck Serono, Peptomyc, Pfizer, Puma Biotechnology, Regeneron, Sanofi; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, MSD, Merck Serono, PeerVoice, Pfizer, Springer, Touch Medical; Financial Interests, Personal, Research Grant: Grant for Oncology Innovation; Merck Healthcare KGaA; Other, Personal, Other, Independent member of the board: GRÍFOLS; Financial Interests, Personal, Advisory Board: Takeda. A.J. van der Wekken: Financial Interests, Institutional, Advisory Board, Outside the submitted work: Astra Zeneca; Financial Interests, Institutional, Research Grant, Outside the submitted work: Astra Zeneca; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Boehringer-Ingelheim; Financial Interests, Institutional, Research Grant, Outside the submitted work: Boehringer-Ingelheim; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Janssen; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Lilly; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Merck; Financial Interests, Institutional, Invited Speaker, Outside the submitted work: Novartis; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Roche; Financial Interests, Institutional, Research Grant, Outside the submitted work: Roche; Financial Interests, Institutional, Invited Speaker, Outside the submitted work: Pfizer; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Pfizer; Financial Interests, Institutional, Research Grant, Outside the submitted work: Pfizer; Financial Interests, Institutional, Invited Speaker, Outside the submitted work: Takeda; Financial Interests, Institutional, Advisory Board, Outside the submitted work: Takeda; Financial Interests, Institutional, Research Grant, Outside the submitted work: Takeda. A. Calles: Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Takeda, MSD, and Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Takeda, MSD, and Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Merck Sharp & Dome, PharmaMar; Financial Interests, Personal, Other, Travel expenses: Roche, Boehringer-Ingelheim, MSD, and Bristol Myers Squibb. M.J. de Miguel: Financial Interests, Personal and Institutional, Other, PI of phase I clinical trials : MSD, Biontech, Roche, Sanofi, PharmaMar, AbbVie, Achilles, Array, Astra Zeneca, Basilea, Bayer, Genmab, Regeneron, Janssen, Faron, Genentech, Macrogenics, Menarini, Nektar, Novartis. D.R. Camidge: Financial Interests, Personal, Advisory Role: Nuvalent; Financial Interests, Personal, Advisory Board: Turning Point. Y. Elamin: Financial Interests, Personal and Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Sponsor/Funding: Takeda; Financial Interests, Personal and Institutional, Advisory Role: Takeda; Financial Interests, Personal and Institutional, Sponsor/Funding: Turning Point Therapeutics; Financial Interests, Personal and Institutional, Advisory Role: Turning Point Therapeutics. G.D.L. Lopes: Financial Interests, Personal, Stocks/Shares: Lucence Diagnostics, Xilis; Financial Interests, Personal, Other, Honoraria: Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck; Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca; Financial Interests, Personal, Funding, Research Funding: AstraZeneca, Lucence, Xilis, E.R. Squibb Sons, LLC; Financial Interests, Institutional, Funding, Research Funding: MSD, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, adaptimmune, Bristol Myers Squibb, GSK, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen, Seattle Genetics, Celgene, ibsen, Pharmacyclics, Merck, AstraZeneca, Seagen. S. Liu: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Beigene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda; Financial Interests, Personal and Institutional, Principal Investigator: Alkermes, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Nuvalent, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics; Financial Interests, Personal, Advisory Board: Turning Point Therapeutics. J. Bauman: Financial Interests, Personal, Advisory Board: Kura, Janssen, BlueprintMedicines, Merck, Beigene, Turning Point, Mirati; Financial Interests, Personal, Advisory Role, consulting: Lilly. D. Haggstrom: Other, Personal, Advisory Board, Relationship ended 2021: Astrazeneca. G. Riley: Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc.; Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc. H.E. Pelish: Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc. V.W. Zhu: Financial Interests, Personal, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Personal, Stocks/Shares: Nuvalent, Inc. A. Drilon: Financial Interests, Personal, Advisory Board: Takeda/Ariad/Millenium, Exelixis, Monopteros, Ignyta/Genentech/Roche, AstraZeneca, EMD Serono, Melendi, 14ner/Elevation Oncology, Novartis, Pfizer, Loxo/Bayer/Lilly, Repare RX, Loxo, Janssen, Amgen; Financial Interests, Personal, Invited Speaker: Helsinn, Beigene, Remedica Ltd., TP Therapeutics, Verastem, Ignyta/Genentech/Roche Ad Board, AstraZeneca, Liberum, Loxo/Bayer/Lilly, Lungevity, Lung Cancer Considered podcasts- RET, NIH, PER, OncLive, Clinical Care Options, Lung Cancer Canada, AIOT; Financial Interests, Personal, Speaker’s Bureau: Helsinn, Beigene, Remedica Ltd., TP Therapeutics, Verastem, Ignyta/Genentech/Roche Ad Board, AstraZeneca, Liberum, Loxo/Bayer/Lilly, Lungevity, Lung Cancer Considered podcasts- RET, NIH, PER, OncLive, Clinical Care Options, Lung Cancer Canada, AIOT; Financial Interests, Personal, Other, consultant: ArcherDX, AbbVie, BergenBio, Hengrui Therapeutics, Blueprint Medicines, Ignyta/Genentech/Roche, AstraZeneca, MORE Health, Tyra Biosciences, Loxo/Bayer/Lilly, Pfizer, Nuvalent, Merus, AXIS, Medscape, Liberum, Med Learning, PeerView, EPG Health; Financial Interests, Institutional, Other, steering committee: Lilly, Bayer/Medscape, Pfizer; Financial Interests, Institutional, Other, Associated research paid to institution: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Financial Interests, Institutional, Other, research: Foundation Medicine; Other, Personal, Other, royalties: Wolters Kluwer; Other, Personal, Other, Food and Beverage: Merck, Puma, Merus, Boehringer Ingelheim; Financial Interests, Personal, Other, consultant: JNCCN/ Harborside, Ology,Clinical Care Options, Medscape, TouchIME, Entos, Treeline, Prelude, Applied Pharmaceutical Science, Inc.; Financial Interests, Personal, Invited Speaker: Chugai Pharm, Sirio Libanes Hospital, Answers in CME, Bayer- ECP Faculty RTP, RV More, Personalized Therapies in Thoracic Oncology Conference, OncLive; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharm, Sirio Libanes Hospital, Answers in CME, Bayer- ECP Faculty RTP, RV More, Personalized Therapies in Thoracic Oncology Conference, OncLive.